Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases

Daniel Falush, Elisabeth W. Almqvist, Ryan R. Brinkmann, Yoh Iwasa, Michael R. Hayden

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

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 neurological disorder caused by the expansion of a CAG-trinucleotide sequence to >35 repeats. The disease is 100% penetrant in individuals with ≥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 ≥10% of currently known cases (95% confidence limits 6%-14%). Analysis of the pattern of flow demonstrates 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.

Original languageEnglish
Pages (from-to)373-385
Number of pages13
JournalAmerican Journal of Human Genetics
Volume68
Issue number2
DOIs
Publication statusPublished - Jan 1 2001

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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