SLC26A2/DTDST Spectrum: A Cohort of 12 Patients Associated with a Comprehensive Review of the Genotype-Phenotype Correlation.

ABSTRACT:

Introduction

Pathogenic variants in the SLC26A2/DTDST gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and recessive-multiple epiphyseal dysplasia (rMED), the first 2 being lethal. Here, we report a cohort and a comprehensive literature review on a genotype-phenotype correlation of SLC26A2/DTDST-related disorders.

Methods

The local patients were genotyped by Sanger sequencing or next-generation sequencing (NGS). We reviewed data from the literature regarding phenotype, zygosity, and genotype in parallel.

Results

The local cohort enrolled 12 patients, including one with a Desbuquois-like phenotype. All but one showed biallelic mutations, however, only one allele mutated in a fetus presenting ACG1B was identified. The literature review identified 42 articles and the analyses of genotype and zygosity included the 12 local patients.

Discussion

The R279W variant was the most prevalent among the local patients. It was in homozygosity (hmz) in 2 patients with rMED and in compound heterozygosity (chtz) in 9 patients. The genotype and zygosity review of all patients led to the following conclusions: DTD is the most common phenotype in Finland due to a Finnish mutation (c.727-1G>C). Outside of Finland, rMED is the most prevalent phenotype, usually associated with R279W in hmz. In contrast, DTD's genotype is usually in chtz. Despite a large number of variants (38), just 8 are recurrent (R279W, C653S, c.-26+2T>C, R178*, K575Sfs*10, V340del, G663R, T512K). The last 3 in hmz lead to lethal phenotypes. The Finnish mutation is found only in chtz outside of Finland, being associated with all 4 classical phenotypes. The p.R178* and p.K575Sfs*10 variants should be viewed as lethal mutations since both were mainly described with lethal phenotypes and were never reported in hmz. The existence of 9 patients with only one mutated allele suggests that other mutations in the other allele of these patients still need to be unveiled.

SUBMITTER: Silveira C 

PROVIDER: S-EPMC9843583 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature