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Autosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene
Wade Jodeh1, Amy J Katz1, Marian Hart1
1Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Context:
Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder resulting from impaired osteoclastic bone resorption. Clinical manifestations frequently include fractures, osteonecrosis (particularly of the jaw or maxilla), osteomyelitis, blindness, and/or bone marrow failure. ADO usually results from heterozygous missense variants in the Chloride Channel 7 gene (CLCN7) that cause disease by a dominant negative mechanism. Variants in the T-cell immune regulator 1 gene (TCIRG1) are commonly identified in autosomal recessive osteopetrosis but have only been reported in 1 patient with ADO.
Case Description:
Here, we report 3 family members with a single heterozygous missense variant (p.Gly579Arg) in TCIRG1 who have a phenotype consistent with ADO. Three of 5 protein prediction programs suggest this variant likely inhibits the function of TCIRG1.
Conclusion:
This is the first description of adult presentation of ADO caused by a TCIRG1 variant. Similar to families with ADO from CLCN7 mutations, this variant in TCIRG1 results in marked phenotype variability, with 2 subjects having severe disease and the third having very mild disease. This family report implicates TCIRG1 missense mutations as a cause of ADO and demonstrates that the marked phenotypic variability in ADO may extend to disease caused by TCIRG1 missense mutations.
Insights
Autosomal dominant osteopetrosis (ADO) can be caused by T-cell immune regulator 1 (TCIRG1) gene variants, not just Chloride Channel 7 (CLCN7). This study reveals significant variability in ADO presentation within a family with a TCIRG1 missense mutation.
Area of Science:
- Genetics
- Molecular Biology
- Skeletal Dysplasias
Background:
- Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder characterized by impaired osteoclastic bone resorption.
- ADO typically presents with fractures, osteonecrosis, osteomyelitis, blindness, and bone marrow failure, often due to heterozygous missense variants in the Chloride Channel 7 gene (CLCN7).
- Variants in the T-cell immune regulator 1 gene (TCIRG1) are known causes of autosomal recessive osteopetrosis but have rarely been associated with ADO.
Purpose of the Study:
- To report the first adult presentation of Autosomal dominant osteopetrosis (ADO) caused by a T-cell immune regulator 1 (TCIRG1) gene variant.
- To investigate the role of TCIRG1 missense mutations in the pathogenesis of ADO.
- To highlight the phenotypic variability associated with TCIRG1-related ADO.
Main Methods:
- Clinical and genetic analysis of three family members presenting with a phenotype consistent with Autosomal dominant osteopetrosis (ADO).
- Identification of a single heterozygous missense variant (p.Gly579Arg) in the T-cell immune regulator 1 (TCIRG1) gene.
- In silico analysis using five protein prediction programs to assess the functional impact of the identified TCIRG1 variant.
Main Results:
- A heterozygous missense variant (p.Gly579Arg) in the TCIRG1 gene was identified in three family members with Autosomal dominant osteopetrosis (ADO).
- Protein prediction programs indicated that the TCIRG1 variant likely inhibits gene function.
- The affected family members exhibited significant phenotypic variability, with two individuals presenting severe disease and one with very mild symptoms.
Conclusions:
- This study establishes T-cell immune regulator 1 (TCIRG1) missense mutations as a cause of Autosomal dominant osteopetrosis (ADO).
- The findings demonstrate that marked phenotypic variability, similar to that observed in CLCN7-related ADO, can also occur in TCIRG1-related ADO.
- This report expands the genetic spectrum of ADO and underscores the importance of considering TCIRG1 in the differential diagnosis of osteopetrosis.
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