The most accurate analytic solutions

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

Oncology

Gene markers
AKT1, ALK, BRAF, EGFR, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET and ROS1

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and is further divided into three distinct histological groups: adenocarcinoma, squamous cell carcinoma and large cell carcinoma. 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. Epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK) are the most frequently mutated genes and rarely found concurrently in the same tumor. 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 gene.

Gene markers
BRCA1 and BRCA2       

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 year. Specific genetic mutations are known to increase the risk of developing breast, ovarian and related cancers. BRCA1 and BRCA2 mutations account for about 20-25% of hereditary breast cancers, 5-10% of all breast cancers and around 15% of all ovarian cancers. BRCA1 and BRCA2 encode tumor suppressor proteins, involved in repairing damaged DNA and, therefore, playing a role in ensuring the stability of the cell’s genetic material. Aberrant proteins may not properly repair DNA damages, causing genetic alterations that can lead to cancer development. Early detection of BRCA1 and BRCA2 mutations could allow the development of personalized treatment options to increase the survival rate of patients harbouring 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, favouring cancer cell death. 

Gene markers
AKT1, APC, BRAF, DCC, KRAS, NRAS, PIK3CA, p53, PTEN, SMAD4 and TGFBR2

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 world. 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 (hereditary) cases. Approximately, 75-80% of colorectal tumours have a sporadic origin and present multiple molecular alterations, belonging to two major pathways. The “canonical” pathway, presented in 80-85% of CRCs, involves high chromosomal instability. It is characterized by allelic losses on chromosome 5q, 17p, and 18q, with subsequent mutations in tumour suppressor genes, such as APC, p53, and DCC, or in oncogenes, such as KRAS. 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 tumour cells are 100- to 1000-fold more frequent compared to normal cells). 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.

Gene markers
HRAS, KRAS, NRAS, PAX8/PPARᵧ, PI3KCA and PTEN

Follicular thyroid cancer (FTC) is the second most common type of thyroid cancer, accounting for 10-20% of all the cases. It occurs more frequently in women over 50 years of age with a female-to-male ratio of approximately 3:1. FTC rarely spreads to the lymph nodes (5%), but at the time of the initial diagnosis, up to 33% of patients may present distant metastasis in the bones, lung, liver, or brain. FTC is known to harbor either RAS mutations (20-50%) or PAX8/PPARᵧ rearrangement (30-40%). These mutations rarely overlap in the same tumor, suggesting that such carcinomas may develop via at least two distinct molecular pathways, initiated by either the aberrant RAS or PAX8-PPARᵧ. RAS point mutations, typically in codons 12, 13, or 61, lead to constitutive activation of downstream pathways, which in turn activate and sustain tumorigenesis. PAX8/PPARᵧ rearrangement, resulting from t(2;3)(q13;p25) translocation, generates a fusion gene containing the PAX8 gene, which encodes a paired domain transcription factor and the peroxisome proliferator–activated receptor (PPARᵧ) gene. This rearrangement results in a fusion protein, which induces uncontrolled cell growth and reduced apoptosis. These mutations are currently being explored as therapeutic targets for FTC. A number of small molecules have been identified and showed antitumor effects in preclinical and ongoing clinical trials.

Gene markers
BRAF, CDH1, EGFR, ERBB4, FLT3, KIT, KRAS, PDGFRA, PTEN, TP53 and VHL

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%).  Patients may be asymptomatic or show gastrointestinal bleeding, abdominal swelling, and/or palpable mass. Familial and sporadic GISTs are frequently associated with oncogenic mutations in one of two receptor tyrosine kinases: KIT (80%) or PDGFRA (5% to 7%). KIT and PDFGRA encode for growth factor receptors, which respectively control 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).

Gene markers
BRAF, CTNNB1, GNA11, GNAQ, HRAS, KIT, KRAS, MEK1 (MAP2K1) and NRAS

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 individuals. Exposure to ultraviolet (UV) radiation from sunlight or tanning lamps and beds is considered as the major risk factor for cutaneous melanoma. 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), KITV559A (?10–20% of mucosal and acral melanomas and <1% of all melanomas cases) and GNA11Q209L (present in 85% of uveal melanomas). 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 disease.

Gene markers
AIBI, AKT2, BRCA2, BRAF, KRAS, MLH, MSH2, MYB, p16/CDKN2A, p21, p53, and SMAD4

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).  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%. 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 conditions. Pancreatic cancer results from the successive accumulation of mutations in cancer related genes, such as oncogenes, tumor-supressor and genome-maintenance genes. 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 migration. 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 proliferation. Pancreatic cancer is resistant to both conventional chemotherapy and radiation. Therefore, the development of drugs targeting the mutated signalling pathways represent a promising approach for the treatment of pancreatic cancer.

Gene markers
FGFR1, MYC, PTEN, RB1, TP53 and TP73

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 smoking. The WHO defines SCLC as a malignant epithelial tumour consisting of small cells with little cytoplasm and expressing neuroendocrine markers. 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 suppressors TP53 and RB1, sometimes by complex genomic rearrangements. Alterations (point mutations or small deletions) in the PTEN gene have been identified in 10% of primary tumours 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 patients. 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 diagnosis.

Gene markers
BAAL, CEBPα, DNMT3A, FLT3, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, MLL and WT-1

Oncofusion genes
AML1-ETO t(8;21), CBFβ-MYH11 inv(16), MLL-fusions der(11q23) and PML-RARα t(15;17)

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 rates. 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 groups. 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 recurring oncofusion proteins resulting from t(8;21), inv(16)/t(16;16), t(15;17), as well as mutations in CEBPα, MLL, and possibly also NPM1. 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 development.

Other names
Chronic myelogenous leukemia, Chronic granulocytic leukemia and Chronic myelocytic leukemia

Gene markers
BCR-ABL1

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasms characterized by increased and unregulated proliferation of immature and mature granulocytes (neutrophils, eosinophils and basophils). CML usually occurs in people who are middle-aged or older and accounts for 15% of all the leukemias in adults. As a rule CML progresses slowly, presenting an initially chronic phase lasting for 3–5 years with few or any symptoms. When symptoms do appear, they may include fever, lack of appetite, and night sweats. This leukemia is one of the first diseases in which a specific chromosomal abnormality has been identified. This genetic abnormality, t(9;22)(q34;q11) or Philadelphia chromosome, involves the ABL1 gene in chromosome 9 and the BCR gene in chromosome 22. The resulting fusion gene, BCR-ABL1, encodes an aberrant protein with constitutively activated tyrosine kinase activity, responsible for the activation of signal transduction pathways associated to the abnormal bone marrow proliferation and to the clinical and morphologic manifestations of this leukemia. Tyrosine kinase inhibitors (imatinib, nilotinib, or dasatinib), targeting the abnormal BCR-ABL1, are now a first-line treatment for chronic-phase CML. These targeted therapies have dramatically improved prognosis of CML patients. Therefore, the only known curative therapy for CML is a bone marrow or stem cell transplant.

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

Gene markers
CBL, KRAS, NF1, NRAS and PTPN11

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 per year. Common symptoms of JMML are pallor, failure to thrive, decreased appetite, irritability, dry cough, tachypnea, skin rashes and diarrhea. 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 tumor suppressor gene NF1 (15%). Some chromosome abnormalities have been also identified in JMML, such as the monosomy 7 or deletion 7q (-7/del(7q)). This malignancy is rapidly fatal with 80% of patients surviving less than three years. 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.

Gene markers
ASXL1, CBL, DNMT3A, EZH2, IDH1, IDH2, KRAS, NRAS, RUNX1, SF3B1, SRSF2, TET2, TP53 and U2AF1

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, patient with MDS present an accumulation of immature myeloid cells in the bone marrow, which 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 leuckaemia. 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 protein.  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 signalling transduction (NRAS, CBL). Treatment for myelodysplastic syndromes usually focuses on controling 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.

Gene markers
BCR-ABL, JAK2, MPL and CALR

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 to 10 per 100,000 population annually. 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 factors. Markers that are relevant for MPN diagnosis and clinical management of patients include the presence of BCR-ABL1 fusion gene (frequent in chronic myelogenous leukemia) or mutations in JAK2, MPL and CALR genes. Recently, a JAK2 inhibitor has been approved as treatment for primary myelofibrosis. Trials with similar inhibitors are in progress to improve the prognosis of other MPN.

Hereditary Cancer

Other names 
BRCA1 and BRCA2 hereditary breast and ovarian cancer, Male breast cancer, HBOC

Inheritance 
Autosomal dominant

Genes 
BRCA1, BRCA2, PALB2

Description
Hereditary breast and ovarian cancer (HBOC) is a markedly increased susceptibility to breast and ovarian cancer, with an especially early onset of breast cancer, and an increased incidence of tumors of other organs, such as the fallopian tubes, prostate, male breast, pancreas and melanoma.  About 1 in 800 individuals carries a mutation in either the BRCA1 or the BRCA2 gene, implicated in the HBOC syndrome. The normal function of these genes is required for efficient repair of damaged DNA, preventing the occurrence of mutations favoring cancer. Women carrying a BRCA1 mutation have 55% to 85% lifetime risk of developing breast cancer and 20% to 40% of developing ovarian cancer. Men carriers of a BRCA2 mutation have 6% to 8% lifetime risk of developing pancreatic, hepatic, prostate and breast cancer. Family history and age at diagnosis are the most important criteria for requesting such genetic tests. When a causative mutation is detected there are various follow-up treatments such as hormone replacement therapy, chemoprevention strategies and prophylactic measures that clinicians can offer to lower the breast/ovarian cancer and overall mortality rate. Due to an increased relevance of different treatments available for the various BRCA gene mutations, the genetic analysis allows clinicians to make an early diagnosis and to select the best treatment options available to improve the survival rate of their patients. 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 seek genetic counseling to learn more about their potential risks, and about the purpose of genetic tests. Recently an additional utility of genotyping BRCA1 and BRCA2 has been related to the poly ADP-ribose polymerase, or PARP, inhibitor for the treatment of metastatic breast and ovarian cancer. PARP inhibitors continue to emerge as a novel class of anticancer agents for the treatment of patients with locally advanced or metastatic breast cancer whose tumors test positive for germline BRCA1/2 mutations.

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

Inheritance 
Autosomal dominant

Genes 
APC

Description
Familial adenomatous polyposis is a dominantly inherited condition characterized by the development of hundreds to thousands of precancerous (adenomatous) polyps, typically beginning in adolescence or early adulthood. These polyps mainly occur in the epithelium of the large intestine, and though starting out benign, malignant transformation into colon cancer occurs when left untreated. Without a prophylactic colectomy, individuals with FAP have a very high lifetime risk of developing colon cancer. One specific, pathognomonic finding is congenital hyperplasia of the retinal pigment epithelium (CHRPE), which requires a specialized eye examination. Three variants of the disease are known: classical FAP and attenuated FAP, both caused by APC gene defects, and autosomal recessive FAP which is caused by MUTYH gene defects (see below MUTYH-associated polyposis). Of the three froms, classical FAP is the most severe and most common. For all three forms, the resulting colonic polyps and cancers are confined to the colon wall. Polyps removal greatly reduces the spread of cancer. Although classical FAP has a nearly 100% lifetime risk of colorectal cancer, it is slightly lower (70%) in the attenuated FAP, as the APC gene is functional but slightly impaired. Attenuated FAP typically presents with far fewer polyps than the hundreds or thousands usually found in classical FAP, and they arise at an age when FAP is usually no longer considered likely - typically between 40 and 70 years of age rather than the more usual 30's upward. Because it has far fewer polyps, options for management may be different.

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 tens to hundreds of adenomatous colorectal polyps. It generally has a less severe clinical presentation than familial adenomatous polyposis (FAP), a clinically similar condition in which hundreds to thousands of colorectal polyps develop. Individuals with MAP have a 40%-100% lifetime risk of developing colorectal cancer. Occasionally, individuals with MAP will develop colon cancer in the absence of polyposis. MAP is also associated with an increased risk of developing upper gastrointestinal tract tumours, including duodenal adenomas as well as cancers of the bladder, skin, and thyroid.  

Other names  
Hereditary non-polyposis colorectal cancer, HNPCC

Inheritance 
Autosomal dominant

Genes 
EPCAM, MLH1, MSH2, MSH6, PMS2

Description
Lynch syndrome is a dominantly inherited susceptibility to develop colorectal and other cancers that occur typically in the fourth decade of life. It is the most common cause of hereditary colon cancer, with between 2%-4% of all colon cancer cases being caused by this disorder. Besides colorectal cancers, patients with this syndrome have an increased risk of having tumours of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women with this disorder also have a high risk of cancer of the endometrium (lining of the uterus) and ovaries. About 80% of individuals who carry a known mutation in one of 5 genes implicated in Lynch syndrome develop adenomas which undergo malignant transformation. In the Western world nearly 1 in 800 individuals carries a gene defect in one of the above listed genes. The main function of these genes consists of repairing DNA. 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 cancer. Family history and age at diagnosis are the most important criteria for a genetic testing request. Individuals with a history of colon and/or endometrial cancer or belonging to a family with positive history of colorectal and stomach or endometrial cancer, should seek genetic counseling to learn more about their potential risks of being affected with Lynch syndrome. When a person is found to carry a harmful mutation in a mismatch repair gene, other family members should then be tested to see if they also carry the familial mutation. Regular surveillance based on well-established prevention guidelines, such as monitoring by colonoscopy, allows to prevent colorectal cancer in almost all patients.

Cardiology

Other names
Familial hypercholesterolemia (FH) ; APOB-related familial hypercholesterolemia, autosomal dominant; hyperlipoproteinemia-type IIA ; LDLR-related familial hypercholesterolemia, autosomal dominant ; PCSK9-related familial hypercholesterolemia, autosomal dominant

Inheritance
Autosomal dominant

Genes
APOB, APOE, LDLR, LDLRAP1, PCSK9

Description
Familial hypercholesterolemia (FH) is a hereditary disorder leading to abnormally high cholesterol levels in the blood, specifically very high levels of low-density lipoprotein (LDL or "bad cholesterol"). Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, a major cause of cardiovascular disease. About 1 in 400 individuals in European populations carries a gene defect involved in FH. Most mutations lie in the LDLR gene, which encodes the LDL receptor protein, or in the APOB gene whose product is the part of LDL that binds with the receptor. Patients who have one abnormal copy (heterozygous patients) of the LDLR gene are at risk of premature cardiovascular disease at the age of 30 to 40, whilst having two abnormal copies (homozygous patients) causes very severe cardiovascular disease already in childhood, with death before the age of 20 if untreated. Fatty skin deposits called xanthomas are observed over parts of the hands, elbows, knees, ankles, and around the cornea of the eye, besides cholesterol deposits in the eyelids (xanthelasmas), chest pain (angina) or other signs of coronary artery disease. Individuals from families with a history of hypercholesterolemia or heart attacks should have blood tests done to determine lipid levels. With 50% functional LDL receptors, heterozygous patients have an excellent response to the usual cholesterol-lowering drugs. Lifestyle modification should always be instituted in parallel, in addition to cholesterol-lowering medication (often more than one) as rigorous dietary intervention indeed works synergistically with these drugs.

Other names
sudden unexplained nocturnal death syndrome

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

Inheritance
Autosomal dominant

Description
Brugada syndrome is a condition that causes a disruption of the heart's normal rhythm. Specifically, this disorder can lead to irregular heartbeats in the heart's lower chambers (ventricles), which is an abnormality called ventricular arrhythmia. If untreated, the irregular heartbeats can cause fainting (syncope), seizures, breathing difficulty, or sudden death. These complications typically occur when an affected person is resting or asleep. Brugada syndrome is much more common in men, typically becoming apparent in adulthood, although it can develop any time throughout life. Sudden death typically occurs around age 40. This condition also explains some cases of sudden infant death syndrome during sleep, which is a major cause of unexplained death in babies younger than 1 year. Brugada syndrome is treatable with preventive measures such as avoiding aggravating medications, reducing fever and, when necessary, using a medical device such as an implantable cardioverter-defibrillator.

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

Genes
ACTC1, ACTN2, CAV3, CSRP3, JPH2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYOZ2, NEXN, PLN, TCAP, TNNC1, TNNI3, TNNT2, TPM1

Inheritance 
Autosomal dominant

Description

Hypertrophic cardiomyopathy (HCM) can affect people of any age, and is usually inherited, being caused by a mutation in some of the genes encoding heart muscle proteins. About one out of every 500 people presents with HCM, affecting men and women equally. It is a common cause of sudden cardiac arrest in young people, including young athletes. It occurs if heart muscle cells enlarge and cause the walls of the ventricles (usually the left ventricle) to thicken. Despite this thickening, the ventricle size often remains normal. However, the thickening may block blood flow out of the ventricle. Symptoms can include chest pain, dizziness, shortness of breath, or fainting. HCM also can affect the heart's mitral valve, causing blood to leak backward through the valve.The entire ventricle may thicken, or the thickening may happen only at the bottom of the heart. The right ventricle also may be affected. In both types of HCM, obstructive and non-obstructive, the thickened muscle makes the inside of the left ventricle smaller, so it holds less blood. The walls of the ventricle may also stiffen, which results in the ventricle being less able to relax and fill with blood.

Synonymous
Jervell and Lange-Nielsen syndrome, Romano-Ward syndrome

Inheritance
Autosomal dominant or recessive

Genes
AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1

Description
Long QT syndrome (LQTS) is a disorder of the heart's electrical activity. It can cause sudden, uncontrollable, dangerous arrhythmias in response to exercise or stress. The term "long QT" refers to an abnormal pattern seen on an electrocardiogram (ECG), a test which records the heart's electrical activity. In patients presenting with long QT syndrome, ECG shows a prolongation of the QT interval. Normally, the QT interval duration is between 350 and 440 milliseconds, whereas in patients QT prolongation occurs, notably after the administration of certain medications, which may be dangerous. In addition to medications, long QT syndrome can be acquired from malnutrition leading to low blood potassium or low blood magnesium, as in anorexia nervosa.
LQTS is a rare inherited or acquired heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsades de pointes, a form of irregular heartbeat that originates from the ventricles. These episodes may lead to palpitations, fainting, and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition. Treatment options are beta blockers, sodium channel blockers, implantable cardioverter-defibrillators, or left cardiac sympathetic denervation. 

Other names 
SQTS

Inheritance
Autosomal dominant

Genes
KCNH2, KCNJ2, KCNQ1

Description
Short QT syndrome is a condition that can cause a disruption of the heart's normal rhythm (arrhythmia). In people with this condition, the heart (cardiac) muscle takes less time than usual to recharge between beats. The term "short QT" refers to a specific pattern of heart activity that is detected with an electrocardiogram (ECG), a test used to measure the electrical activity of the heart. In people with this condition, the part of the heartbeat known as the QT interval is abnormally short. If untreated, the arrhythmia associated with short QT syndrome can lead to a variety of signs and symptoms, from dizziness and fainting (syncope) to cardiac arrest and sudden death. This can occur any time from early infancy to old age. This condition may explain some cases of sudden infant death syndrome, which is a major cause of unexplained death in babies younger than 1 year. However, some people with short QT syndrome never experience any health problems associated with the condition.

Metabolism

Other names 
3beta-HSDH deficiency, 3beta-hydroxy-delta-5-C27-steroid dehydrogenase deficiency, 3beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency, CBAS1

Inheritance 
Autosomal recessive

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

Description
Congenital bile acid synthesis defect type 1 is a disorder characterized by cholestasis, a condition that impairs the production and release of bile from liver cells. Bile is used during digestion to absorb fats and fat-soluble vitamins, such as vitamins A, D, E, and K. People with congenital bile acid synthesis defect type 1 cannot synthesize bile acids, and thus fail to stimulate bile flow to absorb fats and fat-soluble vitamins. The signs and symptoms of congenital bile acid synthesis defect type 1 often develop during the first weeks of life, but they can begin anytime from infancy into adulthood, sometimes resulting in softening and weakening of the bones (rickets). Affected infants often fail to gain weight and grow at the expected rate, and have jaundice manifesting by yellowing of the skin and the white of the eyes. As the condition progresses, affected individuals can develop liver abnormalities. The spleen may also become enlarged (splenomegaly). If left untreated, congenital bile acid synthesis defect type 1 often leads to liver cirrhosis and death in childhood.

Other names 
MODY

Inheritance 
Autosomal dominant

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

Description
Maturity-onset diabetes of the young, or MODY, is a form of diabetes caused by mutations in a number of different genes. Each mutated gene causes a slightly different type of diabetes. MODY is often referred to as "monogenic diabetes" to distinguish it from the more common types of diabetes (especially type 1 and type 2), which involve more complex combinations of causes involving multiple genes and environmental factors. MODY should not be confused with latent autoimmune diabetes of adults (LADA), with slower progression to insulin dependence in later life. The most common forms are HNF1A-MODY (MODY3) and GCK-MODY (MODY2), due to mutations in the HNF1A and GCK genes, respectively. Although MODY is typically diagnosed in late childhood, adolescence, or early adulthood,  it can develop in adults as late as their 50s.  Many people with MODY are misdiagnosed as having type 1 or type 2 diabetes. However, a clear diagnosis of MODY could change the course of treatment and could help to identify other family members with MODY. People with MODY often have symptoms or lab results that are unusual for type 1 or type 2 diabetes.

Other names 
PKD

Inheritance
Autosomal dominant or recessive

Genes 
PKD1, PKD2, PKHD1, PRKD3

Description
Polycystic kidney disease is one of the most common life threatening disorders caused by a single gene defect, and it is the fourth most common cause of kidney failure. It is characterized by multiple fluid-filled cysts that form in the nephrons of both kidneys, and eventually lead to kidney failure in the majority of patients. Two forms of PKD are distinguished by their patterns of inheritance: the autosomal dominant polycystic kidney disease (ADPKD) and a less-common autosomal recessive polycystic kidney disease (ARPKD). The major extra renal complications of ADPKD include cerebral aneurysms, hepatic cysts, pancreatic cysts, cardiac valve disease (especially mitral valve prolapse), colonic diverticula, and aortic root dilatation. Most mutations (85%) lie in the PKD1 gene which codes for a protein involved in regulation of cell cycle and intracellular calcium transport in epithelial cells, while mutations of the PKD2 gene, which codes for proteins involved in voltage-linked calcium channels, are less frequent (15%). ARKPD classically presents in the neonatal period with massively enlarged kidneys and is associated with hepatobiliary disease

Pediatrics

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

Inheritance 
autosomal recessive

Gene 
CFTR

Description
Classical cystic fibrosis (CF) is a life shortening, infancy onset, autosomal recessive disorder with an incidence of about 1 in 2,500 live births and a carrier frequency of about 1 in 25 in individuals from European descent. More than 2’000 variants in the CFTR gene have been identified, of which worldwide fewer than 20 mutations occur with a frequency above 0.1%. The mutations occur with regional or ethnic variation in frequency and give rise to a wide range of clinical symptoms. Genetic and sweat tests for CF are recommended in the presence of nasal polyps, chronic sinus or lung infections, bronchiectasis, recurring bouts of inflamed pancreas (pancreatitis), or male infertility. Age of onset as well as symptoms may vary from one child to another. Symptoms may sometimes not begin until after puberty or even later in life. As time passes, the disease and its complications may improve or worsen. CFTR variants are also found in cystic fibrosis-related phenotypes, such as congenital bilateral aplasia of the vasa deferens (CBAVD), present in 25% of patients with excretory azoospermia. A distinct spectrum of CFTR mutations is typically observed in this male infertility phenotype.

Other names 
Familial Mediterranean Fever, Hyper-IgD Syndrome, TNF Receptor-Associated Periodic Syndrome, Cryopyrin-Associated Periodic Syndrome, Muckle-Wells Syndrome

Inheritance 
Autosomal dominant, autosomal recessive

Genes 
MEFV, MVK, NLRP3, TNFRSF1A

Description
Familial mediterranean fever (FMF) is a hereditary auto-inflammatory disease affecting mainly people originating from around the Mediterranean Sea and is prominently present in Armenian, Sephardi Jews (to a much lesser extent Ashkenazi Jews), Cypriots, Turks and Arabs. About 1 in 200 individuals in populations from Southern Europe carries a gene defect in the MEFV gene, which encodes a protein called pyrin or marenostrin, involved in inflammation. The disease must be treated by analgesia and non steroidal anti-inflammatory drugs. Colchicine, a drug otherwise mainly used in gout, decreases attack frequency in FMF patients and prevents the occurrence of renal amyloidosis. Recessive mutations in the gene MVK are responsible for the Hyper-IgD syndrome (HIDS), characterized by recurrent attacks of fever, abdominal and joint pain, and increased levels of blood immunoglobulin D. TRAPS (TNF Receptor-Associated Periodic Syndrome), whose symptoms are very similar to FMF or HIDS, is caused by dominant mutations of the gene TNFRSF1A. Cryopyrin-associated periodic syndromes (CAPS) are due to pathogenic variants of the NLRP3 gene and can manifest itself clinically, among other presentations, as the association of urticaria, deafness and renal amyloidosis, known as Muckle-Wells syndrome.

Include
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 characterized by a variety of symptoms, such as distinctive craniofacial features, growth anomalies, congenital heart defects, abnormal skin and/or hair, and development of tumors, both benign and cancerous. They are caused by genetic defects that impact the RAS-mitogen-activated protein kinase (MAPK) intracellular signaling pathway.