Abstract
BackgroundHirschsprung 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.ResultsTo 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.ConclusionOur findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.
Highlights
Pathogenic gene variation is a significant contributor to rare diseases, especially in children [1]
To select putative de novo variants (DNVs), the following criteria were used: 1) minimal 10X coverage in patients and parents; 2) a minimal genotype quality score of 10 for both patients and parents; 3) at least 10% of the reads showing the alternative allele in patients; and 4) not more than 10% of the reads showing the alternative allele in parents
Novel RET coding-region variants detected in 117 families with Hirschsprung disease (HSCR) On average, 823.3 million cleaned reads of 100-bp length were generated per sample, except for XHYY019, a male
Summary
Pathogenic gene variation is a significant contributor to rare diseases, especially in children [1]. HSCR or congenital aganglionosis, a heterogeneous genetic disorder, is characterized by the lack of ganglion cells along varying lengths of the intestine resulting in. Jiang et al Orphanet Journal of Rare Diseases (2019) 14:237 the major cause of functional obstruction in children. Genetic studies during the past 25 years have identified rare coding variants in 14 genes that together explain ~ 10% of HSCR cases [9,10,11]. 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
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