The most accurate analytic solutions

We apply the most advanced technologies to diagnose patients within these 5 disorder areas

Oncology

Genes
BRCA1, BRCA2, ERBB2, PIK3CA, TP53

Description
Breast cancer is by far the most common female cancer, representing almost a third (30%) of all cancer cases. Among the list of the ten most common cancers in women, ovarian cancer is the seventh and responsible for approximately 140,000 deaths each year1. It is estimated that roughly 10% of all these cancers are hereditary forms, caused by inherited germline mutations in specific susceptibility genes. The remaining 90% of cases are due to acquired somatic alterations2. The characterization of these alterations has been dramatically improved by the development of high-throughput sequencing approaches. The most common somatic genetic alterations have been identified in PIK3CA and TP53 genes3. Mutations in the PIK3CA gene occur in approximately 16–40% of female breast and ovarian cancers and in about 18% of the affected male4. Alterations of the TP53 gene range from 15% to 71% among different populations5. Moreover, clinically actionable mutations have been identified in breast cancer-specific genes, such as BRCA1, BRCA2, and ERBB2 genes. Molecular signatures have allowed to identify distinct subtypes of breast and ovarian cancers, improving the management of any individual breast cancer patient6.

  1. WHO, IARC GLOBOCAN, Cancer Incidence and Mortality Worldwide in 2008 at http://globocan.iarc.fr/
  2. Lee EY, Muller WJ. Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol. 2010;2:a003236
  3. Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–1113
  4. Campbell IG, Russell SE, Choong DY, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004;64:7678–7681
  5. Børresen-Dale AL. TP53 and breast cancer. Hum Mutat. 2003;21:292–300
  6. Bell DW. Our changing view of the genomic landscape of cancer. J Pathol. 2010;220:231–243

Genes
AKT1, ALK, BRAF, EGFR, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET, ROS1

Description
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers1 and is further divided into three distinct histological groups: adenocarcinoma, squamous cell carcinoma and large cell carcinoma2. Smoking (cigarettes, pipes, or cigars) appears to be the primary cause of this cancer. However, people who have never smoked can also develop NSCLC, due to past lung infections, environmental factors or defined genetic background. At the molecular level, subsets of NSCLC have been defined by the presence of recurrent 'driver' mutations in multiple oncogenes. 'Driver' mutations imply a constitutive activation of aberrant signalling proteins, which directly or indirectly induce uncontrolled cell proliferation, angiogenesis, invasion and metastasis. EGFR, KRAS and ALK are the most frequently mutated genes and rarely found concurrently in the same tumor3. Therefore, the presence of one mutation instead of another can influence the response to targeted therapy. Nowadays, multiple targeted small molecule inhibitors are already available or have been developed for specific mutations and defined subsets of patients. Personalized treatment with EGFR inhibitors (Gefitinib and Erlotinib) has significantly improved the overall survival rate of patients with ‘driver’ mutations in this gene4.

  1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367-80
  2. Travis WD, Brambilla E, Konrad Müller-Hermelink H, et al. eds. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press, 2004:1
  3. Lovly C, Horn L, Pao W. Molecular Profiling of Lung Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/lung-cancer (Updated June 17, 2015)
  4. Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol. 2007 Feb 10. 25(5):587-95

Genes
AKT1, BRAF, KRAS, NRAS, PIK3CA, PTEN, SMAD4, TP53

Description
Colorectal cancer (CRC) is one of the most common cancers in the world, with over 1 million new cases occurring annually. This disease is responsible for approximately 600,000 deaths every year and represents one of the biggest cancer killers in the world1. CRC is caused by the abnormal growth of epithelial cells of the colon or rectum, which form small structures, known as polyps. CRC is traditionally divided into sporadic and familial cases. Approximately, 75-80% of colorectal tumors have a sporadic origin and present multiple molecular alterations, belonging to two major pathways2. The “canonical” pathway, presented in 80-85% of CRCs, involves high chromosomal instability3. It is characterized by a series of genetic changes that involve the activation of proto-oncogenes such as KRAS, and inactivation of tumor-suppressor genes, such as TP53 or SMAD4. The “mutator” pathway, which represents approximately 15-20% of CRCs, is characterized by a significant microsatellite instability, associated to a huge accumulation of mutations (mutation rates in these tumor cells are 100- to 1000-fold more frequent compared to normal cells)4. Globally, the spectrum of somatic mutations may be prognostic or predictive markers for specific therapies. Current treatment options for CRC patients are surgery and chemotherapy, often combined with biological therapies.

  1. WHO, IARC GLOBOCAN, Cancer Incidence and Mortality Worldwide in 2008 at http://globocan.iarc.fr
  2. Moran A, Ortega P, de Juan C, et al. Differential colorectal carcinogenesis: Molecular basis and clinical relevance. World J Gastrointest Oncol. 2010; 2:151-8
  3. Worthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol 2007; 13: 3784-3791
  4. Pawlik TM, Raut CP, Rodriguez-Bigas MA. Colorectal carcinogenesis: MSI-H versus MSI-L. Dis Markers 2004; 20: 199-206 

Genes
BRAF, HRAS, KRAS, NRAS, PI3KCA, PTEN, RET

Description
Thyroid cancer is the most common malignant tumor of the endocrine system and its incidence has continuously increased in the last decades all over the world1. It occurs more frequently in women than in men at an approximate ratio of 3:12. Thyroid cancer starts in the thyroid gland and is characterized by the presence of a lump or nodule without causing necessarily any symptoms. There are several different types of thyroid cancer, which are classified based on the type of cell from which they develop. The most frequent form of thyroid malignancy is the papillary carcinoma, which represents ~80% of all cases. Papillary carcinomas frequently present genetic alterations, leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Those include point mutations within BRAF and RAS genes. Mutations in one of these genes are found in >70% of papillary carcinomas and they rarely occur in the same tumor3. Frequent genetic alterations in the RAS genes have been detected in follicular carcinomas, the second most common type of thyroid malignancy. RET point mutations are crucial for the development of medullary thyroid carcinomas4. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. A number of small molecules have been identified and showed antitumor effects in preclinical and ongoing clinical trials.

  1. Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 2013;2013:965212. doi: 10.1155/2013/965212
  2. National Cancer Institute. SEER stat fact sheets: thyroid cancer. http://seer.cancer.gov/statfacts/html/thyro.html (Accessed January 12, 2015)
  3. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nature reviews. 2006;6:292–306
  4. Yuri E. Nikiforov. Thyroid Carcinoma: Molecular Pathways and Therapeutic Targets. Mod Pathol. 2008 May; 21(Suppl 2): S37–S43

Genes
BRAF, EGFR, ERBB4, KIT, KRAS, PDGFRA, PTEN, TP53

Description
Although rare (0.1-3.0%) gastrointestinal stromal tumors (GISTs) are the most common forms of mesenchymal tumor of the gastrointestinal tract, arising predominantly in the stomach (60%) or small intestine (35%)1. Patients may be asymptomatic or show gastrointestinal bleeding, abdominal swelling, and/or palpable mass2. Familial and sporadic GISTs are frequently associated with oncogenic mutations in one of two genes encoding receptor tyrosine kinases: KIT (80%) or PDGFRA (5-7%)3. These growth factor receptors control respectively cell pathways that up-regulate proliferation, down-regulate apoptosis, and control cell differentiation, adhesion, and motility in normal conditions. Therefore, mutations in KIT and PDGFRA genes lead to constitutive activation of these downstream pathways, inducing uncontrolled cell proliferation and sustained tumorigenesis. Point mutations, deletions or insertions have been identified in different exons or in different regions of a single exon of KIT (exon: 9, 11, 13 and 17) and PGFRA (exon: 12, 14 and 18) genes. Accurate detection of these mutations is then critical for targeted therapy using KIT/PDGFRA tyrosine kinase inhibitors (Imatinib)4.

  1. Reddy P, Boci K, Charbonneau C. The epidemiologic, health-related quality of life, and economic burden of gastrointestinal stromal tumours. J Clin Pharm Ther. 2007;32:557-565
  2. Miettinen M, Lasota J. Gastrointestinal stromal tumors. Review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466-1478
  3. Corless CL & Heinrich MC. Molecular Pathobiology of Gastrointestinal Stromal Sarcomas. Annu. Rev. Pathol.-Mech. 3, 557–586; 10.1146/annurev.pathmechdis.3.121806.151538 (2008)
  4. Demetri GD et al. Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors. New Engl. J. Med. 347, 472–480; 10.1056/NEJMoa020461 (2002)

Genes
BRAF, CTNNB1, GNA11, GNAQ, HRAS, KIT, KRAS, NRAS

Description
Melanoma is a malignancy of the melanocytes, which are melanin-producing cells of neuroectodermal origin that can be found throughout the body, expecially in the skin. Cutaneous melanomas are extremely common in the Western world and cause the majority (75%) of deaths linked to skin cancer with a global incidence of 15–25 per 100,000 individuals1. Exposure to ultraviolet (UV) radiation from sunlight or tanning lamps and beds is considered as the major risk factor for cutaneous melanoma2. The sporadic form, which comprises ~90% of all melanomas, is frequently associated to mutations in the mitogen-activated protein kinase cascade, which represents the most relevant oncogenic and therapeutic pathway for this disease. Recurrent mutations include BRAFV600E (detectable in ~50% of all melanomas), NRASQ61L or NRASQ61R (~15–20% of all the cases)3, KITV559A (~10–20% of mucosal and acral melanomas and <1% of all melanomas cases)4 and GNA11Q209L (present in 85% of uveal melanomas)5. Such mutations lead to constitutive activation of mutant signaling proteins that induce and sustain tumorigenesis. Currently, targeted small molecule inhibitors have been developed for specific molecular profiles. Treatments using BRAFV600E-targeting compounds (Vemurafenib or Dabrafenib), often in combination with MEK inhibitors (Trametinib or Cobimetinib), have significantly improved the prognosis of patients with BRAFV600E mutation in advanced-stage metastatic disease6.

  1. Schadendorf D & Hauschild A. Melanoma in 2013: Melanoma—the run of success continues. Nature Rev. Clin. Oncol. 11, 75–76 (2014)
  2. Lawrence MS et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013)
  3. Jakob JA et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118, 4014–4023 (2012)
  4. Griewank KG et al. Genetic alterations and personalized medicine in melanoma: progress and future prospects. J. Natl. Cancer Inst. 106, djt435 (2014)
  5. Van Raamsdonk CD et al. Mutations in GNA11 in uveal melanoma. N. Engl. J. Med. 363, 2191–2199 (2010)
  6. Flaherty KT et al. Combined BRAF and MEK inhibition in melanoma with BRAFV600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012)

Genes
BRCA2, BRAF, KRAS, MLH, MSH2, p16/CDKN2A, p21/CDKN1A, SMAD4, TP53

Description
Pancreatic cancer is a frequent and lethal disease that represents the eighth leading cause of cancer deaths in men (138,100 deaths annually) and the ninth in women (127,900 deaths annually)1. Cancer of the exocrine part of the pancreas (adenocarcinomas) accounts for the majority of pancreatic malignancies. Even when diagnosed early, this cancer has a poor prognosis, presenting an associated 2-year survival rate of 10%2. The causes of pancreatic cancer remain largely unknown, even though several risk factors are implicated, such as tobacco smoking, obesity, diabetes and certain rare genetic conditions3. Pancreatic cancer results from the successive accumulation of mutations in cancer related genes, such as oncogenes, tumor-supressor and genome-maintenance genes4. Dysfunction of at least two genes, KRAS (>90%) and p16/CDKN2A (80-95%), is considered as a molecular ‘signature’ for pancreatic cancer. Mutations in the oncogene KRAS, usually restricted to codon 12, result in a protein that is constitutively active in signal transduction, inducing alterations in cell proliferation, survival, and migration5. The second pancreatic cancer related alteration is the inactivation of the tumor-supressor p16/CDKN2A gene with the consequent loss of the p16 protein, a regulator of the cell cycle, and a corresponding increase in cell proliferation6. Pancreatic cancer is resistant to both conventional chemotherapy and radiation7. Therefore, the development of drugs targeting the mutated signalling pathways represent a promising approach for the treatment of pancreatic cancer.

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61:69
  2. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer 1995;76:1671–1677
  3. Ryan DP, Hong TS, Bardeesy N (September 2014). Pancreatic adenocarcinoma. N. Engl. J. Med. 371 (11): 1039–49
  4. Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–1806
  5. Smit VT, Boot AJ, Smits AM, et al. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res 1988, 16:7773–7782
  6. Bamford S, Dawson E, Forbes S, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer 2004, 91:355–358
  7. Brand RE, Tempero MA. Pancreatic cancer. Curr Opin Oncol. 1998;10:362–6

Genes
FGFR1, PTEN, TP53

Description
Small cell lung cancer (SCLC) accounts for roughly 15% of all lung cancer cases worldwide and is closely linked to the number of cigarettes smoked each day and the duration of tobacco smoking1. The WHO defines SCLC as a malignant epithelial tumour consisting of small cells with little cytoplasm and expressing neuroendocrine markers2. Similarly to other types of cancer, mutated proteins have been identified and associated to misregulated signalling pathways controlling proliferation, cell cycle, apoptosis and angiogenesis. Nearly every SCLC (80% of the cases) presents bi-allelic inactivation of the tumour suppressor TP533. Alterations (point mutations or small deletions) in the PTEN gene have been identified in 10% of primary tumors and are linked to alteration in cell survival. In rare cases, SCLC exhibits kinase gene mutations, as in the FGFR1 tyrosine kinase gene, providing a possible therapeutic opportunity for individual patients4. At the moment, chemotherapy is the only curative treatment, even though the disease generally relapses and the prognosis is poor, with less than 15% of patients surviving in 3 years after diagnosis5.

  1. Van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet 2011;378:1741-55
  2. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, editors. World Health Organization Classification of tumors. Pathology and genetics of tumors of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. p. 31-4
  3. George J, Lim JS, Jang SJ and 97 others. Comprehensive genomic profiles of small cell lung cancer. Nature, published online ahead of print 13 July 2015
  4. Peifer M, Fernández-Cuesta L, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature Genetics 44:1104-1110 (2012)
  5. Jackman DM & Johnson BE. Small-cell lung cancer. Lancet 366: 1385–1396 (2005)

Genes
CEBPA, DNMT3A, FLT3, IDH1, IDH2, KIT, KRAS, MLL, NPM1, NRAS, RUNX1, WT1

Description
Acute myeloid leukemia (AML) is a type of cancer, in which too many immature granulocytes (a type of white blood cell) are found in the blood and bone marrow. AML is one of the most common types of leukemia among adults (25% of all leukemias cases in the Western world) and shows the lowest survival rates1. General signs and symptoms of the early stages may be similar to those of the flu or other common diseases. This leukemia is characterized by a high degree of heterogeneity in terms of chromosome abnormalities, gene mutations, and changes in expression of multiple genes. All the somatic genetic changes thought to contribute to leukemogenesis are classified into two broadly defined groups2. One group (class I) comprises mutations, which activate signal transduction pathways resulting in increased proliferation and/or survival of leukaemic progenitor cells, such as mutations leading to activation of the receptor tyrosine kinase FLT3 or the RAS signaling pathway. The second group (class II) comprises alterations that affect transcription factors or components of the cell cycle machinery and cause impaired differentiation. Prominent examples are the mutations in CEBPA, MLL, and possibly also NPM1 genes. The diagnosis, prognosis, and treatments of AML are based on genetic, genomic, and molecular characteristics. Several molecules targeting particular AML genetic profiles are currently in preclinical or clinical development3.

  1. Deschler B et al. Acute Myeloid Leukemia: Epidemiology and Etiology. Cancer (2006)
  2. Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet 3:179–98 (2002)
  3. Seegmiller A, Jagasia M, Wheeler S, Vnencak-Jones C. Molecular Profiling of Acute Myeloid Leukemia. My Cancer Genome http://www.mycancergenome.org/content/disease/acute-myeloid-leukemia  (Updated July 15, 2015)

Other names
B-cell chronic lymphocytic leukemia

Genes
ATM, BIRC3, FBXW7, MYD88, NOTCH1, POT1, SF3B1, TP53, XPO1

Description
Chronic lymphocytic leukemia (CLL) represents the most commonly diagnosed adult leukemia in Western countries, accounting for approximately one-third of all cases of leukemia1. It often occurs over the age of 55, more frequently in men than in women2. This type of leukemia is characterized by a progressive accumulation of functionally incompetent lymphocytes (a type of white blood cell) in the bone marrow, blood, spleen and lymph nodes2. In people with CLL, B cell lymphocytes may appear normal in shape, but they are incapable to efficiently protect the body against any pathogenic agents, leading to recurrent infections3. CLL develops slowly with a variable clinical course, which can be explained by its significant genomic heterogeneity4. The most commonly altered genes are involved in the DNA damage response and cell cycle control, the nuclear factor–?B signaling pathway, messenger RNA processing, and NOTCH signaling5. The recent development of NGS technology has allowed to identify a myriad of genetic mutations in CLL, that may influence both prognosis and treatment decisions. Multiple studies have demonstrated the adverse prognostic value of TP53, ATM, SF3B1, NOTCH1, and BIRC3 mutations6. Targeting these genetic lesions with specific inhibitors appear to be particularly promising and many of them are currently under advanced clinical investigation.

  1. Leukemia & Lymphoma Society. Chronic Lymphocytic Leukemia. Available at: http://www.lls.org/#/diseaseinformation/leukemia/chroniclymphocyticleukemia (Accessed December 12, 2014)
  2. Eichhorst B, Hallek M, Dreyling M. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl 2, 50-54
  3. American Cancer Society. Leukemia-Chronic Lymphocytic. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf  (Accessed December 12, 2014)
  4. Sandoval-Sus JD, Stingo FE, Knepper TC, Nodzon L, Padron E, Kharfan-Dabaja MA, Chavez JC and Pinilla-Ibarz J. Mutational Landscape of Chronic Lymphocytic Leukemia Using Next Generation Sequencing Technologies in the Real World Clinical Setting. Blood 2016 128:4366
  5. Strefford JC. The genomic landscape of chronic lymphocytic leukaemia: biological and clinical implications. Br J Haematol. 2015;169(1):14–31
  6. Landau DA et al. Mutations driving CLL and their evolution in progression and relapse. Nature 526, 525–530 (22 October 2015) doi:10.1038/nature15395

Genes
ASXL1, DNMT3A, EZH2, IDH1, IDH2, JAK2, KRAS, NRAS, RUNX1, SRSF2, TET2

Description
Chronic myelomonocytic leukemia (CMML) is a heterogeneous hematologic neoplasm with clinical and pathological signs, similar to a myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS)1. This aggressive malignancy represents the 10% of all the cases of MDS2 and affects mainly adults with a median age of 65–75 years3. CMML is characterized by cytopenia and its associated symptoms (fatigue, dyspnea, susceptibility to infections and rarely bleeding). The prognosis of patients with CMML is generally poor, with an expected median survival of only 20 to 30 months, due to the existence of limited effective therapies2. In recent years, progresses in next generation sequencing technologies have allowed to define the molecular mechanisms behind the pathogenesis of CMML. Several genetic alterations, which affect important cellular processes, have been associated to CMML. Among them, mutations in NRAS, KRAS, TET2, JAK2 and SRSF2 genes are the most frequently reported4. Molecular discoveries, however, have not yet been translated into novel therapies. Therefore, allogeneic stem cell transplantation still remains the only treatment option, which offers a long-term remission and cures some patients.

  1. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. (eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, 2008
  2. Parikh SA, Tefferi A. Chronic myelomonocytic leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012;87(6):610–9
  3. Beran M. Chronic myelomonocytic leukemia. Cancer Treat Res. 2008;142:107–32
  4. Meggendorfer M, Roller A, Haferlach T, Eder C, Dicker F, Grossmann V, et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood. 2012;120(15):3080–8

Other names
Juvenile chronic granulocytic leukemia, chronic myelomonocytic leukemia of infancy and infantile monosomy 7 syndrome

Genes
CBL, KRAS, NF1, NRAS, PTPN11

Description
Juvenile myelomonocytic leukemia (JMML) is a lethal myeloproliferative disease (MPD), affecting child between birth and 6 years of age. JMML represents the 2-3% of all pediatric leukemias with an incidence of 0.6 per million children yearly1. Common symptoms of JMML are pallor, failure to thrive, decreased appetite, irritability, dry cough, tachypnea, skin rashes and diarrhea2. It occurs when too many immature white blood cells, called myelocytes and monocytes, are produced in the bone marrow. Almost 90% of children diagnosed with JMML are discovered to have genetic abnormalities, which are identified in laboratory testing at diagnosis. Recurrent alterations include activating mutations in NRAS, KRAS (35%), and PTPN11 (35%) and disruption of the tumour suppressor gene NF1 (15%)3. This malignancy is rapidly fatal with 80% of patients surviving less than three years4. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment for JMML. However, the identification of gene mutations in the RAS pathway has raised the interest in developing tyrosine kinase inhibitors that can specifically affect particular molecular targets.

  1. Freedman MH, Estrov Z, Chan HSL. Juvenile chronic myelogenous leukemia, American Journal of Pediatric Hematology/Oncology, vol. 10, no. 3, pp. 261–267 (1988)
  2. Chan RJ, Cooper T, Kratz CP, Weiss B, Loh ML. Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium, Leukemia Research, vol. 33, no. 3, pp. 355–362 (2009)
  3. Chang TY, Dvorak CC, Loh ML. Bedside to bench in juvenile myelomonocytic leukemia: Insights into leukemogenesis from a rare pediatric leukemia. Blood 124 (16): 2487–2497 (2014)
  4. Loh ML. Childhood myelodysplastic syndrome: focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia, Hematology. American Society of Hematology. Education Program, vol. 2010, pp. 357–362 (2010)

Genes
ASXL1, CBL, DNMT3A, EZH2, IDH1, IDH2, KRAS, NRAS, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1

Description
Myelodysplastic syndromes (MDS) are a heterogenous group of bone marrow malignancies, primarily affecting older individuals. It develops as a consequence of multiple genetic changes in hematopoietic stem cells, that alter normal hematopoietic growth and differentiation. As a result, patients with MDS present an accumulation of immature myeloid cells in the bone marrow1, that may induce symptomatic anemia, infection, and bleeding, as well as progression to acute myeloid leukemia (AML). Clonal cytogenetic alterations are found in 30-70% of patients with MDS and represent one of the most important prognostic markers of this leuckemia2. The majority of abnormalities are represented by numerical deficiency (aneuploidy) and segmental deletions in chromosome 5 (36% of patients), 7 (21% of patients), 8 (16% of patients), and 20 (7% of patients), inducing haploinsufficiency of critical tumor suppressor protein3.  Pathogenesis and progression of MDS is also associated to point mutations in genes involved in epigenetic regulation and chromatin remodelling (TET2, DNMT3A, ASXL1, IDH1/2, EZH2), splicing (SF3B1, SRSF2, U2AF1), transcription (TP53, RUNX1) and signaling transduction (NRAS, CBL)4. Treatment for myelodysplastic syndromes usually focuses on controlling symptoms and reducing or preventing complications of the disease. The development of therapeutic agents targeting specific genomic alterations might dramatically improve MDS prognosis in the future.

  1. Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med 2009;361(19):1872-1885
  2. Haase D, Germing U, Schanz J, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110(13):4385–4395 (2007)
  3. Hirai, H. Molecular mechanisms of myelodysplastic syndrome. Jpn. J. Clin. Oncol. 2003, 33(4), 153-160
  4. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013;122:3616-3627

Genes
CALR, JAK2, MPL

Description
Myeloproliferative neoplasms (MPN), previously known as myeloproliferative disorders (MPD), are a group of rare diseases of the bone marrow that cause an increase in the number of one or more blood cell types (red cells, white cells or platelets). Globally, these neoplasms present an incidence of 6-10 per 100,000 population annually1. Frequently MPN develop slowly with few or any symptoms in the early stage and get worse gradually, due to the abnormal accumulation of blood cells in the bone marrow and circulating blood. MPN include chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. All these disorders are often the result of a genetic event occurring in hematopoietic stem cells and responsible for the constitutive activation of a tyrosine kinase, which induce an intracellular signaling pathways similar to the one induced by hematopoietic growth factors2. Markers that are relevant for MPN diagnosis and clinical management of patients include mutations in JAK2, MPL and CALR genes. Recently, a JAK2 inhibitor has been approved as treatment for primary myelofibrosis3. Trials with similar inhibitors are in progress to improve the prognosis of other MPN.

  1. Vardiman JW, Brunning RD, Arber DA, et al. Introduction and overview of the classification of the myeloid neoplasms. In Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:18-30
  2. Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood 2011; 118:1723
  3. Tibes R, Bogenberger JM, Benson KL, Mesa RA. Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms. Mol Diagn Ther 16 (5): 269–83. doi:10.1007/s40291-012-0006-3 (October 2012)

Hereditary Cancer

Other names 
HBOC, BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer

Inheritance 

Autosomal dominant

Genes
ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, FAM175A, MRE11A, NBN, PALB2, PIK3CA, RAD50, RAD51C, RAD51D, TP53, XRCC2

Description
Hereditary breast and ovarian cancer (HBOC) is a collective term that describes genetic susceptibility to breast and ovarian cancers, and an increased risk to other cancers such as fallopian tubes, prostate, pancreatic, and melanoma1. 5-10% of all breast and ovarian cancers diagnosed are hereditary. Risk factors for HBOC include a family history with highly penetrant mutations in genes such as BRCA1 and BRCA2, moderately penetrant mutations in other genes (such as ATM, BRIP1, CHEK2 and PALB2 among others), as well as more common genomic variants, including single nucleotide polymorphisms, associated with modest size effects2. Most HBOC cases are associated to mutations in BRCA1 and BRCA2 genes. Women carrying a BRCA1 mutation have 55-85% lifetime risk of developing breast cancer and 20-40% of developing ovarian cancer. Men carriers of a BRCA2 mutation have 6-8% lifetime risk of developing pancreatic, hepatic, prostate and breast cancer1. These genes encode tumor suppressor proteins, involved in repairing damaged DNA and, therefore, playing a role in ensuring the stability of the cell’s genetic material. When one copy of either of these genes is inactivated by a causative germline mutation, DNA is not properly repaired, allowing the accumulation of additional genetic alterations that can lead to cancer development3. Women who have a relative with a harmful BRCA1 or BRCA2 mutation or who appear to be at increased risk of breast and/or ovarian cancer because of their family history should undergo genetic testing to be aware of their potential risks. In addition, early detection of BRCA1 and BRCA2 mutations could allow the development of personalized treatment options to increase the survival rate of patients harboring these mutations. PARP inhibitors represent promising drugs for the treatment of BRCA-related cancers. These drugs block an enzyme, the poly (ADP-ribose) polymerase (PARP), used by cells to repair the DNA, and in turns enhance the activity of chemotherapy and radiation, favoring cancer cell death4.

  1. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. NCBI GeneReviews. (Last Update: December 15, 2016)
  2. Walsh MF, Nathanson KL, Couch FJ, Offit K. Genomic Biomarkers for Breast Cancer Risk. Adv Exp Med Biol. 2016;882:1-32. doi: 10.1007/978-3-319-22909-6_1
  3. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet
  4. Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014; 25:32-40

Other names 
FAP, adenomatous polyposis of the colon, familial multiple polyposis, hereditary polyposis coli, multiple polyposis of the colon

Inheritance
Autosomal dominant

Gene
APC

Description
Familial adenomatous polyposis (FAP) is an inherited colon cancer predisposition syndrome, characterized by the development of hundreds to thousands benign polyps (adenomatous polyps or adenomas) in the colon. These polyps will become malignant, leading to colorectal cancer (CRC) at 39 years on average without a prophylactic colectomy 1. FAP occurs in 1 out of every 8,300 individuals, affecting equally both sexes and accounting for less than 1% of CRC cases2. Most patients are asymptomatic for years until the polyps are large and numerous, causing rectal bleeding or even anemia. A less aggressive variant of FAP, attenuated FAP, is characterized by fewer polyps (usually 10 to 100) and slightly lower cancer risk (70%)2. Classical and attenuated FAP are inherited in an autosomal dominant manner and results from germline mutations in the adenomatous polyposis (APC) gene. These mutations are found in >70% of patients with classical FAP and ~25% of those with an attenuated form3. Mutated APC impairs colon cellular growth and function, leading to the polyp formation1. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is associated to a slightly increased risk of developing CRC (see below MUTYH-associated polyposis). Of the three forms, classical FAP is the most severe and most common. Diagnosis is based on family history, clinical examination, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed2.

  1. https://ghr.nlm.nih.gov/condition/familial-adenomatous-polyposis
  2. Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet Journal of Rare Diseases. 2009;4:22
  3. Balmaña J, Castells A, Cervantes A, on behalf of the ESMO Guidelines Working Group. Familial colorectal cancer risk: ESMO Clinical Practice Guidelines. Ann Oncol (2010) 21 (suppl_5): v78-v81

Other names
MAP, MYH-associated polyposis syndrome, colorectal adenomatous polyposis, multiple colorectal adenoma

Inheritance 
Autosomal recessive

Gene 
MUTYH

Description
MUTYH-associated polyposis (MAP) is a colorectal cancer predisposition syndrome characterized by the growth of multiple polyps (from 5 to more than 100) in the colon1. Affected patients have a nearly 100% risk of developing colorectal cancer by the age of 652. In addition, they present an increased risk to develop upper gastrointestinal tract tumors, including duodenal adenomas as well as cancers of the bladder, skin, and thyroid. MAP is caused by mutations in each of the two copies of the MUTYH gene and inherited in a recessive manner3. MUTYH gene encodes an enzyme involved in DNA repair. When both copies of this gene are altered, DNA repair is impaired, leading to the accumulation of mutations in other genes, which favor cell overgrowth and in turn colon polyp formation4. The two most common MUTYH gene mutations in Western Europeans and North Americans are Y179C and G396D, but additional mutations at different loci have been reported in other populations2. MAP has a prevalence of 1 in 20,000 to 1 in 40,000  and an estimated carrier frequency of 1–2% in the general population5. The diagnosis of individuals with MAP is complex, due to the phenotypic overlap with other polyposis syndromes (i.e., AFAP) and its variable phenotypic expression. Genetic testing is useful to confirm the diagnosis based on clinical signs and is strongly recommended in siblings of an affected individual.

  1. Atlas of Genetics and Cytogenetics in Oncology and Haematology
  2. AMA. MYH-associated polyposis fact sheet
  3. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348:791
  4. https://ghr.nlm.nih.gov/condition/familial-adenomatous-polyposis
  5. Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009;136(4):1251–60

Other names  
Hereditary non-polyposis colorectal cancer, HNPCC

Inheritance 
Autosomal dominant

Genes 
MLH1, MSH2, MSH6, EPCAM, PMS2, PMS2CL

Description
Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), is a dominantly inherited susceptibility to develop many types of cancer, particularly cancers of the colon1. It accounts for approximately 3% of all colon cancer cases2. Besides colorectal cancers, patients with this syndrome have an increased risk of developing tumors in the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women with this disorder also have an increased risk of cancer of the endometrium and ovaries1. HNPCC can be the most challenging hereditary colorectal syndrome to recognize, since it is not associated to a polyposis phenotype. Patients present a small and finite number (<10) of polyps usually in the right colon, that cannot be differentiated endoscopically from sporadic colon polyps. However, these polyps can become cancerous more rapidly (1-3 years)3 when compared to polyps seen in the general population. Several genes have been identified that are linked to Lynch syndrome, such as MLH1, MSH2, MSH6, PMS2, and EPCAM. Approximately 70% of mutations are found in MLH1 and MSH2, whereas the MSH6 and PMS2 genes are less commonly involved, and mutations in MSH6 and PMS2 account for 15% of all known mutations4. All these genes are involved in the DNA repair process, occurring prior to cell division. In cells carrying mutations on both copies of one of these so-called mismatch repair genes, DNA cannot be properly repaired, which strongly increases the probability that such cells accumulate further mutations leading to cancer1. Family history and age at diagnosis are the most important criteria for a genetic testing request. When a person is found to carry a harmful mutation in one of the over-mentioned genes, other family members should undergo genetic testing. Regular surveillance based on well-established prevention guidelines, such as monitoring by colonoscopy, allows to prevent colorectal cancer in almost all patients.

  1. https://ghr.nlm.nih.gov/condition/lynch-syndrome
  2. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:5783–5788
  3. Rijcken FE, Hollema H, Kleibeuker JH. Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation. Gut. 2002;50:382–386
  4. Jang E & Chung DC. Hereditary Colon Cancer: Lynch Syndrome. Gut Liver. 2010 Jun; 4(2): 151–160. doi:  10.5009/gnl.2010.4.2.151

Cardiology

Other names
Autosomal dominant hypercholesterolemia; APOB-related familial hypercholesterolemia, autosomal dominant; hyperlipoproteinemia-type IIA; LDLR-related familial hypercholesterolemia, autosomal dominant; PCSK9-related familial hypercholesterolemia, autosomal dominant

Inheritance
Autosomal dominant or recessive

Genes
APOB, APOE, LDLR, LDLRAP1, PCSK9

Description
Familial hypercholesterolemia (FH) represents the most common form of inherited high cholesterol disease, affecting about 1 in every 500 people1. It is characterized by abnormally high level of total cholesterol and low-density lipoprotein (LDL or "bad cholesterol") in the blood. This causes atherosclerotic plaque deposition in the coronary arteries and proximal aorta, leading to an increased risk for cardiovascular disease2. Fatty skin deposits called xanthomas are also observed over parts of the hands, elbows, knees, ankles, and around the cornea of the eye, as well as in the eyelids (xanthelasmas). In FH patients, genetic mutations impair the mechanism of clearance of LDL and their inheritance may be autosomal dominant or recessive1. Therefore, FH may be classified into an “heterozygous” and an “homozygous” clinical phenotype. The heterozygous form represents the most common inherited cardiovascular disease, with a prevalence of 1 in 200-250 individuals3. It is inherited in an autosomal dominant manner and is mainly due to mutations in one copy of APOB, LDLR, PCSK9 genes. These mutations lead to a reduced number of functional LDL receptors, resulting in defective uptake of plasma LDL and dramatic elevation of LDL-cholesterol levels in the blood. With 50% functional LDL receptors, heterozygous patients have an excellent response to cholesterol-lowering drugs (often more than one) in combination with a lifestyle modification (rigorous dietary intervention, regular physical activities and quit smoking). The homozygous type is a very rare condition, occurring in about 1 in 160,000 to one million people worldwide4. It results from pathogenic variants in both copies of APOB, LDLR, PCSK9 genes, causing a much more severe increase of blood cholesterol level and a high risk of cardiovascular disease already in childhood, with death before the age of 20 if untreated.

  1. Marais AD. Familial Hypercholesterolaemia. Clin Biochem Rev. 2004 Feb; 25(1): 49–68
  2. Ueda M. Familial hypercholesterolemia. Mol Genet Metab. 2005 Dec;86(4):423-6
  3. Youngblom E, Pariani M, Knowles JW. Familial Hypercholesterolemia. GeneReviews® (Last Update: December 8, 2016)
  4. Familial Hypercholesterolemia Foundation

Other names
Bangungut; idiopathic ventricular fibrillation, Brugada type; Pokkuri death syndrome; sudden unexpected nocturnal death syndrome; sudden unexplained death syndrome; SUDS; SUNDS

Inheritance
Autosomal dominant

Genes
CACNA1C, CACNA2D1, CACNB2, GPD1L, HCN4, KCND3, KCNE3, KCNE5, KCNJ8, RANGRF, SCN1B, SCN3B, SCN5A, SLMAP, TRPM4

Description
Brugada syndrome is a rare inherited condition, characterized by a disruption of the heart's normal rhythm. It affects approximately 5 in 10,000 individuals worldwide and occurs much more frequently in young men of South East Asian descent1. Brugada syndrome is caused by an altered flow of sodium ions into the heart cells, that can trigger episodes of abnormal electrical activity. This defect can induce ventricular tachycardia, a condition where the heart beats too quickly to maintain normal blood flow, leading to fainting, or sometimes to cardiac arrest and sudden death. Brugada syndrome is believed to cause 4-12% of all sudden cardiac deaths2, which typically occur around age 40. This condition can also explain some cases of sudden infant death syndrome during sleep, which is a major cause of unexplained death in babies younger than 1 year1. Mutations in SCN5A gene, encoding the cardiac predominant sodium channel, account for 20-30% of patients with Brugada syndrome and mutations in other genes only account for about 5% of patients3. At present, knowledge of a specific mutation does not provide guidance in determining a prognosis. Therefore, genetic testing is most useful for early detection of relatives at potential risk. Currently, there are no drugs available that can efficiently suppress arrhythmias associated with this syndrome, and consequently, for patients at high risk for such events, an implantable cardioverter-defibrillator should be considered4.

  1. https://ghr.nlm.nih.gov/condition/brugada-syndrome
  2. Antzelevitch C, Brugada P, Brugada J, et al. Brugada syndrome: A decade of progress. Circ Res. 2002;91:1114–8
  3. Watanabe H & Minamino T. Genetics of Brugada syndrome. J Hum Genet. 2016 Jan;61(1):57-60. doi: 10.1038/jhg.2015.97. Epub 2015 Jul 30
  4. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: Insights for risk stratification and management. Circulation. 2002;105:1342–7

Other names
CPVT, Bidirectional tachycardia induced by catecholamines, Catecholamine-induced polymorphic ventricular tachycardia, Familial polymorphic ventricular tachycardia, FPVT

Inheritance
Autosomal dominant or recessive

Genes
CASQ2, RYR2

Description

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by an abnormal heart rhythm. The true prevalence of CPVT is unknown with estimates of approximately 1 in 10,000 people1. This condition is frequently caused by mutations in the cardiac ryanodine receptor gene (RYR2) and inherited in an autosomal dominant pattern2. Much less frequently, mutations in the cardiac calsequestrin gene (CASQ2) have been identified in the autosomal recessive form of CPVT3. Mutated proteins participate in the regulation of calcium ion flow in and out of the sarcoplasmatic reticulum of cardiac cells. Therefore, reduced electrical stability of cardiomyocytes may cause the heart to enter a life-threatening state of ventricular arrhythmia as response to the natural release of catecholamines from nerve endings on the heart muscle and from the adrenal glands into the circulation. This rhythm disturbance prevents the heart from pumping blood appropriately. Untreated CPVT carries a poor prognosis, with sudden death in up to one third of affected individuals by the age of 30 years4.

  1. https://ghr.nlm.nih.gov/condition/catecholaminergic-polymorphic-ventricular-tachycardi
  2. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103:196–200
  3. Faggioni M & Knollmann BC. Calsequestrin 2 and arrhythmias. Am J Physiol Heart Circ Physiol. 2012 Mar 15; 302(6): H1250–H1260
  4. Swan H, Piippo K, Viitasalo M, Heikkila P, Paavonen T, Kainulainen K, Kere J, Keto P, Kontula K, Toivonen L. Arrhythmic disorder mapped to chromosome 1q42–q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol. 1999;34:2035–2042

Other names
Jervell and Lange-Nielsen syndrome, Romano-Ward syndrome

Inheritance
Autosomal dominant or recessive

Genes
CACNA1C, KCNE1, KCNE1, KCNH2, KCNJ2, KCNQ1, SCN5A

Description
Long QT syndrome (LQTS) is a life-threatening disorder of the heart's electrical activity, causing sudden, uncontrollable, dangerous arrhythmias in response to emotional or physical stress1. The term "long QT" refers to an abnormal pattern seen on the electrocardiogram (ECG), a test which records the heart's electrical activity. In affected individuals, ECG shows a prolongation of the QT interval, indicating a delayed repolarization of the heart following a heartbeat. This increases the risk of episodes of torsades de pointes (TdP), a form of irregular heartbeat that originates from the ventricles. These episodes may lead to ventricular fibrillation causing sudden death2.  LQTS can be congenital, due to mutations in genes encoding for cardiac ion channels, or acquired in which dysfunction of these ion channels is caused by drugs or metabolic abnormalities. Probably also many of the acquired LQTS cases have a genetic basis, in which common polymorphisms cause alterations in the cardiac ion channels involved in the repolarization. By far, KCNQ1, KCNH2, and SCN5A are the most commonly mutated genes, accounting for 60-75% of inherited cases3. About 5-10% of LQTS patients host multiple mutations in these genes and typically present a more severe phenotype4. The disease-causing gene is the main determinant of the clinical phenotype, but specific disease-causing mutation can contribute to clinical severity1. Therefore, genetic testing provides not only a better diagnose but also a gene-specific and mutation-specific risk stratification and patient management5. Treatment options mainly include beta blockers, sodium channel blockers, implantable cardioverter-defibrillators, or left cardiac sympathetic denervation.

  1. Schwartz PJ, Crotti L, Insolia R. Long-QT Syndrome from Genetics to Management. Circulation: Arrhythmia and Electrophysiology. 2012;5:868-877. http://circep.ahajournals.org/content/5/4/868
  2. Hunter JD, Sharma P, Rathi S. Long QT syndrome
  3. Alders M & Christiaans I. Long QT Syndrome. GeneReviews® (Last Update: June 18, 2015). https://www.ncbi.nlm.nih.gov/books/NBK1129
  4. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507–17
  5. Nakano Y & Shimizu W. Genetics of long-QT syndrome. Journal of Human Genetics. 61, 51–55; doi:10.1038/jhg.2015.74 (2016)

Other names 
SQTS

Inheritance
Autosomal dominant

Genes
CACNA1C, CACNA2D1, CACNB2, KCNH2, KCNJ2, KCNQ1, SCN5A

Description
Short QT syndrome (SQTS) is a rare dominantly inherited electrical heart disease, characterized by disruption of the heart's normal rhythm and increased risk of atrial fibrillation and sudden cardiac death1. The term "short QT" derives from the abnormally short QT intervals on the electrocardiogram test, that measures the electrical activity of the heart. This sign reflects a markedly accelerated cardiac repolarization, due to mutation in potassium and calcium channels2. Five genotypes, labeled SQT1-SQT5, have been identified to date, caused by mutations in six genes (KCNH2, KCNQ1, KCNJ2, CACNA1C, CACNA2D1 and CACNB2). The most common form of SQTS (SQT1) is linked to mutations in KCNH2 gene, whereas mutations in KCNQ1 and KCNJ2 are only rarely reported4,5. Mutations in the KCNH2, KCNJ2, or KCNQ1 genes increase the activity of the channels, enhancing the flow of potassium ions across the membrane of cardiac muscle cells. This change in ion transport alters the electrical activity of the heart, leading to the abnormal heart rhythms characteristic of STQS6. Individuals with clinical symptoms of this syndrome may benefit from diagnostic genetic testing to confirm diagnosis, clarify risks, or inform management. Due the risk of sudden cardiac death, the prevailing treatment is nowadays the use of an implantable cardioverter defibrillator device.

  1. Patel C, Yan GX, Antzelevitch C. Short QT Syndrome: From Bench to Bedside. Circulation: Arrhythmia and Electrophysiology. 2010;3:401-408
  2. Rudic B, Schimpf R, Borggrefe M. Short QT Syndrome – Review of Diagnosis and Treatment. Arrhythm Electrophysiol Rev. 2014 Aug; 3(2): 76–79
  3. Mazzanti A, Kanthan A, Monteforte N, Memmi M, Bloise R, Novelli V, Miceli C, O'Rourke S, Borio G, Zienciuk-Krajka A, Curcio A, Surducan AE, Colombo M, Napolitano C, Priori SG. Novel insight into the natural history of short qt syndrome. J Am Coll Cardiol. 2014;63:1300–1308
  4. Bellocq C, Van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109:2394–2397
  5. Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005;96:800–807
  6. https://ghr.nlm.nih.gov/condition/short-qt-syndrome

Other names 
ARVD, Arrhythmogenic right ventricular cardiomyopathy, ARVC, Right ventricular cardiomyopathy, Right ventricular dysplasia

Inheritance
Autosomal dominant or recessive

Genes
DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43

Description
Arrhythmogenic right ventricular dysplasia (ARVD) is a rare type of inherited cardiomyopathy. It occurs if the muscle tissue (also called myocardium or cardiac muscle) of the right ventricle dies and is replaced with scar tissue, disrupting the heart's electrical signals and causing arrhythmias1. ARVD may not cause any symptoms in its early stages. However, affected individuals may still be at risk of sudden death, especially during physical activity. This disorder occurs in an estimated 1 in 1,000 to 1 in 1,250 people, but it might be underdiagnosed in patients with mild or no symptoms2. ARVD is often caused by mutations in desmosomal proteins, located on the surface of heart muscle cells which link the cells together. The genes underlying ARVC are characterized by considerable natural variability, making a variant of unknown significance a common outcome of genetic testing, further emphasizing the need for careful phenotyping3.

  1. The American Heart Association
  2. https://ghr.nlm.nih.gov/condition/arrhythmogenic-right-ventricular-cardiomyopathy
  3. den Haan AD, Tan BY, Zikusoka MN, Llado LI, Jain R, Daly A, Tichnell C, James C, Amat-Alarcon N, Abraham T, Russell SD, Bluemke DA, Calkins H, Dalal D, Judge DP. Comprehensive desmosome mutation analysis in North Americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009;2:428-435

Other names
Asymmetric septal hypertrophy, Familial hypertrophic cardiomyopathy, Hypertrophic nonobstructive cardiomyopathy, Hypertrophic obstructive cardiomyopathy, Idiopathic hypertrophic subaortic stenosis (IHSS)

Inheritance 
Autosomal dominant

Genes
LMNA, MYBPC3, MYH6, MYH7, MYL2, PLM, PPKAG2, RYR2, SCN5A, TNNI3, TNNT2, TTR

Description
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder characterized by unexplained left ventricular hypertrophy (increased heart muscle thickness), myocyte disarray (disorganized cardiac cells) and fibrosis. It is the most common genetic cardiovascular disorder, affecting approximately 1 out of every 500 people worldwide1. HCM occurs when the heart muscle cells enlarge causing the walls of the ventricles to thicken. The thickening may block blood flow out of the ventricle as well as cause the ventricles walls to stiffen. As a result, the ventricle is less able to relax and fill with blood; thus raising the blood pressure and disrupting the heart’s electrical signals leading to arrhythmias. Symptoms can include chest pain, dizziness, shortness of breath, or fainting2. This condition is attributed to mutations in one of the genes encoding for a component of the sarcomeres, which are the basic units of muscle contraction. Among these genes, mutations in MYH7 and MYPBC3 occur most often and account for approximately 50% of HCM cases, while mutations in TNNT2, TNNI3, ACTC, TPM1, MYL3 and MYL2 collectively account for less than 20% of HCM cases3. Genetic screening is a valuable tool that can confirm the diagnosis in patients with ambiguous noninvasive imaging testing. It may also help to identify high risk individuals with a family history of HCM4. At present there is no cure for HCM, but treatments are available to help control symptoms and prevent complications.

  1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT. Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary artery risk development in (Young) adults. Circulation. 1995;92:785–789
  2. The American Heart Association
  3. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009;54:201–211
  4. European Society of Cardiology

Other names
DCM, Idiopathic dilated cardiomyopathy

Inheritance 
Autosomal dominant

Genes
CTNNA3, DSC2, DSG2, DSP, LMNA, MYBPC3, MYH6, MYH7, MYL2, NKX2.5, PKP2, PLN, SCN5A, TNNI3, TNNT2, TTR

Description

Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy, occurring more frequently in men than in women between the ages of 20 and 60 years1. DCM is rare (1–2 in 100,000) in the pediatric population2. This disease affects the heart's main pumping chamber, the left ventricle, which becomes enlarged and cannot pump blood efficiently to the body3. The decreased heart function can lead to congestive heart failure (CHF) in about 1 in 3 cases4. While the cause of dilated cardiomyopathy is often unknown, up to one-third of the patients inherit it in an autosomal dominant pattern. At least 50 single genes have been identified as linked to familial DCM and more frequently mutations in LMNA, MYH7, MYH6, SCN5A, TNNT2 genes5. With few exceptions, it is not possible to determine which gene is responsible for DCM on clinical grounds. Genetic testing commonly employs multi-gene panels, in which multiple genes can be tested simultaneously. Treatment may include medication, pacemakers, implantable cardiac defibrillators, or heart transplantation5.

  1.  Types of Cardiomyopathy. National Heart, Lung and Blood Institute (NHLBI) (June 22, 2016)
  2. Wilkinson JD, et al. The pediatric cardiomyopathy registry and heart failure: key results from the first 15 years. Heart Fail Clin. 2010;6(4):401–413
  3. Dilated cardiomyopathy. MayClinic.com. (August 19, 2014)
  4. Jameson JN, Kasper DL, Harrison TR, Braunwald E, Fauci AS, Hauser SL, Longo DL. Harrison's principles of internal medicine (16th ed.). New York: McGraw-Hill Medical Publishing Division (2005)
  5. Hershberger RE & Morales A. Dilated Cardiomyopathy Overview. GeneReviews® (Last update: September 24, 2015); https://www.ncbi.nlm.nih.gov/books/NBK1309/

Other names
Idiopathic restrictive cardiomyopathy, Infiltrative cardiomyopathy

Inheritance 
Autosomal dominant

Genes
TNNI3, TTR

Description
Restrictive cardiomyopathy (RCM) is a rare form of cardiomyopathy, representing the least common of the 3 clinically recognized and described cardiomyopathies1. It accounts for approximately 5% of all cases of primary heart muscle disease. Patients present the ventricle walls abnormally rigid with reduced capacity to relax normally and be filled with blood. Blood flow in the heart is reduced over time, leading to problems such as heart failure or arrhythmias2. The etiology of RCM is broad, including genetic disease (sporadic or familial), infiltration (e.g. amyloidisis, sarcoidosis), connective tissue disease (e.g. systemic sclerosis), glycogen storage disease, drugs, and radiation. Inherited RCM can be transmitted in an autosomal dominant pattern3. Mutations in the TNNI3 gene are one of the major causes of this condition. The TNNI3 gene codes a protein called cardiac troponin I, which regulates contraction and relaxation of the heart muscle. Mutations in other genes have been identified, but they account for a small percentage of cases4.

  1. Kushwaha SS,Fallon JT, Fuster V. Restrictive Cardiomyopathy. N Engl J Med; 336:267-276 DOI: 10.1056/NEJM199701233360407 (January 23, 1997)
  2. The American Heart Association
  3. Cahill TJ, Ashrafian H, Watkins H. Genetic Cardiomyopathies Causing Heart Failure. Circulation Research. 2013;113:660-675
  4. https://ghr.nlm.nih.gov/condition/familial-restrictive-cardiomyopathy

Other names
LVNC, Spongy myocardium, Left ventricular hypertrabeculation

Inheritance 
Autosomal dominant

Genes
CASQ2, HCN4, LMNA, MYBPC3, MYH7, PLN, TNNT2

Description
Left ventricular non-compaction (LVNC) is a rare congenital cardiomyopathy, affecting approximately 0.014-1.3% of the general population1. It is characterized by excessive and unusual trabeculations within the mature left ventricle and thickening of the myocardium. Patients with LVNC may be asymptomatic or present progressive deterioration of cardiac function, arrhythmias, thromoboembolic events and sudden cardiac death2. It can be diagnosed at any age, but the worst reported outcomes have been seen in newborns, particularly in those with associated systemic disease and metabolic derangement2. It is assumed that 20-25% of cases of LVNC have a genetic basis3. The more common mutated genes are the ones encoding for proteins found in the sarcomere (MYH7, TNNT2 and ACTC)4, mainly inherited with an autosomal dominant pattern. Treatments, such as blood thinning medication and defibrillators, are available to control symptoms, but in rare cases heart transplantation is needed5.

  1. ESC Council for Cardiology Practice. LEFT VENTRICULAR NONCOMPACTION. VOL.10, N°31 (26 JUN 2012)
  2. Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children. A relatively common form of cardiomyopathy. Circulation 2003; 108:2672–2678.
  3. Callis TE, Jensen BC, Weck KE, Willis MS. Evolving molecular diagnostics for familial cardiomyopathies: at the heart of it all. Expert Rev Mol Diagn. 2010 Apr; 10(3): 329–351. doi:  10.1586/erm.10.13
  4. Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 2008;117(22):2893–2901
  5. Bennett CE & Freudenberger R. The Current Approach to Diagnosis and Management of Left Ventricular Noncompaction Cardiomyopathy: Review of the Literature. Cardiology Research and Practice (Jan 2016)

Other names
Thoracic Aneurysm, Descending Aortic Aneurysm, Thoracic Aortic Dissection

Inheritance 
Autosomal dominant

Genes
ACTA2, TGFBR2

Description
A thoracic aortic aneurysm is a serious and rare condition, occurring in approximately 6-10 per every 100,000 people1, which present an enlargement of the aorta in the thoracic cavity. If the aneurysm is not surgically repaired, it can lead to aortic dissection, defined as separation of the layers within the aortic wall, which allows blood to flow between the aorta’s inner and outer walls. Early detection and treatment are essential to reduce the risk that the aorta will burst, causing massive internal bleeding and death. About 20% of people with thoracic aortic aneurysm and dissection have a genetic predisposition to it2. Mutations in several genes have been associated to the familial form of this disease. Mutations in the ACTA2 gene have been identified in 14-20% of those affected, and TGFBR2 gene mutations have been found in 2.5% of patients3. Many people don’t know they have a genetic predisposition to thoracic aortic aneurysm and dissection. First-degree relatives of affected individuals should be screened by genetic testing for this condition, since it can be rapidly fatal.

  1. Society for Vascular Surgey
  2. The Marfan Syndrome Foundation
  3. https://ghr.nlm.nih.gov/condition/familial-thoracic-aortic-aneurysm-and-dissection

Other names
Ehlers Danlos syndrome, ecchymotic type; Ehlers Danlos syndrome, arterial type; Ehlers Danlos syndrome, Sack-Barabas type, EDS type 4

Inheritance 
Autosomal dominant  

Gene
COL3A1

Description
Ehlers-Danlos syndrome (EDS), vascular type is a genetic connective tissue disorder, inherited in an autosomal dominant manner1. It is generally considered the most severe form of Ehlers-Danlos syndrome and represents approximately 5-10% of all EDS cases2. This disease is caused by defects in a collagen protein, named type III collagen. Collagens provide structure and strength to connective tissue throughout the body. If type III collagen is mutated, collagen fibrils cannot be assembled properly, leading to the signs and symptoms of EDS, vascular type3. Most patients present characteristic facial features, translucent skin with highly visible subcutaneous vessels, easy bruising, and rarely severe arterial, digestive and uterine complications, associated with a shortened lifespan4. Diagnosis is based on clinical signs, non-invasive imaging, and genetic testing of COL3A1 gene. Treatment and management is focused on preventing serious complications and relieving symptoms1.

  1. Pepin MG & Byers PH. Ehlers-Danlos Syndrome Type IV. GeneReviews®  http://www.ncbi.nlm.nih.gov/books/NBK1494/ (Last update: May 2011)
  2. Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis. 2007; 2: 32. doi:  10.1186/1750-1172-2-32
  3. COL3A1Genetics Home Reference (May 2006)
  4. Pauker SP & Stoler J. Clinical manifestations and diagnosis of Ehlers-Danlos syndromes (Updated:  February 22, 2016)

Metabolism

Other names 
BASDs, Bile acid synthesis defects

Inheritance 
Autosomal recessive

Genes 
AMACR, BAAT, CYP7A1, CYP7B1, CYP27A1, HSD3B7, SLC27A5

Description
Bile acid synthesis disorders (BASDs) are a group of rare metabolic disorders, that are responsible for approximately 2% of persistent cholestasis in infants1. BASDs are caused by inherited defects in the enzymes that make bile acids. A mutation in any of the genes encoding for these enzymes could induce an abnormal bile flow and production, often resulting in malabsorption of vital nutrients and accumulation of toxic materials within the body. In all known BASDs, genetic mutations are inherited in autosomal recessive manner2. Congenital bile acid synthesis defect type 1 (CBAS1) is the most common form of BASD and is caused by mutations in HSD3B7 gene, which code for an enzyme called 3 beta-hydroxysteroid dehydrogenase type 73. It is important to diagnose and treat these diseases as early as possible, since untreated patients may develop serious liver complications, as liver failure. Genetic testing may enable early identification and initiation of therapy, which can lead to better outcomes.

  1. Bove KE, et al. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004;7:315–334
  2. National Organization for Rare Disorders
  3. https://ghr.nlm.nih.gov/condition/congenital-bile-acid-synthesis-defect-type-1

Other name
MODY

Inheritance 
Autosomal dominant

Genes 
ABCC8, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11

Description
Maturity-onset diabetes of the young, or MODY, is a clinically rare and heterogeneous form of diabetes, accounting for approximately 1–2% of patients diagnosed with diabetes1. This prevalence is likely underestimated, since MODY is often misdiagnosed as type 1 or type 2 diabetes. It is often referred to as "monogenic diabetes" to distinguish it from the more common types of diabetes, which involve more complex combinations of causes including multiple genes and environmental factors. MODY is characterized by dysfunction of pancreatic ß cells due to a combination of different mutations in at least six different genes, inherited in an autosomal dominant manner2. Each mutated gene is responsible for a slightly different type of diabetes. The most common clinical forms of MODY are type 1 and 3, caused respectively by mutations in the Hepatocyte nuclear factor (HFN) 4 alpha and 1 alpha, and MODY 2, due to mutations in the glycolytic enzyme glucokinase (GCK) genes3. The course of the disease and the risk of developing additional complications are often related to the underlying gene mutation. Genetic testing represents the gold standard to correctly identify MODY diabetes, allowing clinicians to provide personalized treatment to their patients4.

  1. Shepherd M, Ellis I, Ahmad AM, et al. Predictive genetic testing in maturity-onset diabetes of the young (MODY) Diabet Med. 2001;18(5):417–421
  2. Fajans S, Bell GI and Polonsky KS. Molecular Mechanism and Clinical Patho- physiology of Maturity-Onset Diabetes of the Young. The New England Journal of Medi- cine, 345, 971-980 (2001)
  3. Stanik J, Kusekova M, Huckova M et al. Impact of Type 2 Diabetes on Glu- cokinase Diabetes (GCK-MODY) Phenotype in a Roma Family-Case Report. Endocrine Regulations, 46, 99-10 (2012)
  4. Kavvoura FK & Owen KR. Maturity Onset Diabetes of the Young: Clinical Characteristics, Diagnosis and Management. Pediatric Endocrinology Reviews, 10, 234-242 (2013)

Other name
PKD

Inheritance
Autosomal dominant or recessive

Genes 
PKD1, PKD2, PKHD1, PRKD3

Description
Polycystic kidney disease (PKD) is one of the most common life-threatening monogenic disorders, characterized by an uncontrolled growth of fluid-filled cysts in the nephrons of both kidneys1. PKD patients present progressive cyst formation and renal enlargement, often leading to kidney failure. In addition, they can develop extra-renal complications, such as high blood pressure, cysts in the liver, and problems with blood vessels in the brain and heart2. There are two types of PKD, distinguished by patterns of inheritance: autosomal dominant (ADPKD) and autosomal recessive (ARPKD). ADPKD is the more common form, affecting an estimated 12,4 million people worldwide3. It represents the fourth leading cause of kidney failure and is caused by mutations in PKD1 encoding polycystin-1 (PC1; 85% of cases) or PKD2, which encodes polycystin-2 (PC2; 10-15% of cases)4. These two proteins regulate cellular orientation to form tubular structures as well as cell growth and fluid secretion function. If mutated, they induce a wide array of cellular abnormalities. Patients with PKD1 mutations generally present a more severe phenotype and require dialysis at an earlier age compared to those with PKD2 mutations5. ARPKD, is a rare genetic disorder occurring in approximately 1 in 20,000 children, which die shortly after birth due to respiratory insufficiency caused by pulmonary hypoplasia6. Mutations in a single gene, PKHD1, coding a protein known as fibrocystin (or polyductin), causes ARPKD. However, the exact role and function of this protein in the body is still unknown. Genetic testing can help to select appropriate treatments, provide actionable information on which agents to avoid, guide lifestyle-modification and family-planning.

  1. Igarashi P & Somlo S. Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol. 2002 Sep;13(9):2384–2398
  2. National Institute of Diabetes and Digestive and Kidney Diseases
  3. Wilson PD. Polycystic kidney disease. N Engl J Med. 2004;350:151–64. doi: 10.1056/NEJMra022161
  4. Mochizuki T, Tsuchiya K, Nitta K. Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies. Clin Exp Nephrol. 2013;17:317–26. doi: 10.1007/s10157-012-0741-0
  5. PKD foundation
  6. Parfrey PS. Autosomal-recessive polycystic kidney disease. Kidney Int. 2005 Apr;67(4):1638–1648

Pediatrics

Other names 
CF, fibrocystic disease of pancreas, mucoviscidosis, pancreatic fibrosis

Inheritance 
Autosomal recessive

Gene 
CFTR

Description
Cystic fibrosis (CF) is an inherited and progressive disease, that causes persistent lung infections and limits the ability to breathe over time1. It affects approximately 70,000 people worldwide with a prevalence, which varies considerable among populations and regions of the world2. Therefore, this disease occurs predominantly in the white population, with a rate of 1 in 2500 live births2. CF is an autosomal recessive condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which regulates the flow of chloride ions and water across cell membranes. Defects in CFTR protein lead to altered fluid and electrolyte composition of secretions, thereby resulting in their increased viscosity, which is responsible for progressive obstruction and fibrosis of various organs3. Among the 2,000 plus known CFTR mutations, fewer than 20 occur at a worldwide frequency of more than 0.1% and only five mutations at a frequency more than 1%4. The most common of these is F508del (or ?F508), present in approximately 70% of CFTR genes of affected individuals worldwide5. A distinct spectrum of CFTR variants are also found in cystic fibrosis-related phenotypes, such as congenital bilateral aplasia of the vasa deferens (CBAVD), often associated to excretory azoospermia. Genetic testing is highly recommended for anyone with a family history of cystic fibrosis or with a medical condition which might possibly be connected to CF. Nowadays, there is no cure for cystic fibrosis, but treatment can ease symptoms and reduce complications. In some cases, lung transplant becomes the only option to improve patients’ quality of life6.

  1. https://ghr.nlm.nih.gov/condition/cystic-fibrosis
  2. World Health Organization. The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS; June 19, 2002; Genoa, Italy. ©World Health Organization (2004)
  3. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992–2001
  4. Cystic Fibrosis Mutation Database
  5. Castellani C, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96. doi: 10.1016/j.jcf.2008.03.009
  6. https://cysticfibrosisnewstoday.com/

Other names 
Benign paroxysmal peritonitis, Familial paroxysmal polyserositis, FMF, MEF, recurrent polyserositis, Reimann periodic disease, Siegal-Cattan-Mamou disease, Wolff periodic disease

Inheritance 
Autosomal dominant, autosomal recessive

Gene
MEFV

Description
Familial mediterranean fever (FMF) is a hereditary auto-inflammatory disease, characterized by fever and recurrent episodes of painful inflammation in the abdomen, chest, or joints. It is commonly observed among the nations of the Mediterranean region and frequently occurs in Turkish, Armenian, Jewish and Arabic communities1, where it affects 1 in 200-1,000 individuals2. FMF is almost always inherited in an autosomal recessive pattern, caused by mutations in both copies of the MEFV gene. This gene encodes a protein called pyrin or marenostrin, which is expressed in white blood cells and regulates the immune system and the process of inflammation3. Mutated pyrin leads to an inappropriate or prolonged inflammatory response, explaining FMF phenotype. The most common mutation detected in MEFV gene is M694V, that is associated with an increased risk of amyloidosis4. Genetic testing may be considered to confirm a suspected diagnosis in clinically affected individuals and test at-risk relatives. Treatments are available once the diagnosis is confirmed. Colchicine is the only established drug for patients diagnosed with FMF, that can prevent renal amyloidosis3. Other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), can help treat acute episodes and alleviate symptoms3.

  1. Onen F. Familial Mediterranean fever. Rheuma- tol Int 2006; 26: 489-96
  2. https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever
  3. Shohat M & Halpern GJ. Familial Mediterranean fever-a review. Genetics in Medicine. 2011;13(6):487–498
  4. Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R. Familial Mediterranean fever: prevalence, penertrance and genetic drift. Eur J Hum Genet. 2001;9(8):634–637

Other names
Noonan Syndrome, Noonan Syndrome with multiples lentigines (LEOPARD Syndrome), Cardio-facio-cutaneous Syndrome, Costello Syndrome, Neurofibromatosis type 1, Legius Syndrome

Genes 
BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, SHOC2, SOS1, SPRED1

Description
RASopathies are a class of pediatric developmental disorders, representing one of the largest known groups of malformation syndromes and affecting approximately 1 in 1,000 individuals1. They are caused by germline mutations in genes that encode components or regulators of the RAS-mitogen-activated protein kinase (MAPK) intracellular signaling pathway. This pathway is key in controlling cell cycle and differentiation, therefore its dysregulation has profound developmental consequences2. The variety of affected genes and the diversity of mutations within each gene explain the complexity of the phenotypic features. However, since the RASopathies share the common mechanisms of RAS/MAPK pathway dysregulation, they present many overlapping characteristics, such as distinctive craniofacial features, growth anomalies, congenital heart defects, abnormal skin and/or hair, and predisposition to cancer. The diagnosis of patients with a given RASopathy is based on the clinical recognition of phenotypic features, with genetic testing then used to refine the diagnosis. Concerning the treatment, many small-molecule therapeutics are in development or undergoing clinical trials, aiming to ameliorate the progression of signs and symptoms associated with these disorders3.

  1. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14: 355–369. doi:  10.1146/annurev-genom-091212-153523
  2. Tidyman WE & Rauen KA. The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009 Jun; 19(3): 230–236. doi:  10.1016/j.gde.2009.04.001
  3. https://rasopathiesnet.org

Other names 
Congenital hereditary hematuria, Hematuria-nephropathy-deafness syndrome, Hematuric hereditary nephritis, Hemorrhagic familial nephritis, Hemorrhagic hereditary nephritis, Hereditary familial congenital hemorrhagic nephritis, Hereditary hematuria syndrome, Hereditary interstitial pyelonephritis, Hereditary nephritis

Inheritance
Alport Syndrome has 3 different inheritance patterns:
- X-linked, accounting for 80% to 85% of the cases
- Autosomal recessive in 15% of the cases
- Autosomal dominant, representing 5% of the cases

Genes
COL4A3, COL4A4, COL4A5

Description
Alport Syndrome is a rare inherited disease, occurring in approximately 1 in 50,000 newborns1. People with Alport syndrome experience progressive loss of kidney function, abnormalities in the inner ear (cochlea) and eye2. This rare genetic condition is caused by mutations in the type IV collagen genes, as COL4A3, COL4A4, and COL4A53. A diagnosis of Alport syndrome is normally based on the identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. In most cases, genetic testing can be useful to confirm the diagnosis, especially when results of a skin or kidney biopsy are not conclusive. Importantly, genetic testing is the only way to diagnose a female with a family history of X-linked Alport syndrome in absence of symptoms4. Currently, there is no specific therapy for Alport syndrome, which is treated symptomatically by using medications like ACE and aldesterone inhibitors or angiotensin-receptor blockers (ARBs), that can potentially delay the progression of the disease and the onset of kidney failure. Ultimately, in many patients, a kidney transplant is required5.

  1. Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000; 58:925
  2. Cosgrove D. Glomerular pathology in Alport syndrome: a molecular perspective. Pediatr Nephrol. 2012 Jun;27(6):885-90. doi: 10.1007/s00467-011-1868-z. Epub 2011 Apr 1
  3. Alport Syndrome, X-linked, ATS; Online Mendelian Inheritance in Man (OMIM)
  4. Alport Syndrome Foundation, "Diagnosis"
  5. Alport Syndrome Foundation, "Treatment"

Other names 
Muscular dystrophy Duchenne, DMD, Muscular dystrophy pseudohypertrophic progressive Duchenne type

Inheritance
X-linked recessive

Gene
DMD

Description
Duchenne muscular dystrophy (DMD) is the most common fatal genetic condition diagnosed in early childhood, occurring primarily in boys with an incidence of 1 in every 3,500 live male births worldwide (about 20,000 new cases each year)1. It is caused by a mutation in the DMD gene, which encodes the muscle protein dystrophin. As a consequence, muscle cells are easily damaged, leading to progressive loss of muscle function and weakness, progressive difficulty walking, issues with heart and lung function2. This condition is inherited in an X-linked recessive pattern, but approximately 35% of cases are associated to a random spontaneous mutation3. Genetic testing can determine specific genetic mutation, proving information about risk in the family and determining treatment study eligibility2. Currently, medical treatments may only help slow the progression of the disease, but there is no known cure for it4.

  1. Duchenne Connect, “About Duchenne and Becker Muscular Dystrophies” (Accessed June 25, 2015)
  2. Duchenne Connect, “Understanding Genetic Testing” (Accessed August 18, 2016)
  3. Parent Project Muscular Dystrophy, “About Duchenne” (Accessed June 25, 2015)
  4. Haldeman-Englert C. Duchenne muscular dystrophy. MedlinePlus. February 3, 2014 (Accessed April  25, 2015)

Other names 
Marfan's syndrome, MFS

Inheritance
Autosomal dominant

Gene
FBN1

Description
Marfan syndrome is a rare genetic disorder, affecting the connective tissue1. Connective tissue is found throughout the body where it supports, connects or separates different types of tissues and organs. Features of this disorder are most often found in the heart, blood vessels, bones, joints, and eyes. However, the major source of morbidity and early mortality relate to cardiovascular system dysfunctions2. The incidence of Marfan syndrome is approximately 1 in 5,000 people worldwide1 and life expectancy approximates that of the general population when the disease is properly managed. This syndrome is a dominant disorder. It is caused by a mutation in the FBN1 gene3, that affects the function of the protein, fibrillin-1, which is essential for the formation of the elastic fibers found in the connective tissue. Genetic testing can be used to confirm a suspected diagnosis of Marfan syndrome, that cannot be determined through a clinical evaluation4. This syndrome has no cure and patients require individualized treatments, that can help delay or prevent complications.

  1. https://ghr.nlm.nih.gov/condition/marfan-syndrome
  2. The Marfan Syndrome Foundation. https://www.marfan.org/about/marfan
  3. Robinson PN & Godfrey M. The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 2000;37:9-25 doi:10.1136/jmg.37.1.9
  4. The Marfan Syndrome Foundation. https://www.marfan.org/expectations/diagnosis

Other names 
Stargardt macular degeneration, Juvenile macular degeneration, Macular dystrophy with flecks type 1, STGD

Inheritance
Autosomal recessive or dominant

Genes
ABCA4, ELOVL4

Description

Stargardt disease is the most common form of juvenile macular degeneration, affecting 1 in 8,000 to 10,000 individuals1. The signs and symptoms of this genetic disease typically appear before the age of twenty and get progressively worse, leading to vision loss2. In most cases, Stargardt disease is caused by mutations in the ABCA4 gene and is usually a recessive trait. Less often, mutations in the ELOVL4 gene cause this condition and are transmitted through autosomal-dominant inheritance. The ABCA4 and ELOVL4 genes provide instructions for making proteins that are found in light-sensing (photoreceptor) cells in the retina3. Therefore, clinical diagnosis is based on ophthalmological examinations, whilst genetic testing is required to confirm it and determine if a sporadic case is recessive or dominant. While there are no therapies today to cure Stargardt disease, treatments are available to slow its progression3.

  1. https://ghr.nlm.nih.gov/condition/stargardt-macular-degeneration
  2. Sahel JA, Marazova K, Audo I. Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a017111
  3. The American Macular Degeneration Foundation