Clinical case report: mosaic ANK3 pathogenic variant in a patient with autism spectrum disorder and neurodevelopmental delay.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2023-06-01 DOI:10.1101/mcs.a006233
Xiaolan Fang, Timothy Fee, Jessica Davis, Elliot S Stolerman, Raymond C Caylor
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Abstract

Ankyrins are a family of proteins that link integral membrane proteins to the underlying spectrin-actin cytoskeleton and play a key role in activities such as cell motility, activation, proliferation, cell-cell contact, and the maintenance of specialized membrane domains. Ankyrin 3 (ANK3) is one of the three major subtypes of the ankyrin protein family. Ankryin genes are ubiquitously expressed, but their expression is highest in the brain. In the central nervous system, ankyrins have critical roles at the axonal initial segment, the nodes of Ranvier, and at synapses. To date, pathogenic variants in ANK3 have been reported in individuals with neuropsychiatric, cognitive, and neurodevelopmental disorders. The clinical severity is variable in these individuals with both autosomal recessive and autosomal dominant patterns of inheritance observed. These findings have suggested genotype-phenotype correlations and even isoform-specific implications for individuals with ANK3 pathogenic variants. Here, we report a patient with speech delay, autism spectrum disorder, and a language disorder in which a de novo nonsense ANK3 alteration was discovered by exome sequencing. Interestingly, the next-generation sequencing data suggested the change was mosaic in the affected child, and it was confirmed by digital polymerase chain reaction (dPCR) at 22% allelic fraction. To our knowledge, this is the first case of an individual with a pathogenic mosaic ANK3 variant. This finding expands upon the existing genotype-phenotype information available for the ANK3 gene while also highlighting potential gene expression correlations with phenotype.

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临床病例报告:马赛克ANK3致病性变异在自闭症谱系障碍和神经发育迟缓患者。
锚定蛋白是一个将整体膜蛋白与潜在的谱蛋白-肌动蛋白细胞骨架连接起来的蛋白家族,在细胞运动、激活、增殖、细胞-细胞接触和特殊膜结构域的维持等活动中发挥关键作用。锚蛋白3 (ANK3)是锚蛋白家族的三个主要亚型之一。Ankryin基因无处不在,但在大脑中表达最多。在中枢神经系统中,锚定蛋白在轴突初始节段、Ranvier节点和突触中起关键作用。迄今为止,ANK3致病性变异已在神经精神、认知和神经发育障碍患者中报道。这些个体的临床严重程度是可变的,有常染色体隐性遗传和常染色体显性遗传。这些发现提示了基因型-表型相关性,甚至与ANK3致病变异个体的异构体特异性相关。在这里,我们报告了一位患有语言延迟,自闭症谱系障碍和语言障碍的患者,其中通过外显子组测序发现了从头无意义的ANK3改变。有趣的是,下一代测序数据表明,这种变化在受影响的儿童中是镶嵌的,并通过数字聚合酶链反应(dPCR)在22%的等位基因部分得到证实。据我们所知,这是第一例具有致病性马赛克ANK3变异的个体病例。这一发现扩展了现有的ANK3基因的基因型-表型信息,同时也强调了潜在的基因表达与表型的相关性。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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