Abstract
There is a growing interest in standardizing gene-disease associations for the purpose of facilitating the proper classification of variants in the context of Mendelian diseases. One key line of evidence is the independent observation of pathogenic variants in unrelated individuals with similar phenotypes. Here, we expand on our previous effort to exploit the power of autozygosity to produce homozygous pathogenic variants that are otherwise very difficult to encounter in the homozygous state due to their rarity. The identification of such variants in genes with only tentative associations to Mendelian diseases can add to the existing evidence when observed in the context of compatible phenotypes. In this study, we report 20 homozygous variants in 18 genes (ADAMTS18, ARNT2, ASTN1, C3, DMBX1, DUT, GABRB3, GM2A, KIF12, LOXL3, NUP160, PTRHD1, RAP1GDS1, RHOBTB2, SIGMAR1, SPAST, TENM3, and WASHC5) that satisfy the ACMG classification for pathogenic/likely pathogenic if the involved genes had confirmed rather than tentative links to diseases. These variants were selected because they were truncating, founder with compelling segregation or supported by robust functional assays as with the DUT variant that we present its validation using yeast model. Our findings support the previously reported disease associations for these genes and represent a step toward their confirmation.
Highlights
MATERIALS AND METHODSMendelian diseases are collectively common despite the rarity of most individual entities
A dual molecular diagnosis is observed in the patient 13DG0792, who is homozygous for the founder variant PTRHD1 and a ciliopathy phenotype (Caroli disease) caused by the variant WDR35
The determination of whether a given Mendelian gene-disease association is established has been largely subjective until the publication of an evidence-based framework by ClinGen, which represents a major step toward standardization (Strande et al, 2017)
Summary
Mendelian (aka monogenic) diseases are collectively common despite the rarity of most individual entities. In the case of exome or genome sequencing, an additional advantage lies in their potential to detect causal variants in genes with no established disease links in humans, i.e., novel candidates (Alkuraya, 2016). The latter scenario poses a major challenge because variants in such genes cannot be classified according to the current ACMG guidelines as pathogenic or likely pathogenic so these patient’s molecular diagnosis remains ambiguous until such time that sufficient evidence is established in the literature to confirm the diseasegene association (Richards et al, 2015). The native S. cerevisiae DUT1 allele, including the same regulatory regions as yDUT was PCR amplified from yeast DNA using primers with added homology to AB523 using primers DUT1_HO_F and DUT1_natNT1_R (Supplementary Table S3) and assembled into AfeI digested AB523 to create plasmid AB525. Yeast growth was quantified as described previously (Sirr et al, 2020)
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