Sequence characterization of RET in 117 Chinese Hirschsprung disease families identifies a large burden of de novo and parental mosaic mutations

Qian Jiang, Yang Wang, Qi Li, Zhen Zhang, Ping Xiao, Hui Wang, Na Liu, Jian Wu, Feng Zhang, Aravinda Chakravarti, Wei Cai, Long Li

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by the absence of enteric ganglia in the distal part of the gut. RET is the major causative gene and contains > 80% of all known disease-causing mutations. RESULTS: To determine the incidence of RET pathogenic variants, be they Mendelian inherited, mosaic in parents or true de novo variants (DNVs) in 117 Chinese families, we used high-coverage NGS and droplet digital polymerase chain reaction (ddPCR) to identify 15 (12.8%) unique RET coding variants (7 are novel); one was inherited from a heterozygous unaffected mother, 11 were DNVs (73.3%), and 3 full heterozygotes were inherited from parental mosaicism (2 paternal, 1 maternal): two clinically unaffected parents were identified by NGS and confirmed by ddPCR, with mutant allele frequency (13-27%) that was the highest in hair, lowest in urine and similar in blood and saliva. An extremely low-level paternal mosaicism (0.03%) was detected by ddPCR in blood. Six positive-controls were examined to compare the mosaicism detection limit and sensitivity of NGS, amplicon-based deep sequencing and ddPCR. CONCLUSION: Our findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.

Original languageEnglish (US)
Pages (from-to)237
Number of pages1
JournalOrphanet journal of rare diseases
Volume14
Issue number1
DOIs
StatePublished - Oct 30 2019

Keywords

  • Chinese HSCR
  • High coverage NGS
  • Parental mosaicism
  • RET
  • ddPCR

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

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