Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.

RATIONALE: Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder.

PATIENT CONCERNS: Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement.

DIAGNOSES: Hereditary multiple exostoses.

INTERVENTIONS: To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were used after genomic DNA was isolated from peripheral blood leucocytes. Point mutations identified by these methods were verified by Sanger sequencing after PCR amplification.

OUTCOMES: Six mutations in the EXT1 and EXT2 genes were identified, including a heterozygous deletion mutation from exon 2 to exon 8 (Family 1), a c.448C>T, p.(Gln150X) heterozygous nonsense mutation (Family 4), a c.1057-2A>T heterozygous splicing substitution (Family 5), and a c.1468dupC, p.(Leu490fs519X) (Family 6) heterozygous duplication mutation in the EXT1 gene in addition to a heterozygous deletion mutation from exon 2 to exon 3 (Family 2) and a c.1197C>G, p.(Tyr399X) heterozygous nonsense mutation (Family 3) in the EXT2 gene.

LESSONS: Overall, we identified 5 novel mutations and 1 recurrent mutation in the EXT1 and EXT2 genes in 6 Chinese families with HME. Our findings expand the mutational spectrum of the EXT1 and EXT2 genes and are useful for genetic counseling and prenatal diagnosis.