4.6 Article

Case Report: De novo DDX3X mutation caused intellectual disability in a female with skewed X-chromosome inactivation on the mutant allele

Journal

FRONTIERS IN GENETICS
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2022.999442

Keywords

DDX3X; skewed X-chromosome inactivation (XCI); intellectual disability; escaping X-chromosome inactivation (XCI); RNA sequencing

Funding

  1. National Natural Science Foundation of China [81801441, 81901382]
  2. Ministry and the Province of Zhejiang Medical and Health Science and Technology Project [WKJ-ZJ-2127]
  3. Key Research and Development Program of the Zhejiang Province [2019C03025]
  4. Medical Health Science and Technology Project of Zhejiang Provincial Health Commission [2021KY772]
  5. Public Welfare Technology Research Program of Zhejiang Province [LGC20H200003]

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In females with DDX3X-related intellectual disability, extreme skewing of XCI in the mutant allele was found, which was insufficient to reverse the phenotype of neurodevelopmental disorders related to DDX3X defects.
Skewed XCI plays an important role in the phenotypic heterogeneities of many X-linked disorders, even involving in diseases caused by XCI-escaping genes. DDX3X-related intellectual disability is more common in females and less common in males, who usually inherit from unaffected heterozygous mothers. As an X inactivation (XCI) escaping gene, the role of skewed XCI in the phenotype of DDX3X mutant female is unknown. Here we reported a DDX3X: c.694_711dup18 de novo heterozygous mutation in a female with intellectual disability on the maternal X chromosome on the basis of SNPs detected by PCR-sanger sequencing. AR assay revealed that the maternal mutant X chromosome was extremely inactivated in the proband. Using RNA sequencing and whole-exome sequencing, we quantified allelic read counts and allele-specific expression, and confirmed that the mutant X chromosome was inactive. Further, we verified that the mutant DDX3X allele had a lower expression level by RNA sequencing and RT-PCR, and the normal and mutated DDX3X expression accounted for respectively 70% and 30% of total. In conclusion, we found a symptomatic female with extreme skewing XCI in the DDX3X mutant allele. It was discovered that XCI in the mutant allele was insufficient to reverse the phenotype of DDX3X-related neurodevelopmental disorder. It contributed to a better understanding of the role of skewed XCI in phenotypic differences, which can aid in the genetic counseling and prenatal diagnosis of disorders in females with DDX3X defects.

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