Genetics in Medicine · 2017 · 128 citations · 34 references
Life SciencesGeneticsPediatricsGenomicsMedical GeneticsPediatric GeneticsClinical GenomicsGenetic Risk AssessmentGenome SequencingNeonatal GeneticsVariant ClassificationVariant InterpretationClinical Genome ReportingClinical Relevance AssessmentClinical Variant ReportingCurated Data SetsDisease AssociationsDisease RiskGenomic Variant InterpretationRare Genetic Variants
Genomic sequencing of newborns can detect conditions where early knowledge improves outcomes, but a major barrier is the time required to assess the clinical relevance of detected variants and genes for risk reporting. To enable rapid interpretation of newborn genomic sequencing, the authors curated a catalog of genes with putative pediatric relevance based on ClinGen clinical validity criteria, age of onset, penetrance, and inheritance mode. The catalog was created through systematic evaluation of published evidence, genes were classified to guide result return in the BabySeq randomized controlled trial, and the list was applied to the first 15 sequenced newborns, yielding 1,514 gene‑.
Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately.To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project.Here, we present our curated list for 1,514 gene-disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns.Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017.
34
Sue Richards, Nazneen Aziz, Sherri J. Bale et al. · Genetics in Medicine · 2015 · 32.2K citations · Full text
Mutation in blood coagulation factor V associated with resistance to activated protein C
Rogier M. Bertina, Bobby P. C. Koeleman, Ted Koster et al. · Nature · 1994 · 3.8K citations
Medicine, Genetics, Hematology +14