Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene: “Author Summary

Metachondromatosis (MC) is an autosomal dominant condition characterized by exostoses (osteochondromas), commonly of the hands and feet, and enchondromas of long bone metaphyses and iliac crests. MC exostoses may regress or even resolve over time, and short stature is not characteristic of MC. Here, we sequenced the whole genome of a single patient with MC and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which results in premature translation termination and co-segregates with the phenotype. In a second metachondromatosis family, we identified a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Germline gain-of-function missense mutations in PTPN11 cause an overlapping but distinct group of dominant disorders with involvement of the face, heart, skeleton, skin, and brain, including Noonan syndrome (OMIM 163950), Noonan-like disorder with multiple giant cell lesion syndrome (OMIM 163955), and LEOPARD syndrome (OMIM 151100). Nonsense mutations in PTPN11 have not been described in humans and the loss-of-function PTPN11 mutations we report here are the first to be described in human disease.