Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, But Not Ollier Disease or Maffucci Syndrome

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to \(EXT1\) and \(EXT2\), the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in \(PTPN11\) in 4 of the 11 families. Sanger sequence analysis of \(PTPN11\) coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire \(PTPN11\) gene identified an additional family with a 15 kb deletion spanning exon 7 of \(PTPN11\). Microdissected MC lesions from two patients with \(PTPN11\) mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced \(PTPN11\) in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence \(PTPN11\) mutations. We conclude that heterozygous loss-of-function mutations in \(PTPN11\) are a frequent cause of MC, that lesions in patients with MC appear to arise following a ‘‘second hit,’’ that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing \(PTPN11\) mutations, and that \(PTPN11\) mutations are not a common cause of Ollier disease or Maffucci syndrome.