A founder mutation in the TCIRG1 gene causes osteopetrosis in the Ashkenazi Jewish population.

Clinical genetics

PubMedID: 24989235

Anderson SL, Jalas C, Fedick A, Reid KF, Carpenter TO, Chirnomas D, Treff NR, Ekstein J, Rubin BY. A founder mutation in the TCIRG1 gene causes osteopetrosis in the Ashkenazi Jewish population. Clin Genet. 2014;.
Osteopetrosis is a rare and heterogeneous genetic disorder characterized by dense bone mass that is a consequence of defective osteoclast function and/or development. Autosomal recessive osteopetrosis (ARO) is the most severe form and is often fatal within the first years of life; early hematopoietic stem cell transplant (HSCT) remains the only curative?treatment?for?ARO. The majority of the ARO-causing mutations are located in the TCIRG1 gene. We report here the identification and characterization of an A to T transversion in the fourth base of the intron 2 donor splice site (c.117+4A?T) in TCIRG1, a mutation not previously seen in the Ashkenazi Jewish (AJ) population. Analysis of a random sample of individuals of AJ descent revealed a carrier frequency of approximately 1 in 350. Genotyping of five loci adjacent to the c.117+4A?T-containing TCIRG1 allele revealed that the presence of this mutation in the AJ population is due to a single founder. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation.