De novo mutation and skewed X-inactivation in girl withBCAP31-related syndrome

Full genome analysis of a young girl with deafness, dystonia, central hypomyelination, refractory seizure, and fluctuating liver function impairment revealed a heterozygous, de novo variant in theBCAP31gene on chromosome Xq28 (NM_001256447.2:c.92G>A), mutations of which caused the X-linked recessive severe neurologic disorder deafness, dystonia, and cerebral hypomyelination. Reverse transcription-polymerase chain reaction of the patient's white blood cells showed the absence of wild-typeBCAP31messenger RNA (mRNA) but the presence of two novelBCAP31mRNAs. The major alternatively spliced mRNA is due to Exon 2 skipping and the utilization of a new initiation site in Exon 3 that leads to a frameshift and truncated transcript while the minor novel mRNA has a 110 nucleotide insertion to Exon 2. Phasing studies showed that the de novo variant arose in the paternal X chromosome. X chromosome inactivation assay was done and confirmed that the patient's maternal X chromosome was preferentially inactivated, providing evidence that the mutatedBCAP31gene was the one predominantly expressed. According to the American College of Medical Genetics and Genomics guideline, this variant is deemed pathogenic (PS2, PS3, PM2, PP3, and PP4) and deleterious. This is the first reported female patient inBCAP31-related syndrome resulted from skewed X-inactivation and a de novo mutation in the active X chromosome.