Akter Hosneara, Rahaman Md Atikur, Eshaque Tamannyat Binte, Mohamed Nesrin, Islam Amirul, Morshed Mehzabin, Shahin Zaha, Muhaimin Al, Foyzullah Arif Md, Mim Rabeya Akter, Omar Farjana Binta, Hasan Md Nahid, Satsangi Dharana, Ahmed Nahid, Al Saba Abdullah, Jahan Nargis, Hossen Md Arif, Mondol Md Ashadujjaman, Sakib Ahammad Sharif, Kabir Rezwana, Jahan Chowdhury Mohammod Shah, Shams Nusrat, Afroz Shireen, Kanta Shayla Imam, Bhuiyan Sarwar Jahan, Biswas Rabi, Hanif Shehzad, Tambi Richa, Nassir Nasna, Rahman Muhammad Mizanur, Duan Jinjie, D Børglum Anders, Amin Robed, Basiruzzaman Mohammed, Kamruzzaman Md, Sarker Shaoli, Woodbury-Smith Marc, Uddin K M Furkan, Nabi A H M Nurun, Uddin Mohammed
Genetics and Genomic Medicine Centre (GGMC), NeuroGen Healthcare, Dhaka, Bangladesh; Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
Genetics and Genomic Medicine Centre (GGMC), NeuroGen Healthcare, Dhaka, Bangladesh.
Genet Med. 2025 Jan;27(1):101282. doi: 10.1016/j.gim.2024.101282. Epub 2024 Sep 26.
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.
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.
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.
This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort.
不同种族人群，尤其是近亲结婚率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例表型良好且近亲结婚率高（16%）的NDD队列中阐明基因组见解。
我们使用染色体微阵列（CMA；n = 247）、外显子组测序（ES；n = 127）、联合CMA和ES（n = 202）以及长读长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。
CMA的基因诊断率为17%，ES为29.92%，联合CMA和ES为37.13%。值得注意的是，近亲结婚父母的孩子与非近亲结婚父母的孩子相比，诊断率显著更高（P < 0.01）。在ES鉴定出的致病变异中，36.19%（38/105）是新的，涉及35个独特基因。联合检测未解决的癫痫患者的长读长测序确定了FMR1三核苷酸重复序列的扩增。此外，我们在3.65%（12/329）的NDD参与者中鉴定出G6PD中2个复发性X连锁变异。这些变异在大群体对照队列以及欧洲后裔的神经发育和神经精神疾病群体队列中均不存在，表明这可能是古代基因漂变导致的一个潜在相关风险因素。
本研究揭示了来自近亲结婚率高的孟加拉国NDD队列的独特临床和基因组见解。
