Apparent underdiagnosis of Cerebrotendinous Xanthomatosis revealed by analysis of ~ 60,000 human exomes

Highlights

• Cerebrotendinous Xanthomatosis (CTX) is under-diagnosed.

• Data extraction and modeling estimates incidence based on ~ 60,000 subjects.

• CTX incidence is 1:134,970–1:461,358 in Europeans.

• Genetic screening in juvenile cataract patients may increase diagnosis of CTX.

Abstract

Cerebrotendinous Xanthomatosis (CTX) is a treatable inborn error of metabolism caused by recessive variants in CYP27A1. Clinical presentation varies, but typically includes infant-onset chronic diarrhea, juvenile-onset bilateral cataracts, and later-onset tendinous xanthomas and progressive neurological dysfunction. CYP27A1 plays an essential role in side-chain oxidation of cholesterol necessary for the synthesis of the bile acid, chenodeoxycholic acid, and perturbations in this gene that reduce enzyme activity result in elevations of cholestanol. It is commonly held that CTX is exceedingly rare, but epidemiological studies are lacking. In order to provide an accurate incidence estimate of CTX, we studied the ExAC cohort of ~ 60,000 unrelated adults from global populations to determine the allele frequency of the 57 variants in CYP27A1 reported pathogenic for CTX. In addition, we conducted bioinformatics analyses on these CTX-causing variants and determined a bioinformatics profile to predict variants that may be pathogenic but have not yet been reported in the CTX patient literature. An additional 29 variants were identified that met bioinformatics criteria for being potentially pathogenic. Incidence was estimated based allele frequencies of pathogenic CTX variants plus those determined to be potentially pathogenic. One variant, p.P384L, previously reported in three unrelated CTX families had an allele frequency ≥ 1% in European, Latino and Asian populations. Three additional mutations had a frequency of ≥ 0.1% in Asian populations. CTX disease incidence was calculated excluding the high frequency p.P384L and separately using a genetic paradigm where this high frequency variant only causes classic CTX when paired in trans with a null variant. These calculations place CTX incidence ranging from 1:134,970 to 1:461,358 in Europeans, 1:263,222 to 1:468,624 in Africans, 1:71,677 to 1:148,914 in Americans, 1:64,267 to 1:64,712 in East Asians and 1:36,072 to 1:75,601 in South Asians. This work indicates CTX is under-diagnosed and improved patient screening is needed as early intervention prevents disease progression.

Introduction

Cerebrotendinous Xanthomatosis (CTX, OMIM 213700) is an inborn error of bile acid synthesis caused by recessive mutations in CYP27A1 encoding sterol-27-hydroxylase. The classic clinical presentation includes infantile-onset chronic diarrhea, juvenile-onset bilateral cataracts, with later development of tendinous xanthomas and progressive neurological dysfunction including variably spasticity, ataxia, cognitive dysfunction and dementia. However, clinical manifestations can vary significantly even within families. CYP27A1 plays an essential role in normal cholesterol metabolism and perturbations in this gene result in elevations of cholestanol in tissue and plasma, as well as build-up of toxic bile acid intermediates. Treatment is available for this inborn error of metabolism (IEM) which, if started early in life, can prevent the major clinical problems associated with this disease, reviewed in [1]. Thus, the identification of all patients at a young age significantly benefits patients and families.

It is commonly held that CTX is exceedingly rare and while definitive diagnosis can be made with available diagnostic testing of plasma sterols, most often patients who fall into the differential for CTX are not tested for CTX. Given this background and the paucity of epidemiological studies of CTX, we hypothesized that CTX may be under-diagnosed. We sought to provide an accurate disease incidence based on the ExAC cohort, a large cohort of over 60,000 unrelated adults who do not have a diagnosis of CTX and were not ascertained for studies of CTX.

We assessed the previously reported CTX-causing variants bioinformatically. The results of analyzing these known pathogenic variants were then utilized to generate an empirically determined bioinformatic framework for prediction of pathogenicity of other CYP27A1 variants. Few patients with CTX have been reported in the literature and it is most likely that there are pathogenic mutations segregating in the population that have not yet been described. We identified these additional ‘potentially pathogenic’ variants by conducting a multiplex bioinformatic analysis on the variants in the ExAC cohort. The resulting list of pathogenic and ‘potentially pathogenic’ variants was used to calculate CTX disease incidence. Results show this disease is under-diagnosed and raises questions of variable penetrance and possible modified genetic paradigms for CTX as observed in other IEMs such as phenylketonuria (OMIM 261600) and biotinidase deficiency (OMIM 253260) [2], [3], [4].