Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Abstract

BACKGROUND Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. METHODS We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. RESULTS A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P = 1.77×10−7). CONCLUSIONS In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.)

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…Since 2010, genetic analyses based on so-called next-generation sequencing (NGS), such as wholeexome sequencing (WES) (20)(21)(22)(180)(181)(182), have gradually entered medical practice, especially in the past five years. WES allows the simultaneous sequencing of nearly 20 000 genes (20)(21)(22)180).…”

“…Over the past nearly five years, genetic assessment of patients with inherited diseases, including CHH/KS, has increasingly used massively parallel next-generation sequencing (NGS), allowing simultaneous analysis of tens to thousands of genes, depending on whether targeted-exome or whole-exome sequencing is used (2,(20)(21)(22). Consequently, detecting more than one rare but potentially deleterious variants in a given patient (oligogenism or potential oligogenism) is becoming increasingly common (20)(21)(22).…”

“…Consequently, detecting more than one rare but potentially deleterious variants in a given patient (oligogenism or potential oligogenism) is becoming increasingly common (20)(21)(22). This review summarizes the classical modes of transmission for CHH/KS loci reported in the literature, and explores the growing role of oligogenism.…”

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

“…Differences in predicted variant severity or X‐chromosome inactivation studies from blood DNA did not explain the gender‐specific disease expression. Five additional females with DDX3X variants have been described in the literature 12, 13, 14. These reports led us to hypothesize that females with de novo variation in DDX3X may show additional clinical phenotypes.…”

The “New Genetics” in Clinical Practice: A Brief Primer

“…12 Potentially more challenging, however, is the discovery of a secondary (incidental) finding of a genetic disorder not being sought. This very real possibility makes counseling an absolute requirement before WES.…”