Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update

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.

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population

“…Since TBM1 was published in 2015, 19 genes (ACTL6B, ANK3, ASTN1, CDH4, CDK10, CELSR2, CPLX1, DHX37, HELZ, KLHL15, OGDHL, PLEKHG2, PRUNE1, PTPRT, SLC18A2, SMARCA1, and VARS) were confirmed to have an established NDD association with further published cases from the literature and/or functional/animal studies, including two genes (GTF3C1 and TTI1) with ongoing collaborative studies. 57,62,87,88, In the current cohort, we used stringent criteria for identifying candidates (Material and methods), and we have applied additional population genetics/bioinformatic tools (i.e., gnomAD and CADD score) that were not available for the TBM1 cohort. Through these advances, we identified 86 candidate disease-trait-associated NDD genes that fulfill our criteria in TBM2.…”

“…13,86,87 Additionally, biallelic ASTN1 variants were found in DD/ID subjects from Turkey, Poland, and Saudi Arabia (Figure S7). 13,87,88 Taken together, the severe phenotype observed in BAB10738 was most parsimoniously explained by digenic inheritance from double-heterozygous variants in genes encoding interacting proteins.…”

SEL1L-HRD1 interaction is prerequisite for the formation of a functional HRD1 ERAD complex

“…Both proteins are quickly degraded by SEL1L-HRD1 ERAD and accumulated in the ER of ERAD-deficient cells. Indeed, defects in the function of ASTN proteins in humans have been linked to neurodevelopmental symptoms such as developmental delay, intellectual disability and cerebellar dysfunction (58,(64)(65)(66). Hence, we propose that impaired function of specific SEL1L-HRD1 ERAD substrate(s) such as ASTN1/2 may underlie, at least in part, cerebellar ataxia of our KI mice.…”

Catalogue for Transmission Genetics in Arabs (CTGA) Database: Analysing Lebanese Data on Genetic Disorders

“…In its various forms, predominantly type 1A (MIM # 220290), recessive deafness has been reported in subjects from over 30 Lebanese families. The presence of such rare genetic disorders, especially in large consanguineous kindreds, is very useful in the mapping of the causative loci and the identification of the causal gene [26][27][28]. In fact, our survey on the Lebanese population identified 58 separate genetic disorders that were first mapped in Lebanese families (Table 1).…”