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De novo mutation and skewed X-inactivation in girl with BCAP31-related syndrome
  • +7
  • Hsiao-Jung Kao,
  • Hung-Lun Chiang,
  • Hsiao-Huei Chen,
  • Pi-Chuang Fan,
  • Yi-Fang Tu,
  • Yen-Yin Chou,
  • Wuh-Liang Hwu,
  • Chien-Ling Lin,
  • Pui-Yan Kwok,
  • Ni-Chung Lee
Hsiao-Jung Kao
Academia Sinica
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Hung-Lun Chiang
Academia Sinica
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Hsiao-Huei Chen
Academia Sinica
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Pi-Chuang Fan
National Taiwan University Hospital
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Yi-Fang Tu
National Cheng Kung University Hospital
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Yen-Yin Chou
National Cheng Kung University Hospital
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Wuh-Liang Hwu
National Taiwan University Hospital
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Chien-Ling Lin
Academia Sinica
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Pui-Yan Kwok
Academia Sinica
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Ni-Chung Lee
National Taiwan University Hospital
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Peer review status:ACCEPTED

05 May 2020Submitted to Human Mutation
06 May 2020Submission Checks Completed
06 May 2020Assigned to Editor
09 May 2020Reviewer(s) Assigned
24 May 2020Review(s) Completed, Editorial Evaluation Pending
25 Jun 2020Editorial Decision: Revise Minor
01 Jul 20201st Revision Received
03 Jul 2020Submission Checks Completed
03 Jul 2020Assigned to Editor
03 Jul 2020Review(s) Completed, Editorial Evaluation Pending
09 Jul 2020Editorial Decision: Accept

Abstract

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 X28q (NC_000023.11(BCAP31_v001):c.92G>A), mutations of which caused the X-linked recessive severe neurologic disorder DDCH (Deafness, Dystonia, and Cerebral Hypomyelination, OMIM#300475). Reverse transcription-PCR (RT-PCR) of the patient’s white blood cells showed the absence of wild-type BCAP31 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 predominantly expressed. According to the ACMG guideline, this variant is deemed “pathogenic” (PS2, PS3, PM2, PP3, 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.