Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease
Fecha
2023Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Impacto
|
10.1093/hmg/ddac224
Resumen
We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We
performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based
controls (n = 520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140
car ...
[++]
We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We
performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based
controls (n = 520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140
carriers of intermediate alleles. Clinical and family history data were obtained when available. Spanish normal alleles are enriched in
C haplotypes (40.1%), whereas A1 (39.8%) and A2 (31.6%) prevail among intermediate and expanded alleles, respectively. Alleles ≥ 50
CAG repeats are primarily associated with haplotypes A2 (38.9%) and C (32%), which are also present in 50% and 21.4%, respectively,
of HD families with large intergenerational expansions. Non-canonical variants of exon one sequence are less frequent, but much
more diverse, in alleles of ≥27 CAG repeats. The deletion of CAACAG, one of the six rare variants not observed among smaller normal
alleles, is associated with haplotype C and appears to correlate with larger intergenerational expansions and early onset of symptoms.
Spanish HD haplotypes are characterized by a high genetic diversity, potentially admixed with other non-Caucasian populations, with
a higher representation of A2 and C haplotypes than most European populations. Differences in haplotype distributions across the CAG
length range support differential germline expansion dynamics, with A2 and C showing the largest intergenerational expansions. This
haplotype-dependent germline instability may be driven by specific cis-elements, such as the CAACAG deletion. [--]
Materias
Huntington disease,
Spain,
Haplotype diversity,
Allelic diversity
Editor
Oxford University Press
Publicado en
Human molecular genetics, 32(6), 897-906
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila /
Universidad Pública de Navarra. Departamento de Estadística, Informática y Matemáticas /
Nafarroako Unibertsitate Publikoa. Estatistika, Informatika eta Matematika Saila
Versión del editor
Entidades Financiadoras
This study was funded by the Instituto de Salud Carlos III (grant no. FIS PI15/02227), and the CHDI Foundation (Enroll -HD study). A. Ruiz de Sabando was supported by a Fellowship of Departamento de Salud, Gobierno de Navarra (ref. 0011-4809-2018-000001).