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Clin Genet. 2016 Jul;90(1):90-5. doi: 10.1111/cge.12694. Epub 2015 Dec 21.

A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred.

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Molecular Biology & Genetics Department, Medical Research Center, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan.
Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
Institute of Biochemistry, University of Sindh, Jamshoro, Pakistan.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Unit on Pediatric, Developmental & Genetic Ophthalmology, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Orthopedic Surgery, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan.


Skeletal dysplasias (SDs) are highly heterogeneous disorders composed of 40 clinical sub-types that are part of 456 well-delineated syndromes in humans. Here, we enrolled consanguineous kindred from a remote area of Sindh province of Pakistan, with 14 affected individuals suffering with short stature, kyphoscoliosis, joint dislocations, clubfoot, heart valve anomalies and progressive bilateral mixed hearing loss. To identify pathogenic variants in this family, whole exome sequencing (WES) was performed in one affected and one normal individual, which revealed a novel transversion mutation (c.802G>T; p.Glu268*) in CHST3 associated with the phenotype. CHST3 encodes a chondroitin 6-O-sulfotransferase-1 (C6ST-1) enzyme that is essential for the sulfation of proteoglycans found in cartilages. Previously, mutations in CHST3 have largely been reported in sporadic cases of SD, primarily with severe spinal abnormalities, joint dislocations, joint contractures, and clubfoot. Clinical and radiological examination of the affected individuals in this family provides new insights into phenotypic spectrum of CHST3 alleles and disease progression with age.


CHST3; osteochondrodysplasias; skeletal dysplasia; spondyloepiphyseal dysplasia

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