Akbar Amirfiroozy ^1* Maryam Naghinejad ¹ Azim Rezamand ^1* Hamid Farhangi ^2* Zahra Golchehre ^3* Hossein Jalali ^4* Mohammad Keramatipour ^3*

• ¹ Tabriz University of Medical Sciences, Tabriz, Iran
• ² Mashhad University of Medical Sciences, Mashhad, Razavi Khorasan, Iran
• ³ Tehran University of Medical Sciences, Tehran, Tehran, Iran
• ⁴ Mazandaran University of Medical Sciences, Sari, Mazandaran, Iran

Backgrounds: 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. Methods and results: 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. Conclusion: 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 till now, and two were observed in osteopetrosis patients. Our investigations suggest that these variants are potentially deleterious and necessitate further examination using bioinformatics and laboratory tests.