# Prevalence of Smith–Lemli–Opitz Syndrome Carriers and the Spectrum of DHCR7 Pathogenic Variants in Representative Czech and Hungarian Population Cohorts

## TL;DR

This study finds a high carrier frequency of Smith-Lemli-Opitz syndrome in Czech and Hungarian populations and identifies common genetic variants linked to the condition.

## Contribution

The study reports the first population-specific carrier frequency and mutational spectrum of DHCR7 in Central European populations.

## Key findings

- The SLOS carrier frequency in Czech and Hungarian populations is 2.83%.
- The c.452G>A variant is the most common DHCR7 mutation in these populations.
- Central European populations are underrepresented in global genetic databases like gnomAD.

## Abstract

Background: Smith–Lemli–Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis, caused by biallelic mutations in the DHCR7 gene. Genotype–phenotype correlations regarding DHCR7 variants could explain the variation in severity, ranging from in utero demise or severe SLOS to a mild phenotype. Clinical recognition can be challenging. This study aimed to determine the frequency of SLOS carriers in the Central European population, as well as the mutational spectrum of DHCR7 in these carriers. Methods: A retrospective analysis of DHCR7 variants was conducted using next-generation sequencing data from 55,289 individuals in Czech and Hungarian genetic laboratories. Results: The SLOS carrier frequency and the mutational spectrum of the DHCR7 gene in its carriers were established in the Czech and Hungarian sub-cohorts. In the combined dataset, we identified causative DHCR7 variants on 1567 alleles among 55,289 tested individuals, contributing to an SLOS carrier frequency of 2.83%. Of the 31 DHCR7 variants detected, the c.452G>A variant was the most prevalent, accounting for 1.8% of all detected alleles in our cohorts. In contrast, the c.964-1G>C variant was more frequent in non-Finnish Europeans, as indicated by the gnomAD 4.1.0 database. The DHCR7 mutational spectra of patients and carriers were comparable in terms of the most common variants. Conclusions: The high SLOS carrier frequency (2.83%) underscores the importance of SLOS carrier screening in Central European populations. The prevalent DHCR7 null mutations and their potential combinations may explain the lower-than-expected prevalence of SLOS, whilst Central and Eastern European populations remain likely underrepresented in the current gnomAD database.