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 7 families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called DDCH syndrome (Deafness, Dystonia and Cerebral Hypomyelination). 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 2 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.

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review

“…5,8 Our proband's phenotype is consistent with previous reports, where most individuals presented in early infancy with hepatic cholestasis, severe growth failure, profound hypotonia, developmental delay and elevated VLCFAs (Table 2). [5][6][7][8][9] SNHL occurred in 6/8, while cerebral hypomyelination and white matter changes were described in 5/9. Early death in hemizygous males (3-16 months) is common, although a symptomatic 3-year-old girl with CADDS is the longest surviving individual reported.…”

“…at 16 months, 9 and overall, death from respiratory causes is reported in 50% of males with CADDS. 5,6 Pancreatic insufficiency and interstitial lung disease are therefore possible extensions to the CADDS phenotype (Figure 1B).…”

“…Since then, a further six patients with a similar phenotype and variable deletions involving these contiguous genes have been reported, including one symptomatic girl. [6][7][8][9] As in DDCH, severe developmental delay, dystonia, deafness, and white matter abnormalities are commonly reported, while the presence of raised VLCFA is like that seen in isolated ABCD1 defects. However, unlike either DDCH or X-ALD, CADDS affected males have persistent cholestatic liver disease and commonly die in infancy.…”

“…However, unlike either DDCH or X-ALD, CADDS affected males have persistent cholestatic liver disease and commonly die in infancy. [5][6][7][8][9] Here, we describe a severely affected male infant with CADDS who was diagnosed through ultra-rapid whole genome sequencing (WGS). We summarise the clinical and biochemical findings from all previously published cases of CADDS, while also suggesting that pancreatic insufficiency and interstitial lung disease may represent extensions to the phenotype.…”

Complex Diagnostics of Non-Specific Intellectual Developmental Disorder

“…The following supporting information can be downloaded at: . See [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ].…”