CA2 was first reported in relation to autosomal recessive osteopetrosis 3 in 1991 (Venta et al. 1991, PMID: 1928091). Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis (OPT), renal tubular acidosis (RTA), and neurological disorders related to cerebral calcifications. It is also known as Carbonic anhydrase 2 deficiency, Guibaud-Vainsel syndrome, Marble brain disease, Mixed RTA, and RTA type 3. Eleven unique variants (missense, nonsense, frameshift, splice-site) that have been reported in 8 probands in 8 publications (PMIDs: 1928091, 1542674, 7627193, 19556665, 27848944, 33555497, 28509178, 37662627) are included in this curation. Variants in this gene segregated in 4 additional family members (PMIDs: 1542674, 28509178). More proband is reported in the literature but the maximum score for genetic evidence (12 pts) has been reached. This gene-disease relationship is supported by biochemical function study, expression data, and a mouse model replicating the phenotype (PMIDs: 8200964, 6405388, 16396925, 3126501, 18175028). In summary, there is definitive evidence to support the relationship between CA2 and autosomal recessive osteopetrosis 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date June 10th, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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