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. 2023 Jan 17;18(1):13.
doi: 10.1186/s13023-022-02578-1.

Allelic prevalence and geographic distribution of cerebrotendinous xanthomatosis

Tiziano Pramparo  1 , Robert D Steiner  2 , Steve Rodems  3 , Celia Jenkinson  3
Affiliations

Allelic prevalence and geographic distribution of cerebrotendinous xanthomatosis

Tiziano Pramparo et al. Orphanet J Rare Dis. .

Abstract

Background: Cerebrotendinous xanthomatosis (CTX) is a rare recessive genetic disease characterized by disruption of bile acid synthesis due to inactivation of the CYP27A1 gene. Treatment is available in the form of bile acid replacement. CTX is likely underdiagnosed, and prevalence estimates based on case diagnosis are probably inaccurate. Large population-based genomic databases are a valuable resource to estimate prevalence of rare recessive diseases as an orthogonal unbiased approach building upon traditional epidemiological studies.

Methods: We leveraged the Hardy-Weinberg principle and allele frequencies from gnomAD to calculate CTX prevalence. ClinVar and HGMD were used to identify high-confidence pathogenic missense variants and to calculate a disease-specific cutoff. Variant pathogenicity was also assessed by the VarSome implementation of the ACMG/AMP algorithm and the REVEL in silico predictor.

Results: CTX prevalence estimates were highest in Asians (1:44,407-93,084) and lowest in the Finnish population (1:3,388,767). Intermediate estimates were found in Europeans, Americans, and Africans/African Americans (1:70,795-233,597). The REVEL-predicted pathogenic variants accounted for a greater increase in prevalence estimates for Europeans, Americans, and Africans/African Americans compared with Asians. We identified the most frequent alleles designated pathogenic in ClinVar (p.Gly472Ala, p.Arg395Cys), labeled pathogenic based on sequence consequence (p.Met1?), and predicted to be pathogenic by REVEL (p.Met383Lys, p.Arg448His) across populations. Also, we provide a prospective geographic map of estimated disease distribution based on CYP27A1 variation queries performed by healthcare providers from selected specialties.

Conclusions: Prevalence estimates calculated herein support and expand upon existing evidence indicating underdiagnosis of CTX, suggesting that improved detection strategies are needed. Increased awareness of CTX is important for early diagnosis, which is essential for patients as early treatment significantly slows or prevents disease progression.

Keywords: Allele frequency; Cerebrotendinous xanthomatosis (CTX); Genomic variation; Pathogenic variants; Rare metabolic disease.

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Conflict of interest statement

TP, SR, CJ are full-time employees of Travere Therapeutics, Inc., and may have an equity or other financial interest in Travere Therapeutics, Inc. RDS is an employee of PreventionGenetics, an Exact Sciences company. He has equity interest in and has received consulting fees from Acer Therapeutics and PTC Therapeutics. He has received consulting fees from Aeglea BioTherapeutics; Alexion Pharmaceuticals, Inc; Best Doctors; Health Advances LLC; Leadiant, Precision for Value; and Travere Therapeutics, Inc; and honoraria from Medscape/WebMD and The France Foundation. He received no funding to support writing and revising this manuscript. He has received research funding from Alexion Pharmaceuticals, Inc and the Smith Lemli Opitz Foundation.

Figures

Fig. 1
Fig. 1
CTX alleles distribution from gnomAD. Distribution of the CTX alleles with labels for the top alleles (Allele_Freq > 1e-04) and color-coded by sequence consequence. Variant names follow the HGVS transcript or protein consequence. Amino acids are abbreviated by their one letter code
Fig. 2
Fig. 2
CYP27A1 pathogenic variants world map. Geographic distribution of CYP27A1 gene variants queries performed by HCPs of selected clinical/medical professions using the VarSome search engine. The map represents a proxy for clinical activity by country potentially linked to the diagnosis and care of prospective CTX patients. Grey color indicates no queries reported
See this image and copyright information in PMC

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