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

This study looked at a rare genetic condition called Nizon-Isidor syndrome that affects brain development. Previously, doctors thought this condition was always caused by new genetic changes that weren't inherited from parents. However, this research found the first case where a child inherited the genetic change from their mother. The child had developmental delays, intellectual disability, autism, and speech problems.

This discovery is important because it shows the condition can be passed down from parents and may affect family members differently.

This case report describes the first documented instance of maternal inheritance of Nizon-Isidor syndrome (NIZIDS), a rare neurodevelopmental disorder typically caused by de novo MED12L gene variants. The study examined a child with global developmental delay, intellectual disability, autism spectrum disorder, and speech impairment through exome sequencing of the child and both parents. Results confirmed a maternally inherited likely pathogenic MED12L nonsense variant, challenging previous assumptions about inheritance patterns. Additional pathogenic variants in GAMT and TNFRSF13B genes were also identified.

The mother's clinical history suggested variable expressivity of the MED12L variant, demonstrating that some carriers may have milder or different symptom presentations than previously recognized.

This finding suggests genetic counseling approaches for NIZIDS may need revision to include family history assessment and parental testing. Clinicians should consider variable expressivity when evaluating family members. The presence of multiple genetic variants highlights the importance of comprehensive genetic analysis in complex neurodevelopmental presentations.

Single case report limits generalizability of findings. Sample size not specified. Long-term outcomes and detailed clinical assessments not provided. No functional studies to confirm variant pathogenicity. Limited information about maternal phenotype details.

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.