Human Mutation · 2006 · 205 citations · 26 references
Life SciencesGeneticsMolecular GeneticsGenetic CounselingHuman GeneticsMedical GeneticsGenetic DisordersMutation AnalysisMutation ScreeningScreening AssaysVariant AnalysisVariant DetectionAlagille SyndromeGenetic Mutation DetectionMutant DetectionMutationMutation Rate DeterminationPathogenic Variant DetectionPrenatal Molecular DiagnosisSequential Screening
Alagille syndrome (AGS) is caused by heterozygous mutations in JAG1, and mutations have been previously reported in about 70% of patients who meet clinical diagnostic criteria. We studied a cohort of 247 clinically well-defined patients, and using an aggressive and sequential screening approach we identified JAG1 mutations in 94% of individuals. Mutations were found in 232 out of 247 patients studied and 83 of the mutations were novel. This increase in the mutation rate was accomplished by combining rigorous clinical phenotyping, with a combination of mutation detection techniques, including fluorescence in situ hybridization (FISH), genomic and cDNA sequencing, and quantitative PCR. This higher rate of mutation identification has implications for clinical practice, facilitating genetic counseling, prenatal diagnosis, and evaluation of living-related liver transplant donors. Our results suggest that more aggressive screening may similarly increase the rate of mutation detection in other dominant and recessive disorders.
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Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
Linheng Li, Ian D. Krantz, Yu Deng et al. · Nature Genetics · 1997 · 1.3K citations
Mutations in the human Jagged1 gene are responsible for Alagille syndrome
Takaya Oda, Abdel Elkahloun, Brian L. Pike et al. · Nature Genetics · 1997 · 1.2K citations
Arupa Ganguly, Matthew J. Rock, Darwin J. Prockop · Proceedings of the National Academy of Sciences · 1993 · 677 citations