Measurement of the clinical utility of a combined mutation detection protocol in carriers of Duchenne and Becker muscular dystrophy

• Published in: Journal of medical genetics 2007-06, Vol.44 (6), p.368-372
• Main Authors: Taylor, Peter J, Maroulis, Sarah, Mullan, Glenda L, Pedersen, Robyn L, Baumli, Aurora, Elakis, George, Piras, Sara, Walsh, Corrina, Prósper-Gutiérrez, Benito, De La Puente-Alonso, Fernando, Bell, Christopher G, Mowat, David R, Johnston, Heather M, Buckley, Michael F
• Format: Article
• Language: English
• Subjects: Becker muscular dystrophy; Becker's muscular dystrophy; Biological and medical sciences; BMD; BMD, Becker muscular dystrophy; CK, creatine kinase; Creatine; Creatine kinase; D/BMD; D/BMD, Duchenne and Becker muscular dystrophies; Diseases of striated muscles. Neuromuscular diseases; DMD; DMD, Duchenne muscular dystrophy; Duchenne and Becker muscular dystrophies; Duchenne muscular dystrophy; Duchenne's muscular dystrophy; Dystrophin; Female; Fundamental and applied biological sciences. Psychology; Gene deletion; General aspects. Genetic counseling; Genes; Genetic Carrier Screening; Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Heterozygote; Humans; Laboratories; Linkage analysis; Male; Medical genetics; Medical sciences; MLPA; MLPA, multiplex ligation-dependent probe amplification; Molecular and cellular biology; Mothers; multiplex ligation-dependent probe amplification; Muscular Dystrophy, Duchenne - diagnosis; Muscular Dystrophy, Duchenne - genetics; Mutation; Mutation - genetics; Neurology; Nucleotide sequence; Original; Original articles; Pedigree; qfPCR; qfPCR, quantitative fluorescent PCR technique; quantitative fluorescent PCR technique; Rodents; Sequence analysis; short tandem repeat; STR; STR, short tandem repeat; Studies
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2006.047464

Background: Recent methodological advances have improved the detection rate for dystrophin mutations, but there are no published studies that have measured the clinical utility of these protocols for carrier detection compared with conventional carrier testing protocols that use pedigree, serum creatine kinase levels and linkage analysis. Methods and subjects: The clinical utility of a combined mutation detection protocol was measured. It involved quantitative PCR procedures followed by DNA sequence analysis for the identification of dystrophin mutation carriers in 2101 women at risk of being carriers from 348 mutation-known Duchenne or Becker muscular dystrophy pedigrees. Results: The combined mutation detection protocol identified a mutation in 96% and 82% of index cases of Duchenne muscular dystrophy and Becker muscular dystrophy, respectively. An additional 692 (33%) potential carriers were correctly classified by the combined mutation detection protocol compared with pedigree, serum creatine kinase levels and linkage analysis. Significantly lower mutation carrier rates were identified in the mothers of isolated cases with deletion mutations than predicted from theoretical considerations, but these findings were not confirmed for duplication and DNA sequence mutations. Conclusions: There are significant clinical benefits to be gained from a combined mutation detection protocol for carrier detection. It is recommended that mutation-specific carrier frequencies for the different classes of dystrophin mutations should be taken into account in genetic counselling practice.