Key result
LEMD2 p.Ser479Phe variant linked to severe calcific aortic stenosis and high-grade AV block.
Why the study?
Only four cases of Marbach-Rustad progeroid syndrome from the heterozygous LEMD2 c.1436C>T (p.Ser479Phe) variant had been reported, with cardiac involvement absent or only qualitatively described.
Case Report (n=1)
This case demonstrates that the LEMD2 p.Ser479Phe variant in Marbach-Rustad progeroid syndrome can cause severe, premature cardiovascular disease—including high-grade atrioventricular block and severe calcific aortic stenosis requiring pacemaker and transcatheter aortic valve replacement—supporting routine cardiac and metabolic surveillance.
Answers are grounded in this paper and cite their sources.
May warrant cardiac evaluation in Marbach-Rustad progeroid syndrome; extends phenotypic spectrum but remains hypothesis-generating.
BACKGROUND: Marbach-Rustad progeroid syndrome results from the recurrent heterozygous LEMD2 c.1436C>T (p.Ser479Phe) variant. Four cases have been reported, with cardiac involvement absent or only qualitatively described. CASE SUMMARY: A 30-year-old man with short stature, skeletal fragility, and facial dysmorphism presented with syncope from high-grade atrioventricular block. Echocardiography showed premature severe calcific aortic stenosis and mild mitral stenosis. Cardiac magnetic resonance showed preserved biventricular function with no late gadolinium enhancement; computed tomography confirmed valvular calcification but no coronary calcium. Chagas serology was negative. Whole-genome sequencing confirmed the p.Ser479Phe variant. He received a permanent pacemaker and, 6 months later, transcatheter aortic valve replacement. Evaluation also revealed overt type 2 diabetes, severe hypertriglyceridemia, and nephropathy: the most advanced metabolic phenotype reported. DISCUSSION: This case shows that the p.Ser479Phe variant can cause advanced, intervention-requiring cardiovascular disease (objectively quantified and, to our knowledge, the first in vivo characterization by cardiac magnetic resonance). These findings support routine cardiac and metabolic surveillance in LEMD2-associated progeroid syndromes.
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Delamain et al. (2026) conducted a case report in Marbach-Rustad progeroid syndrome with high-grade atrioventricular block and severe calcific aortic stenosis (n=1). LEMD2 c.1436C>T (p.Ser479Phe) variant (treated with permanent pacemaker and transcatheter aortic valve replacement) was evaluated. The LEMD2 p.Ser479Phe variant caused severe calcific aortic stenosis and high-grade AV block in 1 of 1 patient (30-year-old man), requiring a pacemaker and TAVR 6 months later.
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