Insights into genetics, human biology and disease gleaned from family based genomic studies

Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies inDrosophila

“…As whole-exome (WES) and whole-genome sequencing (WGS) become part of the general medical practice in the era of personalized medicine (Posey et al, 2019), the number of variants of unknown significance (VUS) in NOTCH and related genes will likely increase at a rapid pace. Understanding the precise mechanism of how each mutation affects protein function is critical since different therapeutic strategies may need to be used based on the specific type of variant an individual carries (Bellen, Wangler, & Yamamoto, 2019;Harnish, Deal, Chao, Wangler, & Yamamoto, 2019;Wangler et al, 2017).…”

Exome Sequencing in Clinical Hepatology

“…A landmark in history of human genomics occurred in 2009 when WES was first applied for clinical diagnosis, including an unanticipated diagnosis of congenital chloride diarrhea in an infant with suspected renal salt‐wasting disease, and in another patient, to discover a novel genetic defect underlying a multisystemic syndrome of unknown cause . Since then, multiple studies have demonstrated the value of WES in clinical diagnosis and human disease gene discovery . Moreover, these discoveries have led to novel insights into disease mechanisms, provided new diagnostic tests, and identified new therapeutic targets.…”

“…Moreover, these discoveries have led to novel insights into disease mechanisms, provided new diagnostic tests, and identified new therapeutic targets. Thus far, the phenotypic consequence of genetic variants in only 20% of genes comprising the human genome have been delineated . Considering that up to 30% of human genes when mutated are likely to be embryonically lethal, there are as many as 10,000 genes that when mutated could impact human health in ways we have yet to understand .…”

“…(6) Since then, multiple studies have demonstrated the value of WES in clinical diagnosis and human disease gene discovery. (7) Moreover, these discoveries have led to novel insights into disease mechanisms, provided new diagnostic tests, and identified new therapeutic targets. Thus far, the phenotypic consequence of genetic variants in only 20% of genes comprising the human genome have been delineated.…”

“…Thus far, the phenotypic consequence of genetic variants in only 20% of genes comprising the human genome have been delineated. (7) Considering that up to 30% of human genes when mutated are likely to be embryonically lethal, there are as many as 10,000 genes that when mutated could impact human health in ways we have yet to understand. (8) Moreover, the full phenotypic spectrum of most gene alterations remains to be defined as the majority of genotype/ phenotype correlations are confined to the classical phenotypes only.…”