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In 2015, biallelic <jats:italic>PRUNE1<\/jats:italic> loss\u2010of\u2010function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of <jats:italic>PRUNE1<\/jats:italic>\u2010related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous <jats:italic>PRUNE1<\/jats:italic> NM_021222.2:c.933G&gt;A synonymous variant identified in a 6\u2010year\u2010old boy with intellectual and developmental disabilities, hypotonia, and spastic diplegia, but with the absence of microcephaly, brain anomalies, or seizures. Fibroblast RNA sequencing revealed that the <jats:italic>PRUNE1<\/jats:italic> NM_021222.1:c.933G&gt;A variant resulted in an in\u2010frame skipping of the penultimate exon 7, removing 53 amino acids from an important protein domain. This case represents the first synonymous variant and the third pathogenic variant known to date affecting the DHH\u2010associated domain (DHHA2 domain). These findings extend the genotypic and phenotypic spectrums in <jats:italic>PRUNE1<\/jats:italic>\u2010related disorders and highlight the importance of considering synonymous splice site variants in atypical presentations.<\/jats:p>","DOI":"10.1002\/ajmg.a.62704","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T12:51:24Z","timestamp":1645620684000},"page":"1868-1874","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>PRUNE1<\/i> c.<scp>933G<\/scp>&gt;A synonymous variant induces exon 7 skipping, disrupts the <scp>DHHA2<\/scp> domain, and leads to an atypical <scp>NMIHBA<\/scp> syndrome presentation: Case report and review of the literature"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0620-2693","authenticated-orcid":false,"given":"Christina L.","family":"Magyar","sequence":"first","affiliation":[{"name":"Graduate Program in Genetics and Genomics Medical Scientist Training Program  Houston Texas USA"},{"name":"Medical Scientist Training Program Baylor College of Medicine  Houston Texas USA"},{"name":"Jan and Dan Duncan Neurological Research Institute  Houston Texas USA"},{"name":"McNair Medical Institute The Robert and Janice McNair Foundation  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Murdock","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5108-8861","authenticated-orcid":false,"given":"Lindsay C.","family":"Burrage","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongzheng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0707-657X","authenticated-orcid":false,"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Department of Ophthalmology Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuezhen","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section of Diabetes and Endocrinology Texas Children's Hospital, Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcela F.","family":"Astudillo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section of Diabetes and Endocrinology Texas Children's Hospital, Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill A.","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyssa A.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James B.","family":"Gibson","sequence":"additional","affiliation":[{"name":"Section of Metabolic Genetics Dell Children's Medical Group  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos A.","family":"Bacino","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas 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