Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

Abstract

Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-oforigin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers.

Copy number variations in candidate genomic regions confirm genetic heterogeneity and parental bias in Hirschsprung disease

“…Interestingly, an increase in CNV burden in the mothers of children affected by mental retardation (MR) have been recently reported in the Chinese population, suggesting that females might be more tolerant than males to deleterious variations and that MR manifestation for females might require a higher burden of deleterious variants [49]. Consistent with our observation of an excess of inheritance from unaffected mothers, a parental mutation transmission asymmetry has already been reported at the RET locus [50]. Apparently, this bias in the transmission of RET single base mutations was not due to different expression of the disease depending on the gender of the transmitting parent, but rather to differential reproductive rate between male and female carriers, with mothers carrying a severe mutation that would be more likely than fathers to reproduce and transmit [50].…”

Genetic Effects on DNA Methylation and Its Potential Relevance for Obesity in Mexican Americans

“…HSD17B12 has been shown to be involved in the catalytic conversion of oestrone to estradiol and has also been implicated in fatty acid synthesis (reviewed in [55]), which shows sex-specific differences (reviewed in [56]). DNA methylation at RET_seq_54_S260 was increased in males, and although specific sex effects have not been noted, genetic variants within this gene have been shown to have different effects in males and females, and parent of origin effects involving such variants have been noted in Hirschsprung disease [57], [58]. It is important to note that some level of cross-reactivity with sex chromosomes has been reported in ∼6–10% of the autosomal probes used in some of the higher-throughput Illumina platforms (i.e.…”

A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease

“…HSCR is a complex and heterogeneous disease. In addition, the incidence of HSCR is much higher in males, and a higher maternal inheritance than paternal (largely transmitted to the son) is observed in RET coding sequence mutations, based on the assumption of parent-of-origin effect [13] . Although mutations in RET (in particular, a common variant rs2435357 within a conserved enhancer-like sequence) and other genes (such as GDNF , SOX10 , and endothelin-related genes) have partially accounted for HSCR development [3] – [5] , [14] , comprehensive genetic implications for HSCR and ENS development are still not fully understood.…”