Meet the Expert Diagnostics

THE PHENOTYPIC AND GENETIC LANDSCAPE OF INBORN ERRORS OF IMMUNITY IN A LARGE NIAID COHORT

Lecture Time
15:10 - 15:20
Presenter
  • Morgan N. Similuk, United States of America
Room
Copper
Date
18.09.2019, Wednesday
Session Time
14:35 - 15:30
Presentation Topic
Diagnostics

Abstract

Background and Aims

Inborn errors in immunity (IEI) often display variable expressivity and reduced penetrance and have rarely been systematically evaluated in large cohorts. To better understand genetic contributions to IEI, we are collecting standardized data from a large cohort of NIAID research participants.

Methods

One thousand nine hundred participants are enrolled to undergo exome sequencing with interpretation based on American College of Medicine Genetics (ACMG) guidelines. The phenotypes of these individuals are being recorded using the Human Phenotype Ontology (HPO), a standardized, computable, controlled-vocabulary.

Results

Among finalized reports, 18% (27/149) of the reported pathogenic and likely pathogenic variants associated with IEI are not yet present in the literature or reported in ClinVar. Null variants in a gene where loss of function is a known mechanism and being located in a mutational hot spot are types of evidence that significantly contributed to this subset of previously unreported variants. Regarding phenotypic data, three hundred eleven new terms specific to immunology were added to the HPO. Subsequently, the clinical features of 1576 participants were coded using 5000 HPO terms. Initial exploratory analyses show rare combinations of clinical phenotypes as well as disease endotypes ripe for further analysis.

Conclusions

Our findings highlight previously unreported diagnostic variants within the cohort and initial explorations of phenotypic data. These approaches help prioritize areas for in-depth investigation in order to ultimately improve evaluations and genetic counseling for patients with IEI and their families.

This research was supported by the Intramural Research Program of the NIH, NIAID.

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