Asadollahi-Rauch syndrome (MED13L haploinsufficiency syndrome or MED13L-related intellectual disability) is a rare autosomal dominant neurodevelopmental disorder with an estimated prevalence of 1.6 per 100,000 births, which presents with moderate to severe intellectual disability, hypotonia, distinctive facial and variable other features.
While MED13L was originally linked to dextro-looped transposition of the great arteries, Asadollahi et al. (2013) delineated the MED13L haploinsufficiency syndrome presenting with intellectual disability, a recognizable facial gestalt and conotruncal heart defects. To date, >50 patients with likely gene disrupting de novo MED13L defects have been reported, all showing intellectual disability or developmental delay and a spectrum of facial anomalies, but complex congenital heart defects have remained limited to few cases and therefore is considered among variable features with incomplete penetrance. However, congenital heart defects in general, including persistent foramen ovale and ventricular septal defect are reported in up to 30% of the MED13L patients. Frequent facial features of the syndrome include broad/prominent forehead, bitemporal narrowing, low set ears, horizontal eyebrows, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, abnormal chin, hypotonic open mouth and macroglossia, of which the latter abnormalities of mouth and tongue have more often sparked recognition of the syndrome. Other frequent features comprise ataxia or coordination problems, autistic features, seizures or abnormal EEG, and abnormal growth parameters. Abnormal findings in cerebral MRI have been reported in ~30-40% of the patients. Less commonly reported traits in the syndrome include aggressive behaviour, strabismus, cleft palate, Pierre Robin sequence, truncal obesity, umbilical hernia and a range of skeletal features such as club feet.
In addition to the likely gene disrupting variants, MED13L de novo missense variants have also been reported to cause similar features in the patients despite some phenotypic variability, more frequent development of epilepsy, and more severe motor and speech delay in some cases. There are two gains of the whole MED13L and neighbouring genes reported so far which both led to some learning difficulties but no ID. These observations may in fact indicate that copy number gain of the gene results in a milder neurodevelopmental phenotype.