MED13L-Related Syndromic Intellectual Disability via the MED13L Gene

MED13L syndrome is an autosomal dominant disorder characterized by intellectual disability and distinctive facial features, with or without cardiac defects. MED13L syndrome typically presents early in infancy with hypotonia and developmental delays. Most patients learn to walk between 2-3 years old, and while some develop a few words or sentences, many remain nonverbal throughout life. The most commonly reported features of this disorder include intellectual disability (100%), motor delay (100%), speech delay (100%), and hypotonia (70%). Dysmorphic features are also recognizable in a majority of patients, particularly hypotonic open-mouth appearance, cupid-bow upper lip, bulbous nasal tip, depressed and broad nasal bridge, low-set ears, macrostomia, macroglossia, and up-slanting palpebral fissures. Just over half of the patients have a normal brain MRI, whereas those with brain anomalies have variable and typically mild defects including cerebral atrophy, ventriculomegaly, white-matter hyperintensities, Dandy-Walker malformation, agenesis of the corpus callosum, focal cortical dysplasia, and hypomyelination. A minority of patients (<25%) have variable congenital heart malformations - which can include patent foramen ovale, patent ductus arteriosis, transposition of the great arteries, ventricular septal defect, tetralogy of Fallot, or pulmonic stenosis. Additionally, a minority (15-30%) of patients develop seizures or ataxia, are diagnosed with autism, or have behavioral troubles. Other features documented in a small number of patients include club foot, feeding difficulties in infancy, growth delays including intrauterine growth delay, microphthalmia, coloboma, digit abnormalities, genital abnormalities, and hernia. Males and females are affected equally, and the overall incidence of this disorder in the population is ~1.6 affected individuals per 100,000 (Smol et al. 2018. PubMed ID: 29511999; Tørring et al. 2019. PubMed ID: 29959045). As such, MED13L pathogenic variants are expected to be one of the most common single-gene causes of intellectual disability (McRae et al. 2017. PubMed ID: 28135719).

In addition to MED13L-syndrome, described above, which is almost always caused by de novo variants in the MED13L gene, rare inherited variants in MED13L have also been documented in individuals with isolated autism or isolated dextro-looped transposition of the great arteries. Disease penetrance of these associations is documented as incomplete, and the causal link for these gene-disease associations is currently provisional. Some reported individuals may actually fit within the MED13L-syndrome spectrum, and others may have an alternate cause for their symptoms (Muncke et al. 2003. PubMed ID: 14638541; Guo et al. 2018. PubMed ID: 30564305; https://gene.sfari.org/database/human-gene/MED13L#variants-tab).

There are no treatments for MED13L syndrome, yet patients and their families may benefit from a molecular diagnosis for prognostic information, early identification and treatment of symptoms (such as heart defects or autism), or for connecting with relevant family support groups, such as the MED13L foundation (www.med13l.org). For families, knowledge of a de novo variant and the associated reduced recurrence risk, may ease anxiety for future reproductive planning.

MED13L syndrome is an autosomal dominant disorder. A large majority of cases are caused by de novo variants. Germline mosaicism has also been documented. Pathogenic variant types include missense, nonsense, frameshift, splice-altering, and large deletions and duplications (Smol et al. 2018. PubMed ID: 29511999; Tørring et al. 2019. PubMed ID: 29959045; Adegbola et al. 2015. PubMed ID: 25758992). Early termination variants predominate, and are widely spread throughout the gene, including in the final exon. Causative missense variants are found at highly conserved residues and cluster around specific protein domains (exons 15-17 and 25-31). Several missense variants have been reported as recurrent de novo changes. Additionally, patients carrying causative missense changes are at a higher risk of developing epilepsy, and may have a more severe phenotype overall (Smol et al. 2018. PubMed ID: 29511999). Based on current knowledge, MED13L syndrome is thought to be fully penetrant, and none of the known pathogenic variants are present in the gnomAD database. MED13L is highly intolerant to loss-of-function variants (gnomAD).

MED13L, Mediator Complex Subunit 13-like, is located at chromosome 12q24.21, and is encoded by a single transcript of 2210 amino acids (NM_015335). It encodes a single subunit of the "mediator complex", which is the group of proteins important for linking transcription factors (gene expression regulators) to RNA-polymerase II (the enzyme that transcribes DNA to RNA), and as such plays an important role in gene expression. A zebrafish model of Med13b knockdown (a MED13L ortholog) shows abnormalities of the tissues that will develop into the face and jaw, underdeveloped head, as well as microphthalmia (Utami et al. 2014 PubMed ID:25137640). Expression studies show nearly ubiquitous expression in all adult tissues examined, and a majority of fetal tissues, with notably higher expression in the cerebellum than other brain regions (http://www.proteinatlas.org). MED13L has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

A recent PreventionGenetics analysis of the most frequent single-gene causes of developmental delay identified the MED13L gene within the top 10 causes (Top 99 Genetic Causes of Developmental Delay Panel). Additionally, MED13L patients have a recognizable facial gestalt. Based on these factors, we expect the clinical sensitivity for this test to be higher than for many other single gene tests for syndromic intellectual disability. Even so, the clinical and genetic heterogeneity of intellectual developmental disorders is extraordinarily diverse. Based on the wide potential differential diagnosis of most patients with syndromic intellectual disability, we recommend a large panel or exome or genome test as the quickest route to diagnosis. Analytical sensitivity of this test is expected to be near 100%, as this test can detect all types of pathogenic variants identified in MED13L to date, including large deletions and duplications.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the MED13L gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or 2x Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).