Delineating the Phenotypic Spectrum of SLC26A2-related Skeletal Dysplasias in a Cohort of 115 Patients: Evidence for a Novel Complex Allele Modifying Disease Severity.

Purpose

SLC26A2-related skeletal dysplasias range from recessive multiple epiphyseal dysplasia (rMED) to lethal atelosteogenesis type 2, but factors underlying clinical variability are not fully defined. This study aimed to delineate genotype-phenotype correlations and identify disease modifiers in the largest cohort reported to date.

Methods

A total of 115 individuals with biallelic SLC26A2 variants underwent comprehensive clinical and radiographic phenotyping using a novel 30-criterion severity scoring scale. Molecular analyses included Sanger and next-generation sequencing (including panel and GS), targeted RNA-seq, and functional sulfate uptake assays in patient- and parent-derived fibroblasts.

Results

Four recurrent variants: p.(Cys653Ser), p.(Arg279Trp), c.-26+2T>C, p.(Val341del) accounted for 84% of all alleles. Compared with gnomAD v4.1.1, p.(Cys653Ser) was significantly enriched and p.(Arg279Trp) under-represented in a local dataset, indicating ancestry-specific allele frequencies. Functional assays confirmed pathogenicity of ten variants, including five novel ones. A novel complex allele, p.[Cys653Ser;Arg671His], was identified as a cis-acting modifier allele shifting rMED toward severe DTD, supported by functional and structural analyses. The severity scale objectively stratified patients into distinct groups: rMED (score <25), intermediate rMED/DTD (25-28), and DTD (≥29). p.(Cys653Ser) homozygotes exhibited the mildest phenotype, while the complex allele was associated with a DTD as severe as that of p.(Arg178Ter), consistent with a severe, near-null effect of this allele.

Conclusion

Phenotypic variability extends beyond simple biallelic combinations, with complex alleles acting as modifiers. Our severity scale enables standardized clinical stratification, refining the understanding of SLC26A2-related skeletal dysplasias.