MED11 – Neurodegeneration with Developmental Delay, Early Respiratory Failure, Myoclonic Seizures, and Brain Abnormalities

Biallelic MED11 variants underlie neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities in a single fetus. Trio exome sequencing identified two nonsense variants in trans: c.229C>T (p.Gln77Ter) and c.325C>T (p.Arg109Ter) in one proband (n=1 proband) ([PMID:39578696]). The fetus presented with hydrops fetalis (HP:0001789) and abnormal limb posturing, expanding the prenatal phenotype of this disorder.

Independent functional studies of MED11 demonstrated that homozygous c.325C>T (p.Arg109Ter) in seven individuals from five unrelated families leads to C-terminal truncation disrupting MED complex stability in patient fibroblasts and zebrafish knockout models recapitulating neurodegeneration, myoclonic seizures, and premature death, consistent with a loss-of-function mechanism ([PMID:36001086]).

Key Take-home: Biallelic loss-of-function MED11 variants cause a severe autosomal recessive neurodevelopmental syndrome detectable prenatally.

References

• Prenatal diagnosis • 2025 • Prenatal Phenotypic Expansion: A Fetus With Neurodegeneration With Developmental Delay, Early Respiratory Failure, Myoclonic Seizures, and Brain Abnormalities (NDDRSB) and MED11 Variants PMID:39578696
• Genetics in medicine • 2022 • A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease PMID:36001086

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