Abstract
Hereditary multiple exostoses (HME) is a rare skeletal disorder characterized by the formation of multiple benign cartilage-capped tumors, usually in the metaphyseal region of the long bones. Over 70% of HME cases arise from monoallelic mutations in either of the two genes encoding the heparan sulfate (HS) synthesis enzymes, ext1 and ext2. To identify more HME-associated mutations, genomic DNA from members of five independent consanguineous families with HME was sequenced with whole exome sequencing (WES). A novel heterozygous splice site mutation (c.1173+2T>A) in ext2 was detected in all three affected members of family V. Further study showed that the novel mutation caused exon 7 of ext2 mRNA to be skipped during splicing and caused a frameshift after the codon for Arg360, which results in the appearance of new 43 codons, followed by a termination codon. Although the resulting truncated protein was still localized to the Golgi, similar to the full-length EXT2, its HS synthesis activity decreased by 40%. In this study, a novel splice site mutation in ext2 was identified and suggested to be a pathogenic mutation of HME, which may expand the genetic etiology spectrum of HME and may be helpful for clinical genetic counseling and prenatal diagnosis.
Highlights
Hereditary multiple exostoses (HME), known as hereditary multiple osteochondroma, is a rare genetic skeletal disorder characterized by the formation of cartilagecapped benign bone tumors, usually in the metaphyseal region of the long tubular bones, such as the bones of limbs, shoulder blades, ribs and pelvis, with symmetrical distribution (Stieber and Dormans, 2005)
To identify more HME-associated mutations, we recruited five independent consanguineous HME families. Genomic DNA (gDNA) from patients and their relatives were sequenced with whole exome sequencing
HME is a rare dominantly inherited skeletal disorder characterized by the formation of cartilage-capped benign bone tumors, usually in the metaphyseal region of the long tubular bones
Summary
Hereditary multiple exostoses (HME), known as hereditary multiple osteochondroma, is a rare genetic skeletal disorder characterized by the formation of cartilagecapped benign bone tumors, usually in the metaphyseal region of the long tubular bones, such as the bones of limbs, shoulder blades, ribs and pelvis, with symmetrical distribution (Stieber and Dormans, 2005) These growing osteophytes can compress the nearby soft tissues, causing pain and limited joint movement. Over 70% of HME cases were caused by the heterozygous mutation of genes encoding exostosin-1 (EXT1) or exostosin-2 (EXT2), which map to chromosome 8q 24.11-q24.13 and 11p12-p11, respectively (Cook et al, 1993; Wu YQ et al, 1994; Bovée, 2008) Of these identified pathogenic variants of HME, 80% are nonsense, frameshift, or splicing mutations, which typically cause premature termination of translation (Wuyts and Van Hul, 2000). A pathogenesis model of HME has been proposed, suggesting that ectopic BMP signaling in progenitor cells in the perichondrium mediates osteochondromagenesis (Jiao et al, 2007; Cuellar and Reddi, 2013; Inubushi et al, 2017; Pacifici, 2018)
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