title: Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease.
abstract: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary choreic movements, cognitive impairment, and behavioral changes, caused by the expansion of an unstable CAG repeat in HTT. We characterized the genetic diversity of the HD mutation by performing an extensive haplotype analysis of ∼1Mb region flanking HTT in over 300 HD families of Portuguese origin. We observed that haplotype A, marked by HTT delta2642, was enriched in HD chromosomes and carried the two largest expansions reported in the Portuguese population. However, the most frequent HD haplotype B carried one of the largest (+12 CAGs) expansions, which resulted in an allele class change to full penetrance. Despite having a normal CAG distribution skewed to the higher end of the range, these two core haplotypes had similar expanded CAG repeat sizes compared to the other major core haplotypes (C and D) and there was no statistical difference in transmitted repeat instability across haplotypes. We observed a diversity of HTT region haplotypes in both normal and expanded chromosomes, representative of more than one ancestral chromosome underlying HD in Portugal, where multiple independent events on distinct chromosome 4 haplotypes have given rise to expansion into the pathogenic range.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA; UnIGENe, IBMC-Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.
authors: Eliana Marisa
authors: EM
authors: Ramos
authors: Tammy
authors: T
authors: Gillis
authors: Jayalakshmi S
authors: JS
authors: Mysore
authors: Jong-Min
authors: JM
authors: Lee
authors: Martin
authors: M
authors: Gögele
authors: Yuri
authors: Y
authors: D'Elia
authors: Irene
authors: I
authors: Pichler
authors: Jorge
authors: J
authors: Sequeiros
authors: Peter P
authors: PP
authors: Pramstaller
authors: James F
authors: JF
authors: Gusella
authors: Marcy E
authors: ME
authors: MacDonald
authors: Isabel
authors: I
authors: Alonso
mesh_terms: D000483:Alleles; D020029:Base Pairing / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005190:Family; D005260:Female; D042822:Genomic Instability; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011174:Portugal; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
keywords: Delta 2642 allele; Genetic diversity; Haplotype analysis; Huntington's disease; Instability
references: Eur J Hum Genet. 2013 Oct;21(10):1120-7
references: 23463025
references: Acta Neurol Scand. 2003 Oct;108(4):281-6
references: 12956863
references: Am J Hum Genet. 2012 Mar 9;90(3):434-44
references: 22387017
references: Clin Genet. 2009 Mar;75(3):244-50
references: 19250382
references: Am J Med Genet B Neuropsychiatr Genet. 2009 Apr 5;150B(3):425-9
references: 18712713
references: Nat Genet. 1993 Nov;5(3):214-5
references: 8275082
references: Nat Genet. 1993 Oct;5(2):174-9
references: 8252043
references: Mol Cell Probes. 1993 Jun;7(3):235-9
references: 8366869
references: BMC Med Genet. 2007 Jun 05;8:29
references: 17550581
references: Hum Mutat. 2002 Sep;20(3):233
references: 12204002
references: Hum Mol Genet. 1995 Feb;4(2):207-14
references: 7757069
references: Somat Cell Mol Genet. 1994 Jan;20(1):27-38
references: 8197474
references: Nat Genet. 1993 Oct;5(2):168-73
references: 8252042
references: Nat Genet. 1993 Aug;4(4):387-92
references: 8401587
references: Am J Hum Genet. 2009 Dec;85(6):939-42
references: 20004772
references: Hum Mol Genet. 1994 Jul;3(7):1129-32
references: 7981682
references: Clin Genet. 2010 Oct;78(4):381-7
references: 20236117
references: Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):314-20
references: 19455596
references: Hum Mol Genet. 1994 Dec;3(12):2103-14
references: 7881406
references: Hum Mutat. 2005 May;25(5):453-9
references: 15832309
references: J Hum Genet. 2008;53(2):127-135
references: 18157708
references: Nat Genet. 1992 May;1(2):99-103
references: 1302016
references: Cell. 1993 Mar 26;72(6):971-83
references: 8458085
references: Eur J Hum Genet. 2011 May;19(5):561-6
references: 21248742
references: Hum Mol Genet. 1992 May;1(2):142
references: 1339471
references: J Hum Genet. 2006;51(3):189-195
references: 16372132
references: Am J Med Genet B Neuropsychiatr Genet. 2015 Mar;168B(2):135-43
references: 25656686
references: J Hum Genet. 2012 Dec;57(12):796-803
references: 23051704
references: Hum Genet. 1994 Aug;94(2):124-8
references: 8045558
references: Am J Hum Genet. 2009 Mar;84(3):351-66
references: 19249009
references: Mov Disord. 2012 Apr;27(4):583-5
references: 22162197
references: Neurodegeneration. 1995 Sep;4(3):239-44
references: 8581556