The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis

Abstract

Autosomal recessive malignant infantile osteopetrosis is a congenital disease characterized by pathologically increased bone density. Recently, the use of whole exome sequencing has been utilized as a clinical diagnostic tool in a number of Mendelian disorders. In this study, whole exome sequencing (WES) was successfully used in six patients with malignant infantile osteopetrosis (MIOP) and identified mutations in four MIOP-related genes (CLCN7, TCIRG1, SNX10, and TNFRSF11A). We report these patients, describe the mutations and review the current literature.

Successful hematopoietic stem cell transplantation for osteopetrosis using reduced intensity conditioning

“…Mutations in several genes lead to osteopetrosis (e.g. TCIRG1, SNX10, CA2, CLCN7 , and RANK) , although in approximately 30% of cases no genetic diagnosis is found . Inheritance can be autosomal recessive or autosomal dominant, but the most severe cases are almost exclusively autosomal recessive and are termed infantile malignant osteopetrosis (IMO).…”

Utility of Whole-Exome Sequencing in Pediatric and Medical Diagnosis

“…WES was carried out among six patients and was successfully able to identify mutations in four genes: SNX10, TNFRSF11A, TCIRG1 and CLCN7. Mutations in five children were found to behave homozygous, whereas, in the additional one patient, the compound heterozygous mutations in the TCIRG1 gene were identified [30]. Another ARD, the Caroli disease which is complex and rare and is…”

Intermediate autosomal recessive osteopetrosis with a large noncoding deletion in SNX10: A case report

“…(osteopetrosis-associated transmembrane protein 1), and SNX10 (sorting nexin 10) account for 1-5% of ARO cases each. [3][4][5][6][7][8] ARO occurs in an estimated 1 in 250 000 people. In addition, a form termed exceptional intermediate autosomal recessive osteopetrosis (IARO) has been described, with mutations in CLCN7, PLEKHM1 (pleckstrin homology domain-containing family M with RUN domain-member 1), and TCIRG1.…”

“…Many genes are implied in ARO such as TCIRG1 (T‐cell immune regulator 1) and CLCN7 (chloride voltage‐gated channel 7), which are responsible for 70% of genetically confirmed ARO. Four additional genes RANKL (receptor activator of NF‐κB ligand), RANK (receptor activator of NF‐κB), OSTM1 (osteopetrosis‐associated transmembrane protein 1), and SNX10 (sorting nexin 10) account for 1‐5% of ARO cases each . ARO occurs in an estimated 1 in 250 000 people.…”