Dutta Dibyendu, Black Jennifer, Macaya Daniela, McGivern Bobbi, Garg Ria
Department of Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, USA.
Center of Development, Behavior, and Genetics, State University of New York Upstate Medical University, Syracuse, NY, USA.
J Hum Genet. 2025 Sep 16. doi: 10.1038/s10038-025-01407-0.
Nizon-Isidor syndrome (NIZIDS) is a rare neurodevelopmental disorder caused by heterozygous MED12L variants, where previously pathogenic single-nucleotide variants (SNVs) were only reported as de novo events. Here, we report the first case of maternally inherited MED12L nonsense variant in NIZIDS. Clinical assessment and family history evaluation revealed global developmental delay, intellectual disability, autism spectrum disorder, and speech impairment. Exome sequencing (ES) of the proband and both parents confirmed the presence of a maternally inherited likely pathogenic MED12L nonsense variant in the proband. Additional pathogenic variants in GAMT (maternal) and TNFRSF13B (paternal) genes were also identified in the proband. The clinical history of the mother suggested variable expressivity of the MED12L variant. Our case report challenges the presumed de novo inheritance of MED12L SNVs and demonstrates variable expressivity, thereby highlighting the benefit of a complete phenotype-driven approach when analyzing exome and genome data.
尼宗 - 伊西多尔综合征（NIZIDS）是一种由杂合性MED12L变异引起的罕见神经发育障碍，此前致病性单核苷酸变异（SNV）仅作为新生事件被报道。在此，我们报告了首例尼宗 - 伊西多尔综合征中母系遗传的MED12L无义变异病例。临床评估和家族史评估显示存在全面发育迟缓、智力障碍、自闭症谱系障碍和言语障碍。先证者及其父母的外显子组测序（ES）证实先证者存在母系遗传的可能致病性MED12L无义变异。在先证者中还鉴定出GAMT（母亲）和TNFRSF13B（父亲）基因中的其他致病性变异。母亲的临床病史提示MED12L变异具有可变表达性。我们的病例报告对MED12L SNV假定的新生遗传提出了挑战，并证明了可变表达性，从而突出了在分析外显子组和基因组数据时采用完整的表型驱动方法的益处。
