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MMP9 encodes matrix metallopeptidase 9, a zinc-dependent endopeptidase critical for extracellular matrix remodeling. Autosomal recessive mutations in MMP9 underlie metaphyseal anadysplasia type 2 (MANDP2), manifesting with long-bone dysplasia, fibular aplasia, and tibial bowing. Six probands from four families have now been reported with either homozygous or compound heterozygous MMP9 variants leading to characteristic skeletal malformations ([PMID:36035187]). In the most recent case, two novel compound heterozygous variants—c.151C>T (p.Arg51Cys) and c.929del—were identified in a fetus with bilateral femur shortening, absence of right fibula, and curved ipsilateral tibia via trio whole-exome and Sanger sequencing ([PMID:36035187]).
Overall clinical validity is Limited based on a small number of affected individuals and absence of disease-specific functional assays. Genetic evidence is Moderate: multiple unrelated probands and clear autosomal recessive segregation support pathogenicity. Functional evidence is Limited due to lack of in vitro or in vivo models demonstrating variant impact on MMP9 activity in growth plate development. Further mechanistic studies are needed. Key take-home: MMP9 sequencing is recommended for patients or fetuses presenting with metaphyseal anadysplasia type 2 features to confirm diagnosis and guide genetic counseling.
Gene–Disease AssociationLimited6 probands, 4 families; autosomal recessive inheritance; no functional assays Genetic EvidenceModerateRecurrent homozygous or compound heterozygous MMP9 variants in multiple families consistent with AR disease Functional EvidenceLimitedNo disease-specific functional studies demonstrating pathogenic mechanism |