Abstract
Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.
Highlights
Predicting the pathogenicity of biallelic missense variants can be challenging
We searched for missense variants with a deficit of observed homozygous carriers, versus the expected number, in a population set of 153,054 Icelanders who were chipgenotyped and with rare variants imputed based on the Wholegenome sequencing (WGS) of 56,969 Icelanders
We defined a complete deficit as missense variants present in the population set at a minor allele frequency (MAF) high enough to expect at least three homozygous carriers (MAF > 0.40%), assuming Hardy-Weinberg equilibrium, with no homozygous carriers observed
Summary
Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. Wholegenome sequencing (WGS) of a large fraction of the Icelandic population has provided valuable insights into the genetic makeup of an isolated population, facilitating the detection of rare pathogenic genotypes[2,3]. Due to the isolation of the Icelandic population and the founder effect, some sequence variants that may be pathogenic in the homozygous states, reach elevated frequencies[2] This holds the potential of uncovering previously unidentified causes of autosomal recessive (AR) diseases[8]. We have previously mapped out a large set of carriers of biallelic predicted loss-of-function (pLoF) variants in the Icelandic population, i.e., stop-gained, frameshift, or essential splice variants[9]. We observed an overall deficit of double transmissions of pLoF variants from a pair of heterozygous parents to their offspring[9] Such a deficit will appear if the homozygous genotype is expected to (A) be incompatible with early embryonic development (early miscarriage) (B) be incompatible with late embryonic development (late miscarriage, stillbirth), or (C) interfere with reproduction (e.g., by early death or severe disease). We demonstrate that with a large dataset representative of an isolated population, it is possible to assess the pathogenicity of homozygous missense variants based on the deficit of homozygous carriers of such variants
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