The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK

Osma S. Rautila, Karri Kaivola, Harri Rautila, Laura Hokkanen, Jyrki Launes, Timo E. Strandberg, Hannu Laaksovirta, Johanna Palmio, Pentti J. Tienari

Research output: Contribution to journalArticleScientificpeer-review

Abstract

The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18–20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18–20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.

Original languageEnglish
Pages (from-to)383-392
Number of pages10
JournalAMERICAN JOURNAL OF HUMAN GENETICS
Volume111
Issue number2
DOIs
Publication statusPublished - Feb 2024
Publication typeA1 Journal article-refereed

Keywords

  • ALS
  • C9orf72
  • FTD
  • GGGGCC
  • haplotype sharing tree
  • HAPTK
  • HST
  • repeat disorders
  • repeat expansion

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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