Case Report: De novo DDX3X mutation caused intellectual disability in a female with skewed X-chromosome inactivation on the mutant allele.
Case Report: De novo DDX3X mutation caused intellectual disability in a female with skewed X-chromosome inactivation on the mutant allele.
复制标题
病例报告：从头 DDX3X 突变导致突变等位基因上 X 染色体失活偏斜的女性智力障碍
DOI：
10.3389/fgene.2022.999442
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发表时间：
2022
影响因子：
3.7
通讯作者：
Dong, Minyue
中科院分区：
文献类型：
--
作者：
Sun, Yixi;Qian, Yangwen;Sun, Hai-Xi;Chen, Min;Luo, Yuqin;Xu, Xiaojing;Yan, Kai;Wang, Liya;Hu, Junjie;Dong, Minyue
关键词：
偏斜XCI在许多X连锁疾病的表型异质性中起重要作用，甚至涉及XCI逃逸基因引起的疾病。DDX 3X相关的智力残疾在女性中更常见，在男性中不太常见，他们通常从未受影响的杂合子母亲那里遗传。作为一个X失活（XCI）逃逸基因，偏斜XCI在DDX 3X突变雌性表型中的作用尚不清楚。在这里，我们报告了一个DDX 3X：基于通过PCR-sanger测序检测的SNP，在患有智力残疾的女性中，母体X染色体上的c.694_711dup18从头杂合突变。AR试验显示先证者的母体突变X染色体极度失活。使用RNA测序和全外显子组测序，我们定量了等位基因读段计数和等位基因特异性表达，并证实了突变X染色体是无活性的。进一步通过RNA测序和RT-PCR验证突变DDX 3X等位基因的表达水平较低，正常DDX 3X和突变DDX 3X的表达量分别占总数的70%和30%。总之，我们发现了一个有症状的女性与极端偏斜XCI的DDX 3X突变等位基因。发现突变等位基因中的XCI不足以逆转DDX 3X相关神经发育障碍的表型。这有助于更好地理解偏斜XCI在表型差异中的作用，这可以帮助遗传咨询和产前诊断DDX 3X缺陷的女性疾病。
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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影响因子：
16.2
作者：
Lennox, Ashley L.;Hoye, Mariah L.;Sherr, Elliott H.
通讯作者：
Sherr, Elliott H.
影响因子：
6.2
作者：
Tang L;Levy T;Guillory S;Halpern D;Zweifach J;Giserman-Kiss I;Foss-Feig JH;Frank Y;Lozano R;Belani P;Layton C;Lerman B;Frowner E;Breen MS;De Rubeis S;Kostic A;Kolevzon A;Buxbaum JD;Siper PM;Grice DE
通讯作者：
Grice DE
DOI：
10.1073/pnas.1806811115
发表时间：
2018-12-18
影响因子：
11.1
作者：
Garieri, Marco;Stamoulis, Georgios;Antonarakis, Stylianos E.
通讯作者：
Antonarakis, Stylianos E.
影响因子：
4.8
作者：
Dai Y;Yang Z;Guo J;Li H;Gong J;Xie Y;Xiao B;Wang H;Long L
通讯作者：
Long L
影响因子：
11.8
作者：
Werner, Jonathan M.;Ballouz, Sara;Hover, John;Gillis, Jesse
通讯作者：
Gillis, Jesse