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

SLC26A2

Complex SLC26A2 allele p.[Cys653Ser;Arg671His] acting in cis as a modifier shifting the phenotype towards diastrophic dysplasia (DTD), with a near-null effect

SLC26A2-related skeletal dysplasias range from recessive multiple epiphyseal dysplasia (rMED) to lethal atelosteogenesis type 2, and the clinical variability is poorly explained. In the largest reported cohort (115 individuals with biallelic variants), a new 30-criterion severity score separated patients into rMED (<25), intermediate rMED/DTD (25-28) and DTD (≥29). Four recurrent variants account for 84% of alleles, and sulfate uptake assays confirmed the pathogenicity of ten variants, five of them novel. A novel complex allele, p.[Cys653Ser;Arg671His], was identified as a cis-acting modifier shifting rMED towards DTD, with a severity comparable to that of p.(Arg178Ter).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The key finding is that variability is not explained by the combination of two variants alone: a complex allele in cis can change prognosis, which variant-by-variant reading, notably with unphased short-read data, may miss. The severity score provides a stratification tool for genetic counselling, to be validated outside this cohort. The ancestry-specific allele frequencies noted against gnomAD need to be taken into account for interpretation.

Analysis by Dr Thibaut Benquey