OSTM1 and Autosomal Recessive Osteopetrosis

This summary reviews the association between OSTM1 (HGNC:21652) and autosomal recessive osteopetrosis (MONDO:0019026). Multiple independent studies have identified pathogenic variants in OSTM1 that segregate with the severe osteopetrotic phenotype, lending strong support for its role in this disease (PMID:16813530, PMID:32015934). The compiled evidence comes from diverse cohorts where affected individuals from consanguineous populations demonstrate classic features of osteoclast dysfunction and, in some cases, additional neurological involvement.

Genetic evidence is robust, with case reports and multi‐patient studies reporting a broad variant spectrum that includes nonsense, frameshift, and splice‐site mutations. For instance, the variant c.75G>A (p.Trp25Ter) has been reported in patients with autosomal recessive osteopetrosis, exemplifying the damaging effect of truncating mutations in OSTM1. Multiple unrelated probands (exceeding 20 across studies PMID:16813530) underscore the consistency of the gene–disease link.

The mode of inheritance is autosomal recessive with documented segregation among affected relatives. Studies have observed additional affected family members harboring the same pathogenic OSTM1 allele, supporting its pathogenic role. Such familial segregation findings, particularly in consanguineous settings, further corroborate the clinical association and assist in diagnostic decision‑making.

Functional and experimental evidence further strengthens the association. In vitro and in vivo assays demonstrate that OSTM1 is critical for stabilizing the chloride channel ClC-7, which is essential for osteoclast function. Disruption of this interaction leads to impaired bone resorption, and in animal models, OSTM1 deficiency replicates the severe skeletal and neurologic phenotypes observed in patients (PMID:16525474). These rigorous functional studies support a dominant haploinsufficiency or loss-of-function mechanism underlying disease pathogenesis.

Integrating the genetic and functional data provides a coherent narrative linking diverse OSTM1 mutations to autosomal recessive osteopetrosis. Although additional evidence exists that surpasses the ClinGen scoring maximum, the combination of broad mutational spectra, segregation in multiple families, and compelling functional assays ensures a high level of clinical certainty.

Key take‑home sentence: OSTM1 mutations represent a well‐validated genetic determinant of autosomal recessive osteopetrosis, with significant implications for diagnosis, prognosis, and therapeutic intervention.

References

• European Journal of Human Genetics • 2017 • Coexisting variants in OSTM1 cause complex phenotypes PMID:28612835
• Journal of Bone and Mineral Research • 2006 • Mutations in OSTM1 define a subset of osteopetrosis with neural involvement PMID:16813530
• Cureus • 2020 • Malignant Infantile Osteopetrosis: A Case Report PMID:32015934
• Bone • 2013 • Severe neuronopathic autosomal recessive osteopetrosis due to deletions in OSTM1 PMID:23685543
• Nature • 2006 • ClC-7 requires Ostm1 to support bone resorption and lysosomal function PMID:16525474

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