A comprehensive report of the clinical and mutational profiles of 30 Iranian malignant infantile osteopetrosis patients

Osteopetrosis is a group of genetically and clinically diverse inherited disorders characterized by an increase in bone density. The main known cause is an abnormality in the development or function of osteoclasts. Hence, the process of bone resorption is impaired, resulting in: 1- a reduction in bone marrow volume and, subsequently, a decrement in the hematopoietic capacity of bone marrow, which leads to anemia and compromised immunological function; 2- improper bone development, which leads to pressure on peripheral nerves, causing auditory, visual, and movement impairments; and 3- disturbance in the formation of bone microstructure that leads to susceptibility to bone fracture. This study aimed to evaluate the clinical symptoms and genetic causes of 30 patients (probands) who suffered from malignant infantile osteopetrosis, a subtype of this disorder. The Sanger sequencing technique was used to sequence four common genes (TCIRG1, CLCN7, SNX10, and OSTM1) in osteopetrosis. Subsequently, the selected variants were subjected to segregation analysis between the probands and their parents. Consequently, the sequencing of these four genes in probands revealed 16 pathogenic and likely pathogenic mutations, five of which had never been reported before. The TCIRG1 gene has three novel splice site variations and one frameshift variant. The CLCN7 gene had a novel missense variant. Also, a total of five variants of uncertain significance (VUSs) were identified in the analyzed sequences, of which three haven't been reported to date, and two were observed in osteopetrosis patients. Therefore, by documenting these novel likely pathogenic variants and VUS in known genes associated with this disease in patients, specialists can conduct more accurate genetic analysis and counseling when encountering these variants. Additionally, this documentation will facilitate the reclassification of these variants.