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. 2023 Mar 6;32(6):897-906.
doi: 10.1093/hmg/ddac224.

Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease

Ainara Ruiz de Sabando  1   2   3 , Edurne Urrutia Lafuente  3 , Arkaitz Galbete  4 , Marc Ciosi  5 , Fermín García Amigot  1 , Virginia García Solaesa  1 ; Spanish HD Collaborative group; Darren G Monckton  5 , Maria A Ramos-Arroyo  1   3
Collaborators, Affiliations

Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease

Ainara Ruiz de Sabando et al. Hum Mol Genet. .

Abstract

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.

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Figures

Figure 1
Figure 1
HTT haplotype distribution across the CAG range in alleles of the Spanish population represented in (A) three categories (normal, intermediate and expanded alleles), and (B) six categories, subclassing the normal and expanded alleles.
Figure 2
Figure 2
Age at onset by number of CAGs in the different exon one structures (n = 68).
Figure 3
Figure 3
Pie chart representing the haplotype makeup of HD families with unstable CAG transmissions (>5 CAGs). *A5xA1 is a recombinant haplotype, comprising portions of A5 and A1 haplotypes.
Figure 4
Figure 4
Moving averages representing haplotype frequencies of the HTT gene throughout the CAG range.
Figure 5
Figure 5
Flow diagram depicting the study populations, which include: (i) HD subjects (n = 490) and their family members (n = 234), (ii) intermediate allele (IA) carriers (n = 157) and (iii) individuals from population-based cohorts (n = 520). They comprise 991 non-related individuals: 331 HD, 140 IA carriers and 520 controls. Of them, 158 expanded, 93 intermediate and 243 normal chromosomes were CAG-phased for the haplotype study.
Figure 6
Figure 6
Schematic map of HTT gene displaying the genotypes of the selected SNPs that define A/B/C haplogroups (boxes) and the different haplotypes.
See this image and copyright information in PMC

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