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.