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Mandibuloacral dysplasia with type A lipodystrophy (MADA) is a rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis of distal phalanges, and type A lipodystrophy. The A-type lamins encoded by LMNA (HGNC:6636) are critical for nuclear envelope integrity and prelamin A processing. Defects in the C-terminal globular domain of lamin A underlie MADA pathogenesis.
Two independent studies have identified biallelic missense variants in LMNA in MADA patients. A single consanguineous family harbored a homozygous c.1620G>A (p.Met540Ile) variant in the proband (PMID:26602028), with heterozygous parents and prenatal detection in the fetus. Separately, five unrelated Tunisian patients were homozygous for c.1580G>A (p.Arg527His) (PMID:33422685), indicating a possible founder allele in this population.
Inheritance is autosomal recessive, confirmed by parental heterozygosity and consistent biallelic segregation in affected individuals. No additional affected relatives beyond index cases were genotyped, yielding zero informative meioses. Nevertheless, the recurrence of the same missense change in multiple unrelated families and its absence from population databases support pathogenicity.
Genetic evidence is moderate: six probands with two distinct LMNA variants meet ClinGen criteria for Moderate genetic evidence. Both variants are missense changes in the conserved C-terminal domain, predicted deleterious by multiple in silico tools. No loss-of-function alleles have been reported for MADA.
Functional evidence is limited to computational predictions demonstrating reduced protein stability for p.Met540Ile. No cellular or animal models have assessed the effects of these variants on lamin A processing, nuclear morphology, or rescue of phenotype.
Mechanistically, MADA likely results from impaired folding or maturation of prelamin A leading to defective nuclear lamina assembly. The clustering of variants in the C-terminal domain correlates with acroosteolysis and adipose tissue loss, suggesting a domain-specific genotype-phenotype relationship.
In conclusion, LMNA has a Moderate ClinGen gene–disease association with Mandibuloacral Dysplasia Type A, supported by biallelic missense variants in six probands across two studies. Key take-home: Molecular diagnosis of LMNA variants enables accurate confirmation of MADA, informs genetic counseling, and guides prenatal testing.
Gene–Disease AssociationModerateSix probands across two unrelated cohorts with concordant clinical features Genetic EvidenceModerateTwo biallelic missense variants identified in six probands; founder recurrence Functional EvidenceLimitedComputational modeling only; no cellular or animal functional data |