Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases

Abstract

Purpose:Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease.Methods:Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema.Results:Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of “candidate” and “suspected candidate,” respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously.Conclusions:Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.Genet Med 19 2, 224–235.

A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy

“…Genomic DNA extraction, exome library preparation, sequencing, bioinformatics, and data analyses were performed as previously described. 24,25 Identified candidate variants were confirmed via Sanger sequencing.…”

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

“…For individual 10, parent-proband trio WES was performed at Ambry Genetics using the IDT xGen Exome Research Panel and analyzed as previously described. 36,37 On average, $96.6% of the target bases were covered at >203 for the trio. The de novo frameshift alteration identified in this patient by WES was confirmed by Sanger sequencing and interpreted as a (suspected) candidate gene finding.…”

“…The de novo frameshift alteration identified in this patient by WES was confirmed by Sanger sequencing and interpreted as a (suspected) candidate gene finding. 37 …”

Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications

“…The remaining negative reclassification report was due to new literature disputing the pathogenicity of alterations in the identified gene ( SRI ; MIM# 182520). Within the first 500 cases, we previously reported that in cases in which a candidate genetic etiology was initially reported, 51.9% had subsequent corroborating evidence in the literature [Farwell Hagman et al., ]. Of the current cohort of 80 candidate genetic etiology reports, 28 subsequently were issued a reclassification report, that is, 35% of all candidate genetic etiology reports were subsequently reclassified to positive/likely positive in characterized genes.…”