Two rare CHST3 missense variants, p.(Cys247Ser) and p.(Leu294Pro), in the homozygous and compound-heterozygous state cause chondrodysplasia with congenital joint dislocations in a consanguineous Syrian kindred

Abstract

Biallelic loss-of-function variants in the carbohydrate sulfotransferase 3 gene ( CHST3 ), which encodes chondroitin 6-O-sulfotransferase 1, cause an autosomal recessive skeletal dysplasia that unites the former entities recessive Larsen syndrome, hume-ro-spinal dysostosis and spondyloepiphyseal dysplasia Omani type. The disorder presents with congenital dislocations of large joints and variable short stature and evolves into a progressive spondyloepiphyseal dysplasia; cardiac valve disease, hearing loss and dental anomalies occur in a subset of patients. We studied a six-generation consanguineous Syrian kindred with five affected individuals from three sibships clinically suspected with CHST3 -related disease. Trio-exome sequencing in one nuclear family revealed homozygosity for the rare missense variant c.881T>C, p.(Leu294Pro) in exon 3 of CHST3 . Direct Sanger sequencing of exon 3 in all three nuclear families confirmed homozygosity for p.(Leu294Pro) in affected individuals from the first nuclear family and compound-heterozygosity for p.(Leu294Pro) and another ultrarare variant, c.740G>C, p.(Cys247Ser), in affected persons from the other two nuclear families. Each variant was observed only once, in the heterozygous state, among more than 1.5 million alleles in the Genome Aggregation Database. The same two variants had been reported once in a child from another consanguineous family of Syrian origin, suggesting a regional founder effect. Cysteine 247 is invariant across vertebrate orthologues, and leucine 294 is replaced only by other hydrophobic residues. Both variants received high in silico pathogenicity scores, and elastic network modelling of a predicted protein structure indicated destabilization of the enzyme. Leucine 294 lies seven residues upstream of the 3’-phosphate binding motif for the sulfate donor, in the region where the functionally confirmed substitutions p.(Leu286Pro), p.(Arg304Gln) and p.(Leu307Pro) cluster. We classify both variants as likely pathogenic according to current variant interpretation guidelines. The family shows that recessive disease in consanguineous pedigrees can result from compound heterozygosity, so analysis pipelines should not rely solely on regions of homozygosity.