Department of Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.
J Clin Lab Anal. 2022 Feb;36(2):e24241. doi: 10.1002/jcla.24241. Epub 2022 Jan 12.
Intellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders that is characterized by significant impairment in intellectual and adaptive functioning with onset during the developmental period. Whole-exome sequencing (WES)-based studies in the consanguineous families with individuals affected with ID have shown a high burden of relevant variants. So far, over 700 genes have been reported in syndromic and non-syndromic ID. However, genetic causes in more than 50% of ID patients still remain unclear.
Whole-exome sequencing was applied for investigation of various variants of ID, then Sanger sequencing and in silico analysis in ten patients from five Iranian consanguineous families diagnosed with autosomal recessive neurodevelopmental disorders, intellectual disability, performed for confirming the causative mutation within the probands. The most patients presented moderate-to-severe intellectual disability, developmental delay, seizure, speech problem, high level of lactate, and onset before 10 years.
Filtering the data identified by WES, two novel homozygous missense variants in FBXO31 and TIMM50 genes and one previously reported mutation in the CEP290 gene in the probands were found. Sanger sequencing confirmed the homozygote variant's presence of TIMM50 and FBXO31 genes in six patients and two affected siblings in their respective families. Our computational results predicted that the variants are located in the conserved regions across different species and have the impacts on the protein stability.
Hence, we provide evidence for the pathogenicity of two novel variants in the patients which will expand our knowledge about potential mutation involved in the heterogeneous disease.
智力障碍（ID）是一组神经发育障碍，其特征是在发育期间出现明显的智力和适应功能受损。在受 ID 影响的同系亲属中进行的基于全外显子组测序（WES）的研究表明，相关变体负担很高。到目前为止，已经在综合征和非综合征 ID 中报道了超过 700 个基因。然而，超过 50%的 ID 患者的遗传原因仍然不清楚。
对 10 名来自 5 个伊朗同系亲属的患者进行了全外显子组测序，以调查 ID 的各种变体，然后对被诊断为常染色体隐性神经发育障碍、智力障碍、癫痫、言语问题、高乳酸水平和发病年龄在 10 岁之前的患者进行 Sanger 测序和计算机分析，以确认先证者中的致病突变。大多数患者表现为中度至重度智力障碍、发育迟缓、癫痫、言语问题、高水平的乳酸和发病年龄在 10 岁之前。
通过 WES 筛选出的数据，在先证者中发现了 FBXO31 和 TIMM50 基因中的两个新的纯合错义变体和 CEP290 基因中的一个先前报道的突变。Sanger 测序证实了 TIMM50 和 FBXO31 基因在 6 名患者和 2 名受影响的同胞中的纯合变体存在于各自的家庭中。我们的计算结果预测，这些变体位于不同物种的保守区域，对蛋白质稳定性有影响。
因此，我们为患者中两个新变体的致病性提供了证据，这将扩展我们对涉及异质性疾病的潜在突变的认识。
