Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort

IF 6.6 1区医学 Q1 GENETICS & HEREDITY

Genetics in Medicine Pub Date : 2024-09-26 DOI:10.1016/j.gim.2024.101282

Hosneara Akter , Md. Atikur Rahaman , Tamannyat Binte Eshaque , Nesrin Mohamed , Amirul Islam , Mehzabin Morshed , Zaha Shahin , Al Muhaimin , Arif Md. Foyzullah , Rabeya Akter Mim , Farjana Binta Omar , Md. Nahid Hasan , Dharana Satsangi , Nahid Ahmed , Abdullah Al Saba , Nargis Jahan , Md. Arif Hossen , Md.Ashadujjaman Mondol , Ahammad Sharif Sakib , Rezwana Kabir , Mohammed Uddin

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引用次数: 0

Abstract

Purpose

The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort.

Methods

We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis.

Results

Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift.

Conclusion

This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.

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从深度表型的高度近亲神经发育障碍队列中获得的基因组学启示。

目的：不同种族人群，尤其是近亲结婚率较高的人群中神经发育障碍（NDDs）的遗传基础在很大程度上仍未得到探索。在此，我们旨在从 576 个表型良好且高度近亲繁殖（16%）的 NDD 队列中阐明基因组学观点：我们采用染色体微阵列（CMA；样本数：247）、外显子组测序（ES；样本数：127）、CMA 和 ES 联合测序（样本数：202）以及长线程基因组测序来确定遗传病因。深度临床多变量数据与基因组变异相结合，进行分层分析：结果：CMA的基因诊断率为17%，ES的基因诊断率为29.92%，CMA和ES联合诊断率为37.13%。值得注意的是，近亲结婚子女的诊断率明显更高（p 结论：该研究揭示了独特的临床和遗传学特征：本研究从一个血缘关系丰富的孟加拉 NDD 群体中揭示了独特的临床和基因组学见解，强调了 G6PD 与该人群中 NDD 的密切联系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.