Genetic Causes of Congenital Anosmia

The Genetic Causes of Congenital Anosmia study was designed to provide a list of candidate genes that are potentially causal for isolated congenital anosmia (ICA), a rare inherited disorder where individuals lack a sense of smell from birth in the absence of a known genetic syndrome (i.e. Kallman's syndrome). This study includes 193 participants from 18-87 years of age, divided into two cohorts: family and non-family. Genetic data from the family cohort was analyzed in a case-control family design to generate a list of 162 candidate genes for ICA. A targeted search for variants in this list of genes was then conducted in the non-family cohort to create a prioritized list of genes for further study. Ten unrelated families were recruited for the family cohort for a total of 52 participants, 25 of which had anosmia. The non-family cohort consisted of 141 anosmic individuals. 3 additional normosmic participants from incomplete families were collected, one of whom has a participating family member in the non-family cohort, and so has data provided here. Data collection was conducted remotely, resulting in 146 participants recruited from the United States, and 48 recruited internationally from ten different countries. Participants were interviewed for their anosmia status and to confirm that they had no known genetic syndromes. Participants also completed the University of Pennsylvania Brief Smell Identification Test (BSIT; Doty et al., 1984) to confirm their anosmic/normosmic status and provided a saliva sample for whole exome sequencing (WES). Participants who had family members with anosmia provided pedigree information via interview. Data submitted to dbGap include whole exome sequences from 194 individuals (163 anosmic) conducted with Illumina HiSeq2500 and Illumina NovaSeq next generation sequencing technologies. Family pedigree information for the 10 participating families and all participants in the non-family cohort who have non-participating anosmic family members was also included. Our goal was to provide a resource for further research into the genetics of isolated congenital anosmia and to aide in the understanding of this disorder, as well as human olfaction, in general. The WES data provided could be further analyzed for polygenic interactions, additional non-targeted analysis on the non-family cohort, or combined into databases of other anosmic populations for further gene targeting or selection. ]]>
General inclusion criteria: Subjects were 18 years of age or older, and could not be currently pregnant to participate in the study. To qualify as anosmic, subjects had to report having no sense of smell from birth, and no other known congenital syndromes. Anosmia status was confirmed using the University of Pennsylvania Brief Smell Identification Test (BSIT). Control subjects reported having a normal sense of smell, which was also confirmed via BSIT. Criteria for family or non-family cohorts: Each of the ten completed families had at least 4 family members consisting of at least 2 anosmic and 1 normosmic individuals. Criteria for the non-family cohort: Individuals in the non-family cohort had to be anosmic, and had either no family members with anosmia, no participating family members with anosmia, or an inadequate number of participating family members to meet the requirements of the family cohort. ]]>