NEPRO – Anauxetic Dysplasia

This summary reviews the association between NEPRO and anauxetic dysplasia, a severe skeletal disorder characterized by marked short stature, brachydactyly, skin laxity, and joint dislocations. The clinical findings observed in these patients define a distinctive phenotype, which now includes atlantoaxial subluxation, dental anomalies, and craniosynostosis. The association is supported by studies showing biallelic mutations in NEPRO among affected individuals (PMID:37294112).

The clinical validity of the association is supported by evidence from a combined series of case reports and multi‑patient studies. Six probands with type 3 anauxetic dysplasia have been reported to carry a homozygous variant in NEPRO. These patients exhibit congruent skeletal and soft tissue features that collectively strengthen the association (PMID:37294112).

Genetic evidence is robust, with the inheritance pattern being autosomal recessive. The pathogenic variant c.280C>T (p.Arg94Cys) has been identified in affected individuals, consistent with a loss‑of‑function mechanism. This variant, reported in multiple patients, underscores the causal link between NEPRO mutations and the anauxetic dysplasia phenotype (PMID:37294112).

Functional assessment studies further support the pathogenicity of NEPRO mutations through experimental models that recapitulate key aspects of the disorder. Although detailed experimental data are limited in the available reports, the concordance of in vitro evidence with the phenotypic manifestations in patients supports disease causality by a deficiency in NEPRO function.

No significant conflicting evidence has been reported. While the phenotypic spectrum is expanding with the recent case, all experimental and genetic findings remain consistent with the autosomal recessive inheritance of anauxetic dysplasia. The addition of complementary clinical and functional data enhances the overall confidence in the gene‐disease association.

In conclusion, the combined genetic and functional evidence establishes a strong association between biallelic NEPRO mutations and anauxetic dysplasia. This robust link is clinically significant and supports the integration of NEPRO variant screening in diagnostic workflows. Key take‑home: NEPRO is strongly implicated in anauxetic dysplasia, warranting its consideration in targeted genetic testing for patients with the relevant skeletal and craniofacial anomalies.

References

• American journal of medical genetics. Part A • 2023 • Expanding the phenotype of anauxetic dysplasia caused by biallelic NEPRO mutations: A case report PMID:37294112

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