Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity.
Hemophilia B has been considered as a classical monogenic disorder with complete penetrance. Here, we observed that its allelic spectrum encompasses mutations that show least phenotypic variation as well as those showing phenotypic plasticity, thereby establishing hemophilia B as a quasi-quantitative condition with variable expressivity. Thus, we relocate it from simple monogenic diseases with complete penetrance into a space that marks the conceptual continuum of Mendelian to complex diseases. By computational analysis, we show that mutations showing phenotypic variation were characterized by relatively less conserved mutant sites and more tolerated conservative substitutions. We also demonstrate that consideration of continuous phenotypes renders quantitative rigor for interrogation and hence higher predictive value while analyzing for differential properties than classifications based on clinical end points. Certain mutations have been consistently reported to cause mild phenotype, calling for a check in indiscriminate termination of fetuses following prenatal diagnosis.
Chavali
Sreenivas
S
Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi-110 007, India.
Ghosh
Saurabh
S
Bharadwaj
Dwaipayan
D
D000025:Abortion, Eugenic / Q000592:standards; D000465:Algorithms; D000483:Alleles; D019943:Amino Acid Substitution; D016000:Cluster Analysis; D017124:Conserved Sequence; D005164:Factor IX / Q000737:chemistry / Q000235:genetics*; D002836:Hemophilia B / Q000175:diagnosis / Q000196:embryology / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D010314:Partial Thromboplastin Time; D019683:Penetrance; D010641:Phenotype; D011296:Prenatal Diagnosis; D017510:Protein Folding; D012720:Severity of Illness Index; D013329:Structure-Activity Relationship
D005164:Factor IX