Cerebrotendinous Xanthomatosis (CTX) is a lipid storage disease caused by recessively inherited pathogenic variants in CYP27A1 (OMIM 213700). The classic clinical presentation includes infantile-onset chronic diarrhea, juvenile-onset bilateral cataracts, with development of tendon xanthomas and progressive neurological dysfunction. These multisystem clinical features typically appear in different decades of life often confounding diagnosis of CTX. Further complicating diagnosis is the generally held belief that the clinical presentation of CTX varies highly between individuals and even within families. CTX is a treatable disorder and treatment is most effective when started in the first two decades of life, rendering a particular urgency to diagnosis. In this study we bring a novel approach to detecting genotype phenotype associations in CTX. We conducted a systematic review of the literature to identify all functional analyses of pathogenic CYP27A1 variants at the level of mRNA, protein and enzyme activity. We identified missense variants that result in complete loss of function (LOF) as well as missense variants that are have some partial function (hypomorphs). Next, we identified every CTX patient in the medical literature whose genotype and clinical phenotype were reported, and binned them according to functional genotype: LOF vs hypomorph. Analysis of these clinical, biochemical and molecular genetics data revealed a clear genotype phenotype association for CTX based on individuals who had two LOF variants vs two hypomorphs. The prevalence of each clinical feature was significantly higher in individuals with two LOF variants for every feature except tendon xanthoma and pyramidal signs. CTX had a detrimental effect on cognition for almost everyone with two LOF variants (96%), while tendon xanthomas were the most common feature in individuals with two hypomorphs (88%). We suspect this is due to ascertainment bias; individuals with a milder form of CTX may not get diagnosed with CTX unless they have this unusual hallmark of the disease. We studied the population genetics of the pathogenic CYP27A1 alleles in gnomAD (N~800,000). Estimated disease incidence based on carrier frequencies was consistent across the African/African American, Admixed American and European populations (1/308,000). However, no African/African American individuals have been reported in the medical literature as having CTX. Analyses of the pathogenic alleles in each population showed that the frequency of hypomorph pathogenic CYP27A1 alleles was twice as high in African/African Americans (p=3.6E-4) vs Europeans (p=1.2E-4). Conversely, LOF alleles had a lower frequency in African/African Americans than in Europeans, p=6.1E-4 vs p=8.6E-4, respectively. By combining clinical, molecular, functional and populations genetics we uncovered a large health disparity in the diagnosis and treatment of CTX in African Americans and point to the milder clinical presentation of hypomorphs as an underlying component. The results of this study reveal specific opportunities for mitigating this disparity through recognition of the milder form of CTX as a clinical entity that is driven by hypomorph genetic alleles and broad adoption of biochemical testing that utilizes more sensitive biomarkers. Applying the framework and concepts leveraged in this study to the diagnosis of all monogenic disorders will likely result in improved diagnosis and health equity for the rare disease community.

The authors have declared no competing interest.

This study is supported by NIH NINDS RO1 NS08372

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All data used in this study is publicly available in articles indexed in PubMed and in gnomAD https://gnomad.broadinstitute.org/

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All data used in this study is publicly available in articles indexed in PubMed and in gnomAD https://gnomad.broadinstitute.org/