MED13L – Congenital Heart Disease

MED13L haploinsufficiency was first implicated in a syndromic intellectual disability with dextro‐looped transposition of the great arteries in 2003. A follow‐up study described 22 additional unrelated patients (24 total) with de novo MED13L variants, expanding the phenotypic spectrum and revealing congenital heart defects (CHD) in approximately 20–50% of cases (PMID:28645799). Common features include moderate to severe intellectual disability, facial anomalies, severe speech delay, muscular hypotonia, abnormal MRI findings, and CHD ranging from septal defects to complex transpositions.

In the 2017 cohort, two novel de novo MED13L variants were identified by whole‐exome sequencing: a truncating c.2504del (p.Pro835fs) and a recurrent missense c.2579A>G (p.Asp860Gly), the latter predicted in silico to destabilize an α‐helix in MED13L (PMID:28645799). No segregation beyond de novo occurrence was reported.

A large case–control study of CHD (3,684 cases vs. 1,789 controls) demonstrated significant enrichment of de novo protein‐truncating and deleterious missense variants in connectome genes; MED13L ranked among the top 12 NDD genes with damaging variants (OR = 5.08, 95%CI: 2.81–9.20, p=6.3 × 10⁻¹¹; OR = 3.69, 95%CI: 2.02–6.73 after excluding three syndromic CHD genes) (PMID:32341405).

The spectrum of pathogenic MED13L variants in CHD includes loss‐of‐function alleles (nonsense, frameshift, splice site) and recurrent missense changes. Splice donor variants (e.g., c.1009+1G>C) have been shown by RNA analysis to cause retention of intronic sequence, frameshift, and premature termination consistent with haploinsufficiency (PMID:39181712).

Collectively, these data implicate MED13L haploinsufficiency—through loss‐of‐function or structural destabilization—as a key mechanism in cardiac development. Phenotypic variability and reduced penetrance of CHD (20–50%) suggest additional modifiers influence expressivity.

No studies have refuted the MED13L–CHD association, but incomplete penetrance underscores the need for careful clinical interpretation. Genetic screening of MED13L in CHD cohorts enhances diagnostic yield, informs recurrence risk, and guides management.

Key Take-home: Pathogenic MED13L variants cause a syndromic form of congenital heart disease with variable expressivity, supporting inclusion of MED13L in diagnostic gene panels.

References

• European journal of medical genetics • 2017 • Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation. PMID:28645799
• Scientific reports • 2020 • De novo damaging variants associated with congenital heart diseases contribute to the connectome. PMID:32341405
• Journal of medical genetics • 2024 • Splice site variants in the canonical donor site of MED13L exon 7 lead to intron retention in patients with MED13L syndrome. PMID:39181712

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