EXT1 and EXT2 Variants in 22 Chinese Families With Multiple Osteochondromas: Seven New Variants and Potentiation of Preimplantation Genetic Testing and Prenatal Diagnosis.

Ye Wang,Claude Férec,Yan Xu,Liangying Zhong,Yuanjun Ji,David N Cooper,Jian-Min Chen,Lei Ding,Caixia Xu,Sacha Schutz,Yanmin Luo

doi:10.3389/fgene.2020.607838

Abstract

Multiple osteochondromas (MO), the most common type of benign bone tumor, is an autosomal dominant skeletal disorder characterized by multiple cartilage-capped bony protuberances. In most cases, EXT1 and EXT2, which encode glycosyltransferases involved in the biosynthesis of heparan sulfate, are the genes responsible. Here we describe the clinical, phenotypic and genetic characterization of MO in 22 unrelated Chinese families involving a total of 60 patients. Variant detection was performed by means of a battery of different techniques including Sanger sequencing and whole-exome sequencing (WES). The pathogenicity of the missense and splicing variants was explored by means of in silico prediction algorithms. Sixteen unique pathogenic variants, including 10 in the EXT1 gene and 6 in the EXT2 gene, were identified in 18 (82%) of the 22 families. Fourteen (88%) of the 16 variants were predicted to give rise to truncated proteins whereas the remaining two were missense. Seven variants were newly described here, further expanding the spectrum of MO-causing variants in the EXT1 and EXT2 genes. More importantly, the identification of causative variants allowed us to provide genetic counseling to 8 MO patients in terms either of preimplantation genetic testing (PGT) or prenatal diagnosis, thereby preventing the reoccurrence of MO in the corresponding families. This study is the first to report the successful implementation of PGT in MO families and describes the largest number of subjects undergoing prenatal diagnosis to date.

Highlights

Multiple osteochondromas (MO) (OMIM 133700-133701), known as hereditary multiple exostoses (HME) or osteocartilaginous exostosis, is an autosomal dominant skeletal disorder characterized by the formation of benign cartilagecapped bony protuberances, typically arising on the metaphyses of long tubular bones (Bovee, 2008)
We report the genetic findings from 22 Chinese MO families together with the successful use of this information to potentiate preimplantation genetic testing (PGT) and prenatal diagnosis in 8 MO families
In the informative patients, osteochondroma/exostoses generally occurred in the long bones of the upper and lower limbs; chest bones [27.8% (10/36)] and hip [11.1% (4/36)] were the most commonly affected sites whereas vertebral osteochondroma/exostoses were found only in a single patient (i.e., Family 15-III-1)

Summary

Introduction

Multiple osteochondromas (MO) (OMIM 133700-133701), known as hereditary multiple exostoses (HME) or osteocartilaginous exostosis, is an autosomal dominant skeletal disorder characterized by the formation of benign cartilagecapped bony protuberances, typically arising on the metaphyses of long tubular bones (Bovee, 2008). The prevalence of MO is estimated to be 1/50,000 (Wicklund et al, 1995) and would appear to be higher in males (male-to-female ratio, 1.5:1) (D’Arienzo et al, 2019), making it one of the most frequent causes of skeletal dysplasia. MO is characterized by significant inter- and intra-familial phenotypic heterogeneity, including variation in the number and size of osteochondromas, the number and location of the bones involved, and the degree of the deformities arising (Peterson, 1989). 62% of MO patients have a positive family history, with nearly complete penetrance (Schmale et al, 1994)

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