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Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants

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dc.contributor.authorWhalen, S.
dc.contributor.authorShaw, M.
dc.contributor.authorMignot, C.
dc.contributor.authorHéron, D.
dc.contributor.authorBastaraud, S.C.
dc.contributor.authorWalti, C.C.
dc.contributor.authorLiebelt, J.
dc.contributor.authorElmslie, F.
dc.contributor.authorYap, P.
dc.contributor.authorHurst, J.
dc.contributor.authorForsythe, E.
dc.contributor.authorKirmse, B.
dc.contributor.authorOzmore, J.
dc.contributor.authorSpinelli, A.M.
dc.contributor.authorCalabrese, O.
dc.contributor.authorde Villemeur, T.B.
dc.contributor.authorTabet, A.C.
dc.contributor.authorLevy, J.
dc.contributor.authorGuet, A.
dc.contributor.authorKossorotoff, M.
dc.contributor.authoret al.
dc.date.issued2021
dc.descriptionPublished Online : 18 February 2021
dc.description.abstractThe BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.
dc.description.statementofresponsibilitySandra Whalen, Marie Shaw, Cyril Mignot, Delphine Héron, Sandra Chantot Bastaraud, Cecile Cieuta Walti ... et al.
dc.identifier.citationEuropean Journal of Human Genetics, 2021; 29(9):1405-1417
dc.identifier.doi10.1038/s41431-021-00821-0
dc.identifier.issn1018-4813
dc.identifier.issn1476-5438
dc.identifier.orcidShaw, M. [0000-0002-5060-190X]
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/130505
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1091593
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1155224
dc.rights© The Author(s), under exclusive licence to European Society of Human Genetics 2021
dc.source.urihttps://doi.org/10.1038/s41431-021-00821-0
dc.subjectCare4Rare Canada Consortium
dc.subjectHumans
dc.subjectDeafness
dc.subjectHereditary Central Nervous System Demyelinating Diseases
dc.subjectSyndrome
dc.subjectMembrane Proteins
dc.subjectPedigree
dc.subjectPhenotype
dc.subjectMutation, Missense
dc.subjectAdolescent
dc.subjectAdult
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectFemale
dc.subjectMale
dc.subjectIntellectual Disability
dc.subjectLoss of Function Mutation
dc.titleFurther delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants
dc.typeJournal article
pubs.publication-statusPublished

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