正在进行临床外显子组测序的儿童和青少年中与运动语言表型相关的单基因疾病。

IF 6.2 1区医学 Q1 GENETICS & HEREDITY

Genetics in Medicine Pub Date : 2025-04-01 Epub Date: 2025-02-07 DOI:10.1016/j.gim.2025.101374

Marissa W. Mitchel , Matthew Oetjens , Alexander S.F. Berry , Alicia Johns , Andrés Moreno-De-Luca , Rebecca I. Torene , Natasha T. Strande , Marina T. DiStefano , Lindsay Havens Dyer , Tracy Brandt , Brenda M. Finucane , David H. Ledbetter , Kyle Retterer , Christa L. Martin , Scott M. Myers

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引用次数: 0

摘要

目的：以往研究儿童运动语言障碍（MSDs）的遗传结构受到样本量小和专注于失用症的限制。我们旨在通过外显子组测序（ES）在大量儿科人群中鉴定与msd相关的致病性基因组变异。方法：我们选取了2012-2022年间出现临床ES的MSDs患儿。致病/可能致病（P/LP）的比率被认为是MSD表型的病因，由性别和神经发育合并症决定和描述。基于基因的负荷测试比较了MSD病例中每个基因P/LP变异率与临床ES队列的比较。结果：2004例MSDs患者中有527例（26.3%）检测出阳性诊断结果，女性和有神经发育合并症的个体诊断率更高。在262个基因中检测到P/LP序列变异。基于基因的病例负担分析显示，名义上有30个基因与msd相关，其中两个基因（SETBP1和ADCY5）在全外显子组校正后存活下来。结论：超过25%的MSDs患者在262个基因中发现P/LP变异，其中许多基因以前与MSDs无关。潜在的临床意义包括对诊断为单基因致畸的儿童早期实施强化语言治疗。

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Monogenic disorders associated with motor speech phenotypes in children and adolescents undergoing clinical exome sequencing

Purpose

Prior studies investigating the genetic architecture of pediatric motor speech disorders (MSDs) have been limited by small sample sizes and an exclusive focus on apraxia. We aimed to identify pathogenic genomic variants associated with MSDs in a large pediatric population referred for exome sequencing (ES).

Methods

We identified pediatric patients with MSDs who had clinical ES between 2012 and 2022. The rate of pathogenic/likely pathogenic (P/LP) findings considered causative of the MSD phenotype was determined and delineated by sex and neurodevelopmental comorbidity. Gene-based burden testing compared the rate of P/LP variants in each gene in MSD cases with a comparison clinical ES cohort.

Results

Positive diagnostic results were detected in 527 of 2004 (26.3%) patients with MSDs, with higher diagnostic rates in females and individuals with neurodevelopmental comorbidities. P/LP sequence variants were detected in 262 genes. Gene-based case-referent burden analysis revealed that 30 genes were nominally associated with MSDs, 2 of which (SETBP1 and ADCY5) survived exome-wide correction.

Conclusion

Over 25% of patients with MSDs were found to harbor P/LP variants in 262 genes, many of which have not previously been associated with MSDs. Potential clinical implications include early implementation of intensive speech therapy for children diagnosed with monogenic causes of MSDs.

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来源期刊

Genetics in Medicine 医学-遗传学

CiteScore

15.20

自引率

6.80%

发文量

857

审稿时长

1.3 weeks

期刊介绍： Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health. GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.