A Genocentric Approach to Discovery of Mendelian Disorders.

Abstract

The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/j.ajhg.2019.09.027

Publication Info

Hansen, Adam W, Mullai Murugan, He Li, Michael M Khayat, Liwen Wang, Jill Rosenfeld, B Kim Andrews, Shalini N Jhangiani, et al. (2019). A Genocentric Approach to Discovery of Mendelian Disorders. American journal of human genetics, 105(5). pp. 974–986. 10.1016/j.ajhg.2019.09.027 Retrieved from https://hdl.handle.net/10161/24585.

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Scholars@Duke

Ashley-Koch

Allison Elizabeth Ashley-Koch

Professor in Medicine

One of my major research foci is in the genetic basis of psychiatric and neurological disorders. I am currently involved in studies to dissect the genetic etiology of attention deficit hyperactivity disorder (ADHD), autism, chiari type I malformations, essential tremor, and neural tube defects. Additional research foci include genetic modifiers of sickle cell disease, and genetic contributions to birth outcomes, particularly among African American women.

Davis

Erica Ellen Davis

Associate Professor of Pediatrics

Two key questions thematically underscore my research in the Center for Human Disease Modeling at Duke University: First of all, how can variation at the DNA level be functionally interpreted beyond the resolution of genetics arguments alone? Secondly, once empowered with functional information about genetic variants, how can pathogenic alleles be mapped back to disease phenotypes? Using the ciliary disease module as a model system of investigation, we are using multidisciplinary tactics to address these questions and continue to harness these approaches toward the further dissection of the architecture of human genetic disease. Moreover, we have applied the in vivo tools and lessons learned from ciliary phenotypes affecting the renal, craniofacial, and central nervous systems to interrogate rare pediatric disorders characterized by these phenotypic hallmarks.


Katsanis

Nicholas Katsanis

Jean and George W. Brumley, Jr., M.D. Professor of Developmental Biology

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