Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants.
Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from ~200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from ~500,000 individuals.
We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index.
Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population.
…Many individuals in UKB carry rare, deleterious variants in genes where similar variants are known to cause monogenic autosomal dominant DD
Although variants in each gene individually account for extremely rare forms of DD, together they account for a large portion of DD diagnoses and have a surprisingly high burden of rare deleterious variants in UKB. In 184,477 unrelated European individuals with WES data in UKB and across 599 monoallelic DDG2P genes, 9,103 individuals carry a rare (n ≤ 5) LoF variant, 25,288 individuals carry a rare missense variant with REVEL > 0.7, and 79,959 individuals carry a rare synonymous variant. As the gene panel becomes smaller and more stringent, the burden of rare deleterious variants decreases; for example, 3,602, 1,327, and 167 individuals in UKB carry rare LoF variants in smaller more stringent subsets of 325, 125, and 25 DDG2P genes, respectively (Figure 1). In 450,274 individuals with SNP-array data in UKB and across 69 known DD loci, 4,922 individuals carry large deletions and 7,054 individuals carry large duplications.
Individuals in UKB with rare, deleterious variants in loci where similar variants are known to cause monogenic DD display DD-related phenotypes
We performed gene panel (including 599 monoallelic DDG2P genes) and multigenic copy-number (including 53 deletions/duplications syndromes) burden tests for 20 traits in UKB selected to be of relevance (in adults) to developmental phenotypes. Bonferroni-corrected statistically-significant associations were found across most phenotypes in individuals carrying likely damaging variants compared with the rest of the UKB cohort (Table 1, Figure 2, and Figure 3). Individuals carrying these variants generally had lower cognitive performance than the rest of the cohort, with reduced fluid intelligence (LoF group beta: −1.059), slower reaction times (LoF group beta: +0.043), lower numeric memory scores (LoF group beta: −0.068), and longer pairs matching times (LoF group beta: +0.122). They also completed fewer years in education, left education at an earlier age, and were less likely to have a degree. Medically, individuals were more likely to have reported a mental health issue or been diagnosed with either a childhood DD (including mild-severe intellectual disability, epilepsy, autism, ADHD, and congenital malformations) or adult DD (including schizophrenia and bipolar disorder). Individuals were also more likely to be shorter, have a higher BMI, and have had fewer children (though the latter association was only statistically-significant in men). Individuals also had statistically-significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and a higher TDI. Across all phenotypes tested, we observed a trend corresponding to the likely deleteriousness of the variants; the largest effect was generally observed in the group of individuals with multigenic deletions, followed by multigenic duplications, then LoF variants, and finally missense variants in one (or more) DDG2P genes. These trends were robust to the use of different CADD thresholds for selecting of missense variants (see Table S4) and to removal of individuals with a diagnosed childhood developmental disorder (“child DD”, as defined in Material & Method, n = 3,132; see Table S5). In contrast, individuals with only rare synonymous variants in these genes showed no statistically-significant difference in any phenotype compared to the remainder of the cohort, as expected for likely benign variants, suggesting that most of the confounding caused by population sub-structure was appropriately controlled.
…Furthermore, rare predicted-LoF variants were found in individuals in genes in which similar variants are thought to be fully or nearly fully penetrant causes of very well-established developmental syndromes, but without the full clinical phenotype that would be expected, suggesting that there is a range of penetrance and expressivity in the general population.
Despite the large size of UKB, we were limited by the number of individuals of European ancestry carrying rare damaging variants in these genes, which meant some of our analyses were under-powered to show a statistically-significant effect. We were also limited by the clinical and phenotypic data available on these individuals, all of whom were over 40 years of age at recruitment; evaluation and diagnosis of DD was much less routine when these individuals were children and is less likely to be recorded in the HES codes of older adults. Nonetheless, when found in an appropriate clinical pediatric setting, rare damaging variants in these genes are widely considered diagnostic for DD and thus they might not be expected to be present in a population cohort. Our results suggest that, although the penetrance of variants across these genes is lower than would be expected from previous clinical studies, they do still exert a phenotypic effect on adults in the general population who are nonetheless healthy enough, and have sufficient capacity, to volunteer to participate in a biobank.