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.

Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases

“…Non‐paternity was ruled out through identity‐by‐descent analysis. This de novo variant was not seen in internal controls–as previously described (Hansen et al, 2019)—affects a highly conserved residue (GERP++ = 3.54, as obtained from the UCSC Genome Browser) and has a very low MTR score (21 bp window)—0.34—indicative of a region constrained for nonsynonymous variation in control populations (Davydov et al, 2010; Kent et al, 2002; Traynelis et al, 2017).…”

“…Next, we investigated the phenotypes of these two affected siblings compared to previously published and unpublished cases. We used HARLEE (Hansen et al, 2019) to search across >20,000 ES samples from the Baylor Hopkins Center for Mendelian Genomics and a clinical diagnostic lab (see Supporting Information) for cases solved by KIF1A and identified eight such cases (Table 1 and Figure 1). Phenotypes not previously known to associate with monoallelic KIF1A dysfunction were identified in multiple patients, including dystonia (4/10, 40%) and hip subluxation (3/10, 30%).…”

“…Furthermore, this variant occurs in two affected siblings and is likely mosaic in the maternal germline, as blood samples from both parents, in addition to a paternal sperm sample, did not detect the variant at any significant allele fraction. We discuss the range of overlapping Mendelian syndromes reported to associate with KIF1A dysfunction and argue that they are better understood by a genocentric diagnostic model, where genotype is contextualized by phenotype (Hansen et al, 2019). Finally, we present evidence supporting the association of KIF1A dysfunction with hip subluxation and dystonia—observed in multiple patients—as well as additional phenotypic findings observed in one patient, which may or may not be incidental, including cataplexy, coxa valga, and double collecting system.…”

Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation

“…For individuals 1, 6, and 8–13, DNA capture and sequencing of exomes was carried out as previously described by Hansen et al 7 at either the Baylor Genetics (BG) laboratories or at the Baylor College of Medicine Human Genome Sequencing Center (HGSC). Sequencing and analysis for individuals 2 (genome sequencing) and 5 (exome sequencing [ES]) were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG).…”

MendelVar: gene prioritization at GWAS loci using phenotypic enrichment of Mendelian disease genes

“…Modern definition of Mendelian disease is complex, with variable levels of monogenicity, penetrance (Claussnitzer et al, 2020), epistasis, gene x environment interactions and indeed pleiotropy observed (Chakravorty & Hegde, 2017). In MendelVar, we follow the working definitions from Chakravorty & Hegde (2017) and Hansen et al (2019) with broadly defined Mendelian genes to include genes causal for highly penetrant monogenic and oligogenic diseases, including diseases involving cell mosaicism, recurrent de novo structural variants causing mostly developmental diseases, such as Smith-Magenis syndrome and some germline cancer susceptibility genes such as BRCA1/BRCA2. As long as the gene-phenotype association is highly replicable, penetrant, rare, and of large effect, it increases our understanding of biological processes involved in disease pathology and augments our pool for potential therapeutic targets.…”