The CYP27A1 gene encodes sterol 27-hydroxylase, an enzyme that is part of the bile acid biosynthesis pathway, specifically involved in the metabolism of cholesterol and bile acids. CYP27A1 was first reported in relation to autosomal recessive cerebrotendinous xanthomatosis (CTX) in 1991 (Cali et al. PMID: 2019602). CTX is a lipid storage disease clinically characterized by diarrhea in infancy, cataracts onset in childhood, tendon xanthomas appearing in adolescence or early adulthood, and adult-onset progressive neurologic dysfunction (psychiatric symptoms, dementia, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Brain MRI findings include white matter signal abnormalities, diffuse brain and cerebellar atrophy, and bilateral hyperintensity of the dentate nuclei. CTX is biochemically characterized by severely reduced levels of chenodeoxycholic acid (CDCA), accumulation of cholesterol and cholestanol in tissues, and increased excretion of bile acids in urine. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the single disease entity has been maintained: cerebrotendinous xanthomatosis (OMIM#606530).
This curation included one missense, three frameshift, one nonsense, and three splice variants reported in eight probands across five publications (PMIDs:7977352, 33400472, 7860076, 31706903, 26937392). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by biochemical function evidence (PMID: 16816916). In summary, there is definitive evidence supporting the relationship between CYP27A1 and autosomal recessive cerebrotendinous xanthomatosis. 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 Leukodystrophy and Leukoencephalopathy GCEP on the meeting date: September 23, 2024 SOP Version #11.
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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