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

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.

Fig. 1. Scheme of BCAP31 gene showing the LoF and missense variants identified in published patients and those of our study.

The variants identified in patients of our study are located above the gene, and those previously reported are underneath the gene. Reference transcript: NM_001139441.1. Exons are numbered according to Cacciagli et al. [7] and correspond to transcript ENST00000458587.8. Full splice variant denomination is NC_000023.11(NM_001139441.1):g.153723152C>T for P2 and P3; and NC_000023.11(NM_001139441.1):g.153702006C>T for P8.

Fig. 2. Scheme of BCAP31 and flanking genes, showing large deletions of BCAP31 identified in patients of this study and in the literature.

On the top, non-CADDS patients, with deletions including BCAP31 and adjacent genes in 5′ (excluding ABCD1). On the bottom, CADDS patients with deletions including BCAP31 and ABCD1. Reference transcript: NM_001139441.1. Exons are numbered according to Cacciagli et al. [7] and correspond to transcript ENST00000458587.8.

Fig. 3. Facial features of BCAP31 patients.

The males P6 and P9 have a LoF variant of BCAP31. P14 has a missense variant. P13 is a female with a LoF variant. There does not seem to be a specific facial gestalt for BCAP31 anomalies. Some common features have been noted with deep-set eyes, as P6 and P13, hypotonic face as seen in P6, P9, and P14, high nasal bridge for P6, high and narrow bridge for P9 and P13.

Fig. 4. Cerebral MRI of patients 1, 11, and 19.

(A) Patient 1 (LoF intragenic pathogenic variant). At 2 years old (A1: axial FLAIR, A2–A4: axial T2): signal hyperintensity in the peritrigonal white matter (see arrows in A1), small thalami (see arrows in A3), small cerebral peduncles (see arrows in A2), paired T2 hyperintensities in the dorsal pons (see arrows in A4). (B) Patient 11 (LoF intragenic pathogenic variant). At 8 months old (B1: sagittal T1, B2: axial FLAIR): markedly decreased white matter as evidenced by a thin corpus callosum (B1 and B2) as well as the sylvian fissures nearly abutting the lateral ventricles (see arrows in B2). (C) Patient 19 (deletion of BCAP31 and adjacent genes). At 6 months (C1: sagittal T1, C2: axial T2): decreased white matter, myelination delay, cortical atrophy, thin corpus callosum and ventricular dilatation. At 2 years old (C3: sagittal T2, C4: axial T2): increased white matter anomalies, marked cortical atrophy, vermian atrophy, and ventricular dilatation.