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

Sandra Whalen 1 Marie Shaw 2 Cyril Mignot 3 Delphine Héron 3 Sandra Chantot Bastaraud 4 Cecile Cieuta Walti 5 Jan Liebelt 6 Frances Elmslie 7 Patrick Yap 8 Jane Hurst 9 Elisabeth Forsythe 9 Brian Kirmse 10 Jillian Ozmore 11 Alessandro Mauro Spinelli 12 Olga Calabrese 12 Thierry Billette de Villemeur 4 Anne Claude Tabet 13 Jonathan Levy 13 Agnes Guet 14 Manoëlle Kossorotoff 15 Benjamin Kamien 16 Jenny Morton 17 Anne Mccabe 17 Elise Brischoux-Boucher 18 Annick Raas-Rothschild 19 Antonella Pini 20 Renée Carroll 2 Jessica Hartley 21 Patrick Frosk 21 Anne Slavotinek 22 Kristen Truxal 23 Carroll Jennifer 23 Annelies Dheedene 24 Hong Cui 25 Vishal Kumar 22 Glen Thomson 26 Florence Riccardi 27 Jozef Gecz 2 Laurent Villard 27 
Abstract : The 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.
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Submitted on : Thursday, February 25, 2021 - 9:03:52 AM
Last modification on : Wednesday, May 11, 2022 - 12:49:15 PM
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Sandra Whalen, Marie Shaw, Cyril Mignot, Delphine Héron, Sandra Chantot Bastaraud, et al.. Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants. European Journal of Human Genetics, Nature Publishing Group, 2021, ⟨10.1038/s41431-021-00821-0⟩. ⟨hal-03149040⟩



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