Background Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred.
Methods We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect.
Results The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.
- skeletal defects
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Contributors AT and SM were responsible for the concept and design of the study. GN and NA generated and interpreted the data. SM and RMKS contributed the clinical data. AT, SM, GN and NA drafted the manuscript. All authors revised the manuscript.
Funding This study was supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK 114Z829 to AT) and URF-QAU, Pakistan (2013-2014 to SM).
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval The ethical review committee of Quaid-i-Azam University and the Boğaziçi University Institutional Review Board for Research with Human Participants.
Provenance and peer review Not commissioned; externally peer reviewed.
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