Case Study – Hospitales Universitarios Virgen de las Nieves and Clínico San Cecilio

The Genetics Laboratories at the Hospitales Universitarios Virgen de las Nieves and Clínico San Cecilio in Granada, Spain are affiliated with the Andalusian Health Service (Servicio Andaluz de Salud) and act as reference laboratories for the Andalusian region, primarily investigating inherited diseases and assessing hereditary cancers. The laboratories receive and analyze hereditary cancer samples from a 1.5 million-person reference population across Granada and Huelva, assessing approximately 1000 samples per year.

Research Case

A couple, who were discovered to be consanguineous, birthed a healthy daughter in 2012 and then had two further children both of whom died before they were 2 months old – a 43 day-old male in 2019 and a 20 day-old female in 2022. In 2019, a sample from the male neonate was sent to an external laboratory for exome and targeted sequencing, with inconclusive results. Microarray-based comparative genomic hybridization (aCGH) was also conducted, but no anomalies were detected. In 2022, the H. Virgen de las Nieves and Clínico San Cecilio laboratories received a sample from the 20-day-old female neonate to investigate the underlying cause(s) that may have led to her death.

Approach

The H. Virgen de las Nieves and Clínico San Cecilio laboratories used the SOPHiA DDM™ Platform to conduct familial variant analysis (FVA) on a trio of samples from the mother, father, and female neonate proband, using clinical exome data. This allowed them to look for inheritance patterns to determine whether pathogenic variant(s) were inherited or if the mutation was de novo.

Results

The SOPHiA DDM™ Platform identified a homozygous variant of unknown significance in the proband, that caused a frameshift in the SMPD4 gene: NM_001171083.2 (SMPD4) c.444_445del p.(Ala149Leufs*52). The FVA found that the variant was heterozygous in both parents and homozygous in the proband, and after further investigation also homozygous in the male neonate, suggesting an autosomal recessive inheritance. The mutation was confirmed by orthogonal testing. SMPD4 has previously been associated with neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA), aligning clinically with the neonates’ phenotypes.