Introduction
Developmental delay and congenital neurologic disorder are rare conditions caused by gene mutations that are hard to identify due to phenotypic and genetic heterogeneity. While whole exome sequencing (WES) has been successful in identifying some causal mutations, most cases remain unsolved. Since 2012, multiple groups have reported that males with hemizygous defect in BCAP31 gene on Xq28 involving splicing site mutations, nonsense or small indels result in severe phenotypes such as Deafness, Dystonia, And Cerebral Hypomyelination (DDCH, OMIM#300475) or contiguous ABCD1/DXS1375E deletion syndrome (CADDS) (Albanyan, Al Teneiji, Monfared, & Mercimek-Mahmutoglu, 2017; Cacciagli et al., 2013; Rinaldi, Van Hoof, Corveleyn, Van Cauter, & de Ravel, 2020; Shimizu et al., 2020; Vittal, Hall, & Berry-Kravis, 2015; Vittal, Hall, Dames, Mao, & Berry-Kravis, 2016; Whalen et al., 2019). These phenotypes are also found with microdeletions betweenSLC6A8 and ABCD1 or partial deletion ofSLC6A8 -BCAP31 (Calhoun & Raymond, 2014; Osaka et al., 2012; van de Kamp et al., 2015). BCAP31 encodes B-cell receptor-associated protein 31, with ubiquitous expression and is abundant in endoplasmic reticulum (ER) membrane. BCAP31 is found to be involved in the anterograde transport of ER-to-Golgi exchanges, in ER associated-degradation (ERAD) and in caspase 8-mediated apoptosis (Annaert, Becker, Kistner, Reth, & Jahn, 1997; Nguyen, Breckenridge, Ducret, & Shore, 2000; Wakana et al., 2008).
Among the reported cases involving BCAP31 mutations, only one derived from a de novo mutation (Rinaldi et al., 2020). Most male patients inherited mutated chromosome X (chrX) from non-symptomatic carrier mothers; however, in two of the reported cases, the patients’ mothers presented mild features. In addition, one heterozygous mother has bilateral sensorineural hearing loss (Albanyan et al., 2017), and another heterozygous mother has similar facial features to her two affected sons, such as long face and ocular hypotelorism, but no neurological or cognitive symptoms (Vittal et al., 2016).
Female carriers of X-linked disorders such as DDCH are normally not affected because they carry a normal copy of the gene. However, to compensate for the dosage effect of different X chromosome numbers in male (XY) and female (XX), X chromosome inactivation (XCI) happens in female cells (Minks, Robinson, & Brown, 2008). XCI is an epigenetic remodeling through random methylation of each parental chromosome at the 8–16 cell stage (Amos-Landgraf et al., 2006; Shvetsova et al., 2019; van den Berg et al., 2009). Once XCI is established in each cell, the imprinting XCI pattern is stably penetrated to the divided cells. Individuals who have balanced inactivation between paternal and maternal X chromosomes present 50:50 XCI in cell pools. However, some individuals are found to have an unbalanced XCI ratio, resulting in skewed XCI, commonly defined as a ratio of inactivation to activation >70%, with preferential inactivation of one parental X chromosome. Theoretically, a female carrying a mutation in gene associated with an X-linked recessive disorder will be symptomatic if she has skewed XCI in which the X chromosome with the wild-type allele is preferentially inactivated.
In this report, we present evidence that the molecular defect of a young girl with deafness, dystonia, central hypomyelination, refractory seizure, and fluctuating liver function abnormalities is due to ade novo variant in BCAP31 arose in her paternal X chromosome and skewed X-inactivation of her maternal X chromosome. This is the first report of a female patient of BCAP31-related syndrome due to a pathogenic mutation in BCAP31 in the context of skewed X-inactivation.