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

Abstract

Skeletal dysplasias are highly heterogeneous disorders composed of 40 clinical subtypes 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 fourteen 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 skeletal dysplasia, 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.

Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis

“…CHST3 encodes chondroitin 6-O-sulfotransferase 1 (C6ST1), which transfers a sulfate group from 3 -phosphoadenosine 5phosphosulfate (PAPS) to the C-6 hydroxy group of GalNAc residues in CS chains (Figure 3; Fukuta et al, 1998). Homozygous mutations in CHST3 cause spondyloepiphyseal dysplasia with congenital joint dislocations, which is characterized by a short stature, severe kyphoscoliosis, mild brachydactyly, arthritic joints, joint dislocation, rhizomelia, fusion of the carpal bones, metacarpal shortening, osteoarthritis of the elbow, deafness, and ventricular septal, mitral, and/or tricuspid defects (Table 2; Rajab et al, 2004;Thiele et al, 2004;van Roij et al, 2008;Tuysuz et al, 2009;Tanteles et al, 2013;Muys et al, 2016;Waryah et al, 2016;Srivastava et al, 2017). Loss of C6ST activity as well as the decrease of 6-O-sulfated CS were demonstrated in skin fibroblasts from patients (Thiele et al, 2004;van Roij et al, 2008).…”

The genetics of isolated and syndromic clubfoot

“…63,64 CHST3 encodes an enzyme that catalyzes sulfation of chondroitin containing proteoglycan, which is a necessary part of connective tissues. 65 Mutations in CHST3 have been associated with skeletal dysplasias that can present with clubfoot, including humero-spinal dysostosis and spondyloepiphyseal dysplasia, as well as recessive Larsen syndrome. 61,65 Initiation and polymerization of GAG occurs in the Golgi apparatus.…”

“…65 Mutations in CHST3 have been associated with skeletal dysplasias that can present with clubfoot, including humero-spinal dysostosis and spondyloepiphyseal dysplasia, as well as recessive Larsen syndrome. 61,65 Initiation and polymerization of GAG occurs in the Golgi apparatus. A mutation in COG4 has been found to disrupt this process, resulting in a rare cause of dwarfism that presents with multiple limb malformations including clubfoot, known as Saul-Wilson syndrome.…”

MTHFR and F5 genetic variations have association with preeclampsia in Pakistani patients: a case control study

“…Ten ml of venous blood was collected in 50 ml tube containing 400 μl of anticoagulant ethylene diamine tetra acetic acid (EDTA), 0.5 M from both preeclamptic and normal pregnant women. Genomic DNA was extracted by inorganic method, described as previously [22].…”