[Genetic and phenotypic analysis of three children with Neurodevelopmental disorders due to variants of DEAF1 gene].

چکیده اصلی

OBJECTIVE: To explore the genetic characteristics and clinical phenotypes of three children with novel DEAF1 gene variants. METHODS: Three children who were referred to Capital Children's Medical Center Affiliated to Capital Medical University between January 2018 and December 2025 were selected as study subjects and underwent whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing, and their pathogenicity was evaluated based on the guidelines from American College of Medical Genetics and Genomics (ACMG). A systematic search of databases including PubMed and CNKI was conducted to compile previously reported cases of DEAF1 variants for clinical phenotype comparison. For the non-canonical splice site variant c.870+5G>C located in the intronic region, wild-type and mutant minigene reporter vectors were constructed and transfected into HeLa and 293T cells, respectively, and the splicing patterns were analyzed by RT-PCR and Sanger sequencing. This study was approved by the Medical Ethics Committee of Capital Institute of Pediatrics (Ethics No.: SHERLL 2020001). RESULTS: All three children were found to have carried de novo heterozygous variants of the DEAF1 gene, including two missense variants (c.764G>A, c.641T>C) in the important SAND domain and a splice site variant (c.870+5G>C) in a non-canonical splicing region. The c.764G>A and c.870+5G>C variants were unreported previously. All children had presented with intellectual developmental delay, and two were accompanied by autism spectrum disorder, and two had epilepsy and sleep disorders. In vitro minigene splicing assay showed that the c.870+5G>C variant can lead to abnormal splicing. CONCLUSIONS: This study reported three children with novel DEAF1 variants, two of which have not been previously described, thereby enriched the mutational spectrum of the DEAF1 gene. In vitro functional assay combined with the clinical manifestations of the patients confirmed the pathogenicity of the non-canonical splice site variant in the intronic region.

ترجمه فارسی چکیده

هدف این مطالعه بررسی ویژگی‌های ژنتیکی و فنوتیپ بالینی سه کودک دارای تغییرات جدید ژن DEAF1 بود. سه کودک مراجعه‌کننده به مرکز پزشکی کودکان پایتخت از ژانویه ۲۰۱۸ تا دسامبر ۲۰۲۵ به عنوان نمونه‌های مطالعه انتخاب شدند و از توالی‌یابی تمام اکسون (WES) استفاده شد. تغییرات احتمالی با توالی‌یابی Sanger تأیید و خطرات بالینی آن‌ها بر اساس دستورالعمل‌های کالج پزشکی و ژنتیک آمریکا (ACMG) ارزیابی شد. همچنین از پایگاه‌های داده مانند PubMed و CNKI برای جمع‌آوری موارد گزارش‌شده قبلی استفاده شد. برای تغییر سایت اسپلیسینگ غیرکلاسیک c.870+5G>C، وکتورهای گزارشگر مینی‌ژن نوع وحشی و جهش‌یافته ساخته و در سلول‌های HeLa و ۲۹۳T انتقال داده شدند و الگوهای اسپلیسینگ با RT-PCR و توالی‌یابی Sanger تحلیل شد. این مطالعه توسط کمیته اخلاق پزشکی مرکز کودکان پایتخت تأیید شد.

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