NEW YORK – Recessive Mendelian disorders are caused by mutations in both copies of a gene, but heterozygous carriers can sometimes also show mild phenotypes.
To study such incomplete penetrance of disease variants in greater detail, researchers have analyzed genetic data from the UK Biobank.
"We wanted to investigate the question 'Are traditional Mendelian recessive variants truly recessive, or do they have more mild effects in heterozygous carriers?'" said Alison Barton, a researcher at Brigham and Women's Hospital and Harvard Medical School, who presented results from the unpublished study at the American Society of Human Genetics annual meeting, held virtually this week.
The study focused on almost 3,500 imputed exome variants found in the UK Biobank cohort, most of them very rare, that had previously been classified as pathogenic or likely pathogenic and as causing an autosomal recessive disease.
Initially, the researchers tested if heterozygous carriers of those variants showed associations with 57 quantitative traits and found 104 significant associations covering 39 traits and 36 recessive diseases. They then expanded the analysis to 1,257 binary disease traits and found five additional significant associations.
Among them was the gene ABCA3, which causes pulmonary surfactant metabolism dysfunction in homozygous individuals with a variant. Heterozygous carriers of the variant turned out to have reduced lung function.
Another example was HBB, homozygous mutations in which cause sickle cell anemia. Carriers of a pathogenic HBB variant showed mild signs of thalassemia.
A less expected result was in the gene IFT140, which encodes a protein involved in ciliary function. Homozygous mutations in IFT140 have been linked to retinitis pigmentosa 80, causing vision problems. Carriers of the mutation, however, were at increased risk of having cystic kidney disease, the study found.
The researchers also looked into whether two of the more common serious autosomal recessive Mendelian diseases — cystic fibrosis and spinal muscular atrophy — showed related, mitigated phenotypes in carriers.
For cystic fibrosis, they found that carriers of the most common pathogenic mutations showed associations with several respiratory diseases, as well as duodenal ulcer and male infertility.
In the case of SMA, which is caused by copy number changes in the SMN1 and SMN2 genes, they did not find such links. Carriers, which have a deletion of the SMN1 gene, did not show any association with an expected phenotype. "This stands in contrast to cystic fibrosis and supports the idea that some Mendelian recessive diseases are truly recessive," Barton said.
Next, the researchers wanted to address the mechanism behind the incomplete penetrance of mild phenotypes in carriers. One model, called "modified penetrance," suggests that effects of loss-of-function variants in one allele may be modulated by variants that affect the expression of the functional allele on the opposite haplotype.
To test this, the researchers looked at CFTR, mutations in which cause cystic fibrosis, which has a 3 percent carrier frequency in the UK Biobank, and at the gene FLG, for which 10 percent of the UK Biobank participants carry a loss-of-function variant. Homozygous mutations in FLG cause ichthyosis vulgaris, a skin disorder, and carriers have an increased risk of asthma and atopic dermatitis.
The investigators looked for associations between phenotypes in carriers of CFTR or FLG mutations and SNPs in the non-carrier chromosome that might mitigate such phenotypes, but they did not find any. "Despite a well-powered sample, we found no conclusive evidence for common variants modifying the penetrance of disease variants on the opposite haplotype in the same gene," Barton said.