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Clin Genet. 2015 Jul;88(1):74-9. doi: 10.1111/cge.12448. Epub 2014 Jul 31.

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

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Department of Biological Sciences, Fordham University, Bronx, NY, 10458, USA.
Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, 11204, USA.
Department of Microbiology and Molecular Genetics, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
Yale University School of Medicine, Departments of Pediatrics (Endocrinology) and Orthopedics and Rehabilitation, New Haven, CT, 06520, USA.
Reproductive Medicine Associates of New Jersey, Department of Research, Morristown, NJ, 07960, USA.
Dor Yeshorim, The Committee for Prevention of Jewish Diseases, Brooklyn, NY, 11211, USA.


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.


Ashkenazi Jewish; TCIRG1; founder mutation; osteopetrosis

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