LEMD2 – Marbach-Rustad progeroid syndrome

Marbach-Rustad progeroid syndrome is an ultra-rare autosomal dominant premature aging disorder characterized by premature birth, facial abnormalities, feeding difficulties, skull defects, and delayed motor milestones. To date, only three unrelated probands have been reported harboring a recurrent de novo c.1436C>T (p.Ser479Phe) variant in LEMD2 (PMID:37867468). Sanger sequencing confirmed absence of this variant in parents and siblings, indicating a dominant de novo inheritance pattern. The c.1436C>T change affects a conserved residue within the LEM domain, essential for nuclear envelope integrity. No additional familial segregation has been observed, consistent with a de novo mechanism in each case.

Functional evidence from a Lemd2 p.Leu13Arg knock-in mouse model demonstrates nuclear membrane rupture, increased DNA damage, premature senescence, and activation of the cGAS/STING pathway, indicating that LEM domain disruption exerts a dominant-negative effect on nuclear envelope repair (PMID:36656972). Although this model was developed for cardiomyopathy, the shared mechanism of impaired nuclear integrity and DNA repair likely underlies the premature aging phenotype in Marbach-Rustad progeroid syndrome. No conflicting data have been reported. Key take-home: heterozygous de novo LEMD2 variants cause Marbach-Rustad progeroid syndrome through dominant disruption of nuclear envelope dynamics, and reanalysis of exome data in unsolved progeroid cases is recommended for improved molecular diagnosis.

References

• Clinical Genetics • 2024 • The third case of Marbach-Rustad progeroid syndrome caused by a de novo LEMD2 variant. PMID:37867468
• Circulation Research • 2023 • Mechanistic Insights of the LEMD2 p.L13R Mutation and Its Role in Cardiomyopathy. PMID:36656972

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