{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T12:45:25Z","timestamp":1742388325282,"version":"3.37.3"},"reference-count":0,"publisher":"Cold Spring Harbor Laboratory","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"abstract":"<jats:p>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. \nSEPSECS 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.<\/jats:p>","DOI":"10.1101\/mcs.a006165","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T23:00:25Z","timestamp":1643410825000},"page":"mcs.a006165","source":"Crossref","is-referenced-by-count":1,"title":["Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease."],"prefix":"10.1101","author":[{"given":"Swetha","family":"Ramadesikan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott E","family":"Hickey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"De Los Reyes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9313-1541","authenticated-orcid":false,"given":"Anup D","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel J","family":"Franklin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Brennan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin","family":"Crist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristy","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5218-5903","authenticated-orcid":false,"given":"Peter","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim L","family":"McBride","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel C","family":"Koboldt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard K","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"246","published-online":{"date-parts":[[2022,1,28]]},"container-title":["Molecular Case Studies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/mcs.a006165","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T23:00:26Z","timestamp":1643410826000},"score":1,"resource":{"primary":{"URL":"http:\/\/molecularcasestudies.cshlp.org\/lookup\/doi\/10.1101\/mcs.a006165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,28]]},"references-count":0,"alternative-id":["10.1101\/mcs.a006165"],"URL":"https:\/\/doi.org\/10.1101\/mcs.a006165","relation":{},"ISSN":["2373-2865","2373-2873"],"issn-type":[{"type":"print","value":"2373-2865"},{"type":"electronic","value":"2373-2873"}],"subject":[],"published":{"date-parts":[[2022,1,28]]}}}