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Noncoding and synonymous coding variants that exert their effects via alternative splicing are increasingly recognized as an important category of disease-causing variants. In this report, we describe two siblings who presented with hypotonia, profound developmental delays, and seizures. Brain MRI in the proband at 5 years showed diffuse cerebral and cerebellar white matter volume loss. Both siblings later developed ventilator-dependent respiratory insufficiency, scoliosis and are currently nonverbal and non-ambulatory. Extensive molecular testing including oligo array and clinical exome sequencing was non-diagnostic. Research genome sequencing under an IRB-approved study protocol revealed that both affected children were compound-heterozygous for variants in the SEPSECS gene. One variant was an initiator codon change (c.1A&gt;T) that disrupted protein translation, consistent with the observation that most disease-causing variants are loss-of-function changes. The other variant was a coding change (c.846G&gt;A) that was predicted to be synonymous but had been demonstrated to disrupt mRNA splicing in a minigene assay. SEPSECS gene encodes O-phosphoseryl-tRNA(Sec) selenium transferase; an enzyme that  participates in the biosynthesis and transport of selenoproteins in the body. Variations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (PCHT 2D; OMIM #613811), a neurodegenerative condition characterized by progressive cerebrocerebellar atrophy, microcephaly, and epileptic encephalopathy. The identification of biallelic pathogenic variants in this family- one of which was a synonymous change not identified by prior clinical testing- not only ended the diagnostic odyssey for this family, but also highlights the contribution of occult pathogenic variants that may not be recognized by standard genetic testing methodologies.

molecular case studies

Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease.