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


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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Fig. 1: Scheme of BCAP31 gene showing the LoF and missense variants identified in published patients and those of our study.
Fig. 2: Scheme of BCAP31 and flanking genes, showing large deletions of BCAP31 identified in patients of this study and in the literature.
Fig. 3: Facial features of BCAP31 patients.
Fig. 4: Cerebral MRI of patients 1, 11, and 19.


  1. 1.

    Manley HA, Lennon VA. Endoplasmic reticulum membrane-sorting protein of lymphocytes (BAP31) is highly expressed in neurons and discrete endocrine cells. J Histochem Cytochem J Histochem Soc. 2001;49:1235–43.

    CAS  Article  Google Scholar 

  2. 2.

    Bell AW, Ward MA, Blackstock WP, Freeman HN, Choudhary JS, Lewis AP, et al. Proteomics characterization of abundant Golgi membrane proteins. J Biol Chem. 2001;276:5152–65.

    CAS  Article  Google Scholar 

  3. 3.

    Annaert WG, Becker B, Kistner U, Reth M, Jahn R. Export of cellubrevin from the endoplasmic reticulum is controlled by BAP31. J Cell Biol. 1997;139:1397–410.

    CAS  Article  Google Scholar 

  4. 4.

    Paquet M-E, Cohen-Doyle M, Shore GC, Williams DB. Bap29/31 influences the intracellular traffic of MHC class I molecules. J Immunol. 2004;172:7548–55.

    CAS  Article  Google Scholar 

  5. 5.

    Geiger R, Andritschke D, Friebe S, Herzog F, Luisoni S, Heger T, et al. BAP31 and BiP are essential for dislocation of SV40 from the endoplasmic reticulum to the cytosol. Nat Cell Biol. 2011;13:1305–14.

    CAS  Article  Google Scholar 

  6. 6.

    Wakana Y, Takai S, Nakajima K, Tani K, Yamamoto A, Watson P, et al. Bap31 is an itinerant protein that moves between the peripheral endoplasmic reticulum (ER) and a Juxtanuclear compartment related to ER-associated degradation. Mol Biol Cell. 2008;19:1825–36.

    CAS  Article  Google Scholar 

  7. 7.

    Cacciagli P, Sutera-Sardo J, Borges-Correia A, Roux J-C, Dorboz I, Desvignes J-P, et al. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus. Am J Hum Genet. 2013;93:579–86.

    CAS  Article  Google Scholar 

  8. 8.

    Roboti P, Swanton E, High S. Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein. J Cell Sci. 2009;122:3942–53.

    CAS  Article  Google Scholar 

  9. 9.

    Albanyan S, Al Teneiji A, Monfared N, Mercimek-Mahmutoglu S. BCAP31-associated encephalopathy and complex movement disorder mimicking mitochondrial encephalopathy. Am J Med Genet A. 2017;173:1640–3.

    CAS  Article  Google Scholar 

  10. 10.

    Rinaldi B, Van Hoof E, Corveleyn A, Van Cauter A, de Ravel T. BCAP31-related syndrome: the first de novo report. Eur J Med Genet. 2019;63:103732.

    Article  Google Scholar 

  11. 11.

    Shimizu K, Oba D, Nambu R, Tanaka M, Oguma E, Murayama K, et al. Possible mitochondrial dysfunction in a patient with deafness, dystonia, and cerebral hypomyelination (DDCH) due to BCAP31 Mutation. Mol Genet Genom Med. 2020;8:e1129.

    CAS  Google Scholar 

  12. 12.

    Vittal P, Hall DA, Dames S, Mao R, Berry-Kravis E. BCAP31 mutation causing a syndrome of congenital dystonia, facial dysorphism and central hypomyelination discovered using exome sequencing. Mov Disord Clin Pract. 2016;3:197–9.

    Article  Google Scholar 

  13. 13.

    Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51.

    Article  Google Scholar 

  14. 14.

    van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, Grünewald S, Anselm I, et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet. 2013;50:463–72.

    Article  Google Scholar 

  15. 15.

    Corzo D, Gibson W, Johnson K, Mitchell G, LePage G, Cox GF, et al. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002;70:1520–31.

    CAS  Article  Google Scholar 

  16. 16.

    Calhoun ARUL, Raymond GV. Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature. Am J Med Genet A. 2014;164A:2613–7.

    Article  Google Scholar 

  17. 17.

    Iwasa M, Yamagata T, Mizuguchi M, Itoh M, Matsumoto A, Hironaka M, et al. Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathol J Jpn Soc Neuropathol. 2013;33:292–8.

    CAS  Article  Google Scholar 

  18. 18.

    Osaka H, Takagi A, Tsuyusaki Y, Wada T, Iai M, Yamashita S, et al. Contiguous deletion of SLC6A8 and BAP31 in a patient with severe dystonia and sensorineural deafness. Mol Genet Metab. 2012;106:43–7.

    CAS  Article  Google Scholar 

  19. 19.

    van de Kamp JM, Errami A, Howidi M, Anselm I, Winter S, Phalin-Roque J, et al. Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clin Genet. 2015;87:141–7.

    Article  Google Scholar 

  20. 20.

    Firouzabadi SG, Kariminejad R, Vameghi R, Darvish H, Ghaedi H, Banihashemi S, et al. Copy number variants in patients with autism and additional clinical features: report of VIPR2 duplication and a novel microduplication syndrome. Mol Neurobiol. 2017;54:7019–27.

    CAS  Article  Google Scholar 

  21. 21.

    Anselm IM, Alkuraya FS, Salomons GS, Jakobs C, Fulton AB, Mazumdar M, et al. X-linked creatine transporter defect: A report on two unrelated boys with a severe clinical phenotype. J Inherit Metab Dis. 2006;29:214–9.

    CAS  Article  Google Scholar 

  22. 22.

    Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho Y-Y, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med J Am Coll Med Genet. 2017;19:1105–17.

    Google Scholar 

  23. 23.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med J Am Coll Med Genet. 2015;17:405–24.

    Google Scholar 

  24. 24.

    Rosenberg C, Freitas ÉL, Uehara DT, Auricchio MTBM, Costa SS, Oiticica J, et al. Genomic copy number alterations in non-syndromic hearing loss. Clin Genet. 2016;89:473–7.

    CAS  Article  Google Scholar 

  25. 25.

    Alford RL, Arnos KS, Fox M, Lin JW, Palmer CG, Pandya A, et al. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med J Am Coll Med Genet. 2014;16:347–55.

    Google Scholar 

  26. 26.

    Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018;39:1593–613.

    Article  Google Scholar 

  27. 27.

    Wu Z, Yang F, Jiang S, Sun X, Xu J. Induction of liver steatosis in BAP31-deficient mice burdened with tunicamycin-induced endoplasmic reticulum stress. Int J Mol Sci. 2018;19:2291.

    Article  Google Scholar 

  28. 28.

    Xu J-L, Li L-Y, Wang Y-Q, Li Y-Q, Shan M, Sun S-Z, et al. Hepatocyte-specific deletion of BAP31 promotes SREBP1C activation, promotes hepatic lipid accumulation, and worsens IR in mice. J Lipid Res. 2018;59:35–47.

    CAS  Article  Google Scholar 

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HC is an employee of GeneDx, Inc. JG was supported by NHMRC Grants APP1155224 and APP1091593 and Channel 7 Children’s Research Foundation. AS’s research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number U01HG009599. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Amendola et. al. American Journal of Human Genetics. 2018 Sep 6;103(3):319–327. doi: 10.1016/j.ajhg.2018.08.007.

Care4Rare Canada Consortium

Kym Boycott34, Michael Brudno35, Francois Bernier36, Clara van Karnebeek37, David Dyment38, Kristin Kernohan39, Micheil Innes36, Ryan Lamont36, Jillian Parboosingh36, Deborah Marshall36, Christian Marshall35, Roberto Mendoza35, James Dowling35, Robin Hayeems35, Bartha Knoppers40, Anna Lehman37, Sara Mostafavi37

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Correspondence to Sandra Whalen.

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Whalen, S., Shaw, M., Mignot, C. et al. Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants. Eur J Hum Genet (2021).

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