Akter Hosneara, Rahman Muhammad Mizanur, Mim Rabeya Akter, Rahaman Atikur, Eshaque Tamannyat Binte, Hossain Syed Akib, Ganguly Athoi, Omar Farjana Binta, Taniya Masuma Afrin, Hasan Nahid, Islam Amirul, Jamalalail Bassam, Nassir Nasna, Zehra Binte, Sarker Shaoli, Uddin K M Furkan, Nabi A H M Nurun, Woodbury-Smith Marc, Uddin Mohammed
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh.
Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
Genet Med Open. 2025 May 19;3:103438. doi: 10.1016/j.gimo.2025.103438. eCollection 2025.
Rett syndrome (RTT) is a neurological disorder marked by the loss of developmental milestones. Classic RTT involves variants in the methyl-CpG-binding protein 2 () gene. Our study examines the genetic basis of typical and atypical RTT, along with RTT-like phenotypes, using -targeted sequencing (TS) and exome sequencing (ES).
sequencing was conducted on 27 Bangladeshi female participants with RTT features. ES was subsequently conducted on the 13 participants who tested negative for variants. Data were processed using the Genome Analysis Toolkit and American College of Medical Genetics and Genomics-guided pathogenicity analysis was conducted with ANNOVAR and GenomeArc Horizon. Copy-number variation analysis was performed using CNVkit, and variants were classified according to the American College of Medical Genetics and Genomics guidelines.
Of the 27 participants, 51.9% (14/27) had pathogenic variants all exhibiting the classic RTT phenotype, yielding an 87.5% (14/16) diagnostic rate for classic RTT through TS. The identified variants included 3 missense, 3 nonsense, and 3 frameshift deletions. Among the 13 -negative participants who underwent ES, 69.2% (9/13) harbored pathogenic variants, whereas 23.1% (3/13) carried a variant of uncertain significance, and 7.7% (1/13) had no clinically relevant variants. ES analysis identified 6 candidate genes were associated with atypical RTT () and RTT-like phenotypes (, , , , and ). The overall diagnostic yield for TS and ES was 85.2% (23/27).
This genetic study of clinically diagnosed Bangladeshi RTT participants identifies new genes involved in the etiology of RTT-like phenotypes and expands the phenotypic spectrum of known genes linked to neurodevelopmental disorders.
雷特综合征（RTT）是一种以发育里程碑丧失为特征的神经疾病。典型的RTT涉及甲基CpG结合蛋白2（MECP2）基因的变异。我们的研究使用MECP2靶向测序（TS）和外显子组测序（ES）来研究典型和非典型RTT以及RTT样表型的遗传基础。
对27名具有RTT特征的孟加拉国女性参与者进行了MECP2测序。随后对13名MECP2变异检测呈阴性的参与者进行了ES。使用基因组分析工具包处理数据，并使用ANNOVAR和GenomeArc Horizon进行美国医学遗传学与基因组学学会指导的致病性分析。使用CNVkit进行拷贝数变异分析，并根据美国医学遗传学与基因组学学会的指南对变异进行分类。
在27名参与者中，51.9%（14/27）有致病性MECP2变异，均表现出典型的RTT表型，通过TS对典型RTT的诊断率为87.5%（14/16）。鉴定出的变异包括3个错义变异、3个无义变异和3个移码缺失。在接受ES的13名MECP2阴性参与者中，69.2%（9/13）携带致病性变异，而23.1%（3/13）携带意义不确定的变异，7.7%（1/13）没有临床相关变异。ES分析确定了6个候选基因与非典型RTT（ATRX）和RTT样表型（CHD8、KMT2D、SCN2A、SMARCA2和SPEN）相关。TS和ES的总体诊断率为85.2%（23/27）。
这项对临床诊断的孟加拉国RTT参与者的遗传学研究确定了与RTT样表型病因相关的新基因，并扩展了与神经发育障碍相关的已知基因的表型谱。
