We describe a new approach for analysis of the epidemiology of progressive genetic disorders that
quantifies the rate of progression of the disease in the population by measuring the mutational
flow.
The framework is applied to Huntington disease (HD), a dominant neurologicaldisorder caused by the expansion
of a CAG-trinucleotide sequence to >35 repeats. The disease is 100% penetrant in individuals with > or = 42 repeats.
Measurement of the flow from disease alleles provides a minimum estimate of the flow in the whole
population and implies that the new mutation rate for HD in each generation is > or = 10% of currently known cases (95%
confidence limits 6%-14%).
Analysis of the pattern of flow demo-nstrates systematic underascertainment for repeat lengths
<44. Ascertainment falls to <50% for individuals with 40 repeats and to <5% for individuals with 36-38 repeats.
Clinicians should not assume that HD is rare outside known pedigrees or that most cases have onset
at age <50 years.
In February 2991 , Dr. Michael Hayden and colleagues estimated a mutation rate
of ten percent.
Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial
underascertainment of late-onset cases.
Falush D, Almqvist EW, Brinkmann RR, Iwasa Y, Hayden MR.Department of Biology,
Faculty of Science, Kyushu University, Japan. Email
