MED13L syndrome (Asadollahi-Rauch syndrome) is mainly caused by de novo heterozygous likely gene disrupting variants including copy number losses and intragenic gains, as well as frameshift, stop and splice site sequence variants affecting MED13L.
De novo and deleterious heterozygous missense variants with convincing pathogenicity have also been described which appear to cluster in specific mutational hot-spots (NM_015335.4, exons 15–17 and 25–31). Several missense variants with unknown inheritance or inherited from healthy parents have been described in a variety of phenotypes and remain of uncertain significance. Copy number gain of the entire MED13L and neighboring genes results in a milder neurodevelopmental phenotype.
Based on the reported cases, haploinsufficiency of MED13L is likely the main mechanism but possibility of dominant negative effect of some of the disease causing missense variants have also been proposed.
Targeted Sanger sequencing of MED13L for detection of sequence variants in case of clinical suspicion, chromosomal microarray analysis for detecting copy number variants and next generation sequencing (NGS) based panel testing, as well as exome and genome sequencing have led to the detection of causal variants in MED13L. For detection of exonic CNVs within MED13L, high-resolution array with exonic coverage, targeted MLPA or NGS-based copy number analysis are required.
For searching reported variants or submitting new variants in MED13L, you can visit https://www.LOVD.nl/MED13L.