Evidence of maternal inheritance of Nizon-Isidor syndrome in an individual with GAMT and TNFRSF13B sequence variants.

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.