Identifying candidate genes underlying isolated congenital anosmia

Abstract

An estimated 1 in 10 000 people are born without the ability to smell, a condition known as congenital anosmia, and about one third of those people have non-syndromic, or isolated congenital anosmia (ICA). Despite the significant impact of olfaction for our quality of life, the underlying causes of ICA remain largely unknown. Using whole exome sequencing (WES) in 10 families and 141 individuals with ICA, we identified a candidate list of 162 rare, segregating, deleterious variants in 158 genes. We confirmed the involvement of CNGA2, a previously implicated ICA gene that is an essential component of the olfactory transduction pathway. Furthermore, we found a loss-of-function variant in SREK1IP1 from the family gene candidate list, which was also observed in 5% of individuals in an additional non-family cohort with ICA. Although SREK1IP1 has not been previously associated with olfaction, its role in zinc ion binding suggests a potential influence on olfactory signaling. This study provides a more comprehensive understanding of the spectrum of genetic alterations and their etiology in ICA patients, which may improve the diagnosis, prognosis, and treatment of this disorder and lead to better understanding of the mechanisms governing basic olfactory function.

Keywords: CNGA2; anosmia; olfaction; smell loss.

Figure 1.. ICA Family Cohort Variant Selection Pipeline.

A graphical representation of the three main variant selection steps that resulted in the family gene list of 162 segregating, rare, deleterious variants annotated in 158 genes.

Figure 2.. Selected Variants in Family and non-family cohorts.

Rare, segregating, deleterious variants were selected in the family cohort and examined in the non-family cohort. a) For the family cohort, 6,159 variants were selected from the 740,613 quality-filtered variants called from WES. The listed number of variants selected for each family is represented by the area of the rectangle subdivided into inheritance pattern (blue=dominant, green=recessive, orange=X-linked). Only two families had genes called from the X-linked inheritance model: Family 13, and Family 25. Each family space includes the pedigree dictating the selected inheritance model. Affected individuals are filled in squares (male) or circles (female). The star (*) represents participants whose BSIT result does not match their reported anosmia/normosmia status. Grey diamonds represent non-participating family members. b) The non-family cohort was analyzed for the presence of variants that were an exact match for variants selected from families, or that fell within the same gene as selected family variants. This is an example for variants found in the gene TLN2, where the gene is depicted as an arrow with the exons in black. The red lines indicate the location of variants found in the family (top), and non-family cohorts (middle and bottom). 3 non-family individuals had the variant rs140301741 (middle) which was also found in family 47. There were 9 additional variants found in TLN2 in the non-family cohort (bottom).

Figure 3.. ICA Family Candidate Genes

a) This waterfall plot indicates families (left of gray line) and individuals from the non-family cohort (right of gray line) with variants in the 20 genes with the highest priority scores. Non-family individuals are grouped by k-means clustering based on the variants present in the individual. The deleteriousness of the variants is coded by color from cool (low CADD score) to hot (high CADD score). b) Each point represents one of the 162 unique variants from the candidate gene list selected from families with ICA. The CADD PHRED-ranked score is a measure of the deleteriousness of the genes, with CADD scores over 20 representing variants that are more deleterious than 99% of all predicted variants. The size of the dot is representative of the VarElect Score, which is a measure of the known relationship of each gene to olfactory phenotype, either directly (blue), indirectly (green), or no known relationship (orange). The labeled genes are those that have the highest priority scores, have selected variants in more than one family, and/or have some known relationship or mechanism relating to olfaction. The dotted line represents the cutoff for the top 20 genes (priority score > 2.8).