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

Sabando, A. R. et al. (2023) Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease. Human Molecular Genetics, 32(6), pp. 897-906. (doi: 10.1093/hmg/ddac224) (PMID:36130218) (PMCID:PMC9990985)

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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%), while 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 characterised 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.

Item Type:Articles
Additional Information: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).
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren and Ciosi, Dr Marc
Authors: Sabando, A. R., Lafuente, E. U., Galbete, A., Ciosi, M., Amigot, F. G., Solaesa, V. G., Martínez, V. Á., Martinez-Descals, A., Mila, M., Trujillo-Tiebas, M. J., López-Sendón, J. L., Fenollar-Cortés, M., Legarda, I., Noguera, S. B., Millán, J. M., Durán-Herrera, C., Monckton, D. G., and Ramos-Arroyo, M. A.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN (Online):1460-2083
Published Online:20 September 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Human Molecular Genetics 32(6): 897-906
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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