Cerebrotendinous Xanthomatosis occurs at high frequency in Ashkenazi Jews.

Cerebrotendinous Xanthomatosis (CTX) is a treatable, inborn error of bile acids metabolism caused by pathogenic variants in CYP27A1. CTX is a multi-organ system disorder that progresses over decades. Clinical features include cerebellar dysfunction, pyramidal tract dysfunction, cognitive deficits and decline, peripheral neuropathy, chronic diarrhea, bilateral cataracts, and tendon xanthomas. Treatment is effective when started early, but diagnostic delays often result in individuals not being diagnosed until after the window of highest treatment efficacy. CTX is documented to occur in most global populations, however, no CTX-causing genetic variants have been reported in Ashkenazi Jews. We conducted a systematic review of every case of CTX reported in a person identified as Jewish and the specific CYP27A1 variants present. We also leveraged the Israeli Medical Genetics Database and the population genetics data resource gnomAD to identify CTX-causing alleles in Ashkenazi Jews. We found that there are three pathogenic CYP27A1 variants in the Ashkenazi Jewish population segregating at an appreciable frequency, with a gene carrier rate of 0.002 based on the gnomAD Ashkenazi Jewish data. One pathogenic variant appears only in the Ashkenazi Jewish group in gnomAD, which contains genetic data from across the globe. We compared the carrier frequency for CTX to the carrier frequencies for diseases that are commonly included in carrier screening for Ashkenazi Jews. These results show that CTX occurs in Ashkenazi Jews, and that both Sephardi and Ashkenazi Jews may benefit from newborn and carrier screening for CTX.