Assessing the general population frequency of rare coding variants in the EXT1 and EXT2 genes previously implicated in hereditary multiple exostoses.
Hereditary multiple exostoses (HME) is a rare childhood-onset skeletal disease linked to mutations in exostosin glycosyltransferase 1 (EXT1) or 2 (EXT2). Patients are heterozygous for either an EXT1 or EXT2 mutation, and it is widely assumed that exostosis formation and associated defects, such as growth retardation and skeletal deformities, require loss-of-heterozygosity or a second hit in affected cells. However, the relevance and phenotypic impact of many presumed pathogenic EXT variants remain uncertain. We extracted all amino acid-altering (missense) and loss of function (LoF; nonsense, frameshift, or splice-site) variants from the Exome Aggregation Consortium (ExAC), a large population-based repository of exome sequence data from diverse ancestries that has screened out severe pediatric disease, to assess the overall mutation spectrum of predicted protein-damaging variants across these two genes in the general population. We then determined whether clinically-identified, presumably pathogenic variants implicated in HME exist among healthy individuals. We found six EXT1 and four EXT2 missense mutations in ExAC, suggesting that these mutations have either been misclassified as pathogenic or are not fully penetrant. Furthermore, EXT1 is heavily selectively constrained, while EXT2 is more tolerant to protein-damaging variants, especially at its C-terminus, possibly explaining the genotype-phenotype correlation that EXT1 variants usually result in more severe disease. In conclusion, population-based exome data is a useful filter for determining whether clinically detected variants are likely pathogenic, as well as revealing biological insight into rare disease genes such as EXT1 and EXT2.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, USA; Department of Genetics, University of Pennsylvania, Philadelphia, USA. Electronic address: cousminerd@email.chop.edu.
Diana L
DL
Cousminer
Division of Orthopedic Surgery, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, USA.
Alexandre
A
Arkader
Department of Genetics, University of Pennsylvania, Philadelphia, USA; Department of Systems Pharmacology and Translation Therapeutics, University of Pennsylvania, Philadelphia, USA; Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, USA.
Benjamin F
BF
Voight
Division of Orthopedic Surgery, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, USA.
Maurizio
M
Pacifici
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, USA. Electronic address: grants@email.chop.edu.
Struan F A
SFA
Grant
D030541:Databases, Genetic; D005097:Exostoses, Multiple Hereditary / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D011159:Population Surveillance; D000099065:Exostosin 2; D000099058:Exostosin 1
D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1; D000099065:Exostosin 2
Exome; Exostosin-1; Exostosin-2; Hereditary multiple exostoses; Osteochondroma