Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-24 Print Date: 2022-02-01 DOI:10.1101/mcs.a006180
Jesse M Hunter, Lauren J Massingham, Kandamurugu Manickam, Dennis Bartholomew, Rachel K Williamson, Jennifer L Schwab, Mohammad Marhabaie, Amy Siemon, Emily de Los Reyes, Shalini C Reshmi, Catherine E Cottrell, Richard K Wilson, Daniel C Koboldt
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引用次数: 7

Abstract

Alterations in the TAOK1 gene have recently emerged as the cause of developmental delay with or without intellectual impairment or behavioral abnormalities (MIM # 619575). The 32 cases currently described in the literature have predominantly de novo alterations in TAOK1 and a wide spectrum of neurodevelopmental abnormalities. Here, we report four patients with novel pathogenic TAOK1 variants identified by research genome sequencing, clinical exome sequencing, and international matchmaking. The overlapping clinical features of our patients are consistent with the emerging core phenotype of TAOK1-associated syndrome: facial dysmorphism, feeding difficulties, global developmental delay, joint laxity, and hypotonia. However, behavioral abnormalities and gastrointestinal issues are more common in our cohort than previously reported. Two patients have de novo TAOK1 variants (one missense, one splice site) consistent with most known alterations in this gene. However, we also report the first sibling pair who both inherited a TAOK1 frameshift variant from a mildly affected mother. Our findings suggest that incomplete penetrance and variable expressivity are relatively common in TAOK1-associated syndrome, which holds important implications for clinical genetic testing.

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遗传和新生变异扩展了taok1相关神经发育障碍的病因学。
最近发现,TAOK1基因的改变是有或没有智力障碍或行为异常的发育迟缓的原因(MIM # 619575)。目前文献中描述的32例病例主要是TAOK1的新生改变和广泛的神经发育异常。在这里,我们报告了4例通过研究基因组测序、临床外显子组测序和国际配对确定的新型致病性TAOK1变异患者。我们患者的重叠临床特征与taok1相关综合征的新兴核心表型一致:面部畸形、喂养困难、整体发育迟缓、关节松弛和张力低下。然而,行为异常和胃肠道问题在我们的队列中比以前报道的更常见。两名患者有新的TAOK1变异(一个错义,一个剪接位点),与该基因的大多数已知变异一致。然而,我们也报道了第一对兄弟姐妹都从轻度患病的母亲那里遗传了TAOK1移码变异。我们的研究结果表明,不完全外显性和可变表达性在taok1相关综合征中相对常见,这对临床基因检测具有重要意义。
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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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