Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY Human Genetics Pub Date : 2024-02-01 DOI:10.1007/s00439-023-02636-z
Ashraf Yahia, Danyang Li, Sanna Lejerkrans, Shyam Rajagopalan, Nelli Kalnak, Kristiina Tammimies
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Abstract

Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.

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对瑞典严重发育性语言障碍患者进行全外显子组测序和多基因评估。
发育性语言障碍(DLD)与其他神经发育障碍(NDD)在临床、遗传和病理上都有重叠,证实了 NDD 连续体的概念。目前还缺乏了解 DLD 患者整个遗传谱的研究。此前,我们从59个家庭中招募了61名重度DLD患者,并使用芯片基因分型技术对其中59人及其家庭进行了检查,诊断率为6.8%。在此,我们使用全外显子组测序(WES)对其中的 53 名疑似患者进行了研究。此外,我们还利用多基因风险评分(PRS)来了解神经发育障碍在家族内的富集情况,并研究了探究者的语言相关测试结果与语言相关风险评分之间的关联。我们在四名受试者中发现了具有临床意义的变异,分子诊断率为 7.5%(4/53)。这些变异位于 PAK2、MED13、PLCB4 和 TNRC6B 中。我们还优先选择了其他变异,包括 PARD3 和 DIP2C 中的高影响变异,以便在未来研究它们在 DLD 中的作用。PRS并不能解释这些家族中神经发育障碍的聚集现象。我们没有发现语言相关测试与语言相关 PRS 之间存在明显关联。我们的研究结果支持将 WES 作为 DLD 的一级基因检测,因为它能识别单基因 DLD 形态。需要对 DLD 进行大规模测序研究,以确定新的基因并调查多基因对该疾病的影响。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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