Rafat Karima, Abdel-Aleem Asmaa F, Elbendary Hasnaa M, Issa Mahmoud Y, Essawi Mona L, Abdel-Ghafar Sherif F, Abdel-Salam Ghada M H, Abdel-Hamid Mohamed S, Zaki Maha S
Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Sci Rep. 2025 Jun 27;15(1):20329. doi: 10.1038/s41598-025-06857-2.
Biallelic variants in the adenosine deaminase tRNA specific 3 (ADAT3) gene are associated with a distinct neurodevelopmental disorder characterized by dysmorphic facies, poor growth, cognitive impairment, and variable brain anomalies. We describe 24 patients from 16 unrelated Egyptian families with ADAT3-related neurodevelopmental disorder. All patients presented with developmental delay, growth retardation, cognitive impairment, and the characteristic facial features of the disorder, which appears to be more recognizable in older patients. Seizures were noted in 20% of patients and showed favorable responses to treatment. Brain imaging showed corpus callosum abnormalities in most patients (91.6%), followed by delayed myelination and cortical atrophy. Exome sequencing identified three ADAT3 variants, including the Saudi founder variant c.430G > A (p.Val144Met), which was detected in 17 patients (70%). In addition, two novel variants were identified, c.319G > A (p.Glu107Lys) and c.1013_1018dup (p.Arg338_Ile339dup). The c.319G > A (p.Glu107Lys) was recurrent in 6 patients (25%) who shared a similar haplotype, suggesting a likely founder effect in our population. On the other hand, the c.1013_1018dup (p.Arg338_Ile339dup) was identified in a single patient. Our study reports a large cohort of patients with ADAT3-related neurodevelopmental disorder from Egypt and reinforces the clinical and brain imaging characteristics of the disorder. The high prevalence of the c.430G > A (p.Val144Met) in our population strongly suggests the existence of a founder effect of this variant in the Middle East and Arab region. In addition, we report a new founder variant expanding the mutational spectrum of this rare disorder.
腺苷脱氨酶tRNA特异性3（ADAT3）基因的双等位基因变异与一种独特的神经发育障碍相关，其特征为面部畸形、生长发育迟缓、认知障碍以及多种脑结构异常。我们描述了来自16个不相关埃及家庭的24例患有ADAT3相关神经发育障碍的患者。所有患者均表现出发育迟缓、生长发育迟缓、认知障碍以及该疾病特有的面部特征，这些特征在年龄较大的患者中似乎更易识别。20%的患者出现癫痫发作，且对治疗反应良好。脑部影像学检查显示，大多数患者（91.6%）存在胼胝体异常，其次是髓鞘形成延迟和皮质萎缩。外显子组测序鉴定出三个ADAT3变异，包括沙特奠基者变异c.430G＞A（p.Val144Met），在17例患者（70%）中检测到。此外，还鉴定出两个新变异，c.319G＞A（p.Glu107Lys）和c.1013_1018dup（p.Arg338_Ile339dup）。c.319G＞A（p.Glu107Lys）在6例患者（25%）中反复出现，这些患者共享相似的单倍型，提示在我们的人群中可能存在奠基者效应。另一方面，c.1013_1018dup（p.Arg338_Ile339dup）仅在1例患者中被鉴定出。我们的研究报告了来自埃及的一大组患有ADAT3相关神经发育障碍的患者，并强化了该疾病的临床和脑部影像学特征。我们人群中c.430G＞A（p.Val144Met）的高患病率强烈提示该变异在中东和阿拉伯地区存在奠基者效应。此外，我们报告了一个新的奠基者变异，扩展了这种罕见疾病的突变谱。
