Mirahmadi Maryam, Kahani Seyyed Mohammad, Sharifi-Zarchi Ali, Firouzabadi Saghar Ghasemi, Behjati Farkhondeh, Garshasbi Masoud
Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Department of Exomine, PardisGene Company, Tehran, Iran.
Biochem Genet. 2025 Aug 16. doi: 10.1007/s10528-025-11226-9.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by abnormal social interactions, verbal communication difficulties, and restricted repetitive behaviors. Identifying the underlying genetic factors is crucial because of the complex genetic and environmental etiology. In this study, we performed whole-exome sequencing (WES), whole-genome sequencing (WGS), and array comparative genomic hybridization (aCGH) of four Iranian families with ASD-related conditions to identify novel genomic alterations. Five previously undescribed mutations were identified in these families. Family 1: A homozygous 290.7 kb deletion CNV (chr8:103,652,204-103942926; hg38) encompassing exons 2-16 of RIMS2 (NM_001348484), confirmed in a 7-year-old male proband with developmental delay and cone-rod synaptic disorder. Family 2: A heterozygous nonsense mutation in FOXG1 (NM_005249.5:c.839C > A; p.Ser280Ter) in a 6-year-old female with Rett-like features, resulting in a truncated protein lacking corepressor domains. Family 3: A splice donor site mutation in AUTS2 (NM_015570.4:c.742 + 1G > C) in a 10-year-old female with ASD and Attention-deficit/hyperactivity disorder, generating a frameshift and premature stop codon affecting mRNA-binding functionality. Family 4: A heterozygous nonsense mutation in ZCCHC17 (NM_016505.4:c.220C > T; p.Arg74Ter) and a splicing variant in SPTBN5 (NM_016642.4:c.3470 + 2T > A) in two male siblings with ASD were predicted to result in truncated proteins and aberrant splicing. Pathogenicity was supported through in silico analyses and structural modeling using I-TASSER, and segregation was confirmed using Sanger sequencing. This study highlights the genetic diversity of ASD and underscores the importance of advanced sequencing technologies in identifying novel mutations. Our findings contribute to the growing body of knowledge regarding the genetic basis of ASD, paving the way for personalized treatment strategies and early diagnosis.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征为社交互动异常、语言交流困难以及受限的重复行为。由于其复杂的遗传和环境病因，确定潜在的遗传因素至关重要。在本研究中，我们对四个患有ASD相关病症的伊朗家庭进行了全外显子组测序（WES）、全基因组测序（WGS）和阵列比较基因组杂交（aCGH），以鉴定新的基因组改变。在这些家庭中鉴定出了五个先前未描述的突变。家庭1：一个纯合的290.7 kb缺失CNV（chr8:103,652,204 - 103942926；hg38），涵盖RIMS2（NM_001348484）的外显子2 - 16，在一名患有发育迟缓及视锥 - 视杆突触障碍的7岁男性先证者中得到证实。家庭2：一名具有雷特氏症样特征的6岁女性中，FOXG1（NM_005249.5:c.839C＞A；p.Ser280Ter）存在杂合性无义突变，导致一种缺乏共抑制域的截短蛋白。家庭3：一名患有ASD和注意力缺陷多动障碍的10岁女性中，AUTS2（NM_015570.4:c.742 + 1G＞C）存在剪接供体位点突变，产生移码和过早的终止密码子，影响mRNA结合功能。家庭4：两名患有ASD的男性同胞中，ZCCHC17（NM_016505.4:c.220C＞T；p.Arg74Ter）存在杂合性无义突变，SPTBN5（NM_016642.4:c.3470 + 2T＞A）存在剪接变体，预计会导致截短蛋白和异常剪接。通过使用I-TASSER的计算机分析和结构建模支持了致病性，并使用桑格测序确认了分离情况。本研究突出了ASD的遗传多样性，并强调了先进测序技术在鉴定新突变中的重要性。我们的发现有助于增加关于ASD遗传基础的知识体系，为个性化治疗策略和早期诊断铺平道路。
