Further delineation of the phenotypic spectrum of pathogenic variants in MED13

Abstract

Abstract Introduction:Diagnostic yield of the genetic testing in search for the molecular basis of neurodevelopmental diseases remains low due to incomplete knowledge of the phenotypic spectrum of pathogenic variants in a specific gene. Recently the MED13 gene was linked to neurodevelopmental disease. Methods:Four families with children affected by autism spectrum disorder (ASD) were recruited to the study. Extensive genetic testing was performed for each proband: CGG repeat expansion analysis in FMR1 gene; whole exome sequencing (WES); array comparative genomic hybridization (aCGH); maternity and paternity confirmation. Genetic variants which were revealed by WES were verified with Sanger sequencing or aCGH in probands and their relatives. Results:Four rare heterozygous genetic variants in MED13 gene were identified in four unrelated patients with clinical features matching MED13-associated phenotype: intellectual disability (ID) of various degrees, speech delay, ASD and mild facial dysmorphisms. Three of the variants occurred de novo, while one was inherited maternally, in accordance with previous findings, suggesting incomplete penetrance. A patient with a de novo missense mutation in the intrinsic disordered region of MED13 developed seizures similarly to the only other reported patient with a pathogenic missense variant in this region. Limitations:Additional functional studies are needed to elucidate molecular mechanisms of the disease and distinguish between pathogenic and non-pathogenic variation.Conclusion:Our data strongly support the role of MED13 in neurodevelopmental disease by eliminating other common genetic defects. We expand the phenotypic spectrum of the disease causing variants: pathogenic missense variants in the intrinsic disordered region of MED13 may lead to a phenotype with seizures and incomplete penetrance of the maternally inherited variants may occur.