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This summary reviews the association of NEPRO (HGNC:24496) with anauxetic dysplasia 1 (MONDO:0054560). Multiple lines of evidence from case reports and multi‐patient studies support an autosomal recessive mode of inheritance. Affected individuals present with a constellation of skeletal features including severe short stature, brachydactyly, joint hypermobility, joint dislocations, cutis laxa, short metacarpals, and metaphyseal irregularities (PMID:31250547).
Genetic evidence includes the identification of biallelic missense variants in NEPRO. In one report a 6‐year‐old girl was found to harbor the variant c.435G>C (p.Leu145Phe) following trio exome sequencing, and similar domain‐specific variants were reported in two additional families comprising four affected individuals (PMID:31250547). This clustering of variants in a key functional domain combined with segregation in families supports the causative role of NEPRO in anauxetic dysplasia 1.
The inheritance pattern is consistent with autosomal recessive transmission. Segregation analysis revealed that four additional affected relatives across multiple families carried the pathogenic variants, further strengthening the genetic evidence for the association (PMID:31250547).
Functional investigations provided complementary evidence. Protein modeling and stability predictions demonstrate that the missense variant c.435G>C (p.Leu145Phe) results in decreased protein stability, supporting a loss‐of‐function mechanism. This experimental data correlates well with the observed clinical phenotypes.
No significant conflicting evidence has been reported. Although the overall number of reported cases is modest, the convergence of genetic findings and experimental validation provides robust support for the association between NEPRO variants and anauxetic dysplasia 1.
Key take‑home sentence: NEPRO genetic testing should be considered in patients with skeletal dysplasia presenting with the described phenotype, as the identification of biallelic variants can be directly integrated into clinical diagnostic and management strategies.
Gene–Disease AssociationModerateFive affected individuals across three families exhibit biallelic NEPRO variants with supportive segregation and functional data (PMID:31250547). Genetic EvidenceModerateBiallelic missense variants, including c.435G>C (p.Leu145Phe), have been reported in a proband and in two families with four affected individuals, demonstrating autosomal recessive inheritance and domain-specific clustering (PMID:31250547). Functional EvidenceModerateProtein modeling and stability predictions indicate decreased stability of the mutant NEPRO protein, supporting a loss‑of‑function mechanism in skeletal dysplasia (PMID:31250547). |