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 the BCAP31 gene 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‐type BCAP31 messenger RNA (mRNA) but the presence of two novel BCAP31 mRNAs. 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 mutated BCAP31 gene 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 in BCAP31‐related syndrome resulted from skewed X‐inactivation and a de novo mutation in the active X chromosome.

中文翻译：

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BCAP31 相关综合征女孩的从头突变和偏态 X 失活。

对一名患有耳聋、肌张力障碍、中枢性髓鞘发育不全、难治性癫痫发作和波动性肝功能损害的年轻女孩进行全基因组分析，发现染色体 Xq28 上的BCAP31基因有一个杂合的从头变异（NM_001256447.2:c.92G>A），突变其中导致X连锁隐性重度神经障碍性耳聋、肌张力障碍和脑髓鞘发育不全。患者白细胞的逆转录聚合酶链反应显示不存在野生型BCAP31信使 RNA (mRNA)，但存在两种新的BCAP31mRNA。主要的可变剪接 mRNA 是由于外显子 2 的跳跃和外显子 3 中新起始位点的利用导致移码和截短的转录本，而次要的新 mRNA 在外显子 2 中插入了 110 个核苷酸。 novo 变异出现在父系 X 染色体中。进行了 X 染色体失活测定并确认患者的母体 X 染色体优先失活，提供了突变BCAP31基因是主要表达的证据。根据美国医学遗传学和基因组学指南，这种变异被认为是“致病的”（PS2、PS3、PM2、PP3 和 PP4）并且是有害的。这是BCAP31报告的首例女性患者相关综合征是由歪斜的 X 失活和活性 X 染色体的从头突变引起的。