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Penetrance of Mendelian Disease Variants Ranges in Heterozygous Carriers

NEW YORK – Using genetic data from the UK Biobank, a team from Brigham and Women's Hospital, the Broad Institute, Harvard Medical School, and the Massachusetts Institute of Technology has documented various levels of recessiveness for variants previously implicated in Mendelian conditions.

"With increasing exome sequencing of population biobank cohorts, a new opportunity to search for carrier phenotypes in a phenome-wide, exome-wide manner has emerged," senior and co-corresponding author Po-Ru Loh, a researcher affiliated with Brigham and Women's Hospital and the Broad Institute, and his colleagues explained, adding that "biobank datasets present an opportunity to ameliorate ascertainment biases by assessing phenotypes in population cohorts, complementing analyses of affected individuals and their families."

As they reported in the American Journal of Human Genetics on Tuesday, the researchers analyzed exome sequence and phenotypic data for roughly half a million UK Biobank participants, focusing on nearly 3,500 rare variants that have been reported in databases such as ClinVar or the Online Mendelian Inheritance in Man (OMIM) collection. When they analyzed these variants in relation to some 58 quantitative traits, they tracked down 102 significant associations involving variants linked to nearly three dozen Mendelian conditions in the past.

"Our results show that many disease-associated recessive variants can produce mitigated phenotypes in heterozygous carriers and motivate further work exploring penetrance mechanisms," the authors reported.

The team's follow-up haplotype analyses in Mendelian disease risk variant carriers indicated that the incomplete penetrance found in some carriers could not be easily explained by the so-called modified penetrance model, which argues that penetrance may be modified by interactions between risk variants and neighboring expression quantitative trait loci.

On the contrary, the authors noted that "the modified penetrance model is unlikely to underlie incomplete penetrance of these carrier phenotypes" in carriers of risk variants in the FLG or CFTR genes, which are involved in ichthyosis vulgaris and cystic fibrosis, respectively.

While some conditions did appear to be completely recessive, occurring only in individuals who carried disease-related variants in both copies of a given gene, the team also documented Mendelian disease-linked variants that appeared to cause relatively mild phenotypes when found in a heterozygous state, affecting just one copy of the gene.

In the case of spinal muscular atrophy, for example, the investigators did not detect muscle strength-associated features in study participants carrying one copy of the risk allele. In contrast, heterozygous carriers of risk variants linked to several other Mendelian conditions showed modest phenotypes related to the known diseases.

In particular, the team saw muted phenotypes in cystic fibrosis carriers, along with reduced lung function in individuals who had one copy of a missense ABCA3 variant known for its role in interstitial lung disease. In participants carrying one copy of a POR gene variant that has been linked to a skeletal and skull-related Mendelian condition called Antley-Bixler syndrome, meanwhile, they documented a tendency for carriers to be taller than usual.

"As even larger, well-phenotyped cohorts with [whole-exome sequencing] or whole-genome sequencing become available, our ability to determine the extent of mild carrier phenotypes will increase," the authors wrote. "More comprehensive phenome-wide and genome-wide studies will allow for an assessment of how common the phenomenon of incomplete recessivity is among severe Mendelian diseases and the spectrum of phenotypes that can manifest."