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Allelic Diversity, De Novo CAG Expansions and Intergenerational Instability at the HTT Locus in a Sample from India

Published online by Cambridge University Press:  26 May 2025

Nikhil Ratna Open the ORCID record for Nikhil Ratna [Opens in a new window] ,
Sowmya Devatha Venkatesh ,
Swathi Pasupulati ,
Geetanjali Murari ,
Nitish Kamble ,
Biju Viswanath ,
Ravi Yadav Open the ORCID record for Ravi Yadav [Opens in a new window] ,
Mathew Varghese ,
Pramod Kumar Pal Open the ORCID record for Pramod Kumar Pal [Opens in a new window]  and
Sanjeev Jain
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Nikhil Ratna*
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
Sowmya Devatha Venkatesh
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
Swathi Pasupulati
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
Geetanjali Murari
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
Nitish Kamble
Affiliation:
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
Biju Viswanath
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
Ravi Yadav
Affiliation:
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
Mathew Varghese
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
Pramod Kumar Pal
Affiliation:
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
Sanjeev Jain
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
Meera Purushottam
Affiliation:
Molecular Genetics laboratory and Genetic Counseling and Testing Clinic (GCAT), Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, India
*
Corresponding author: Nikhil Ratna; Email: mybrainjourney@gmail.com
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Abstract

Background:

Huntington’s disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of an unstable CAG repeat sequence in the Huntingtin (HTT) gene. The prevalence of HD, allelic diversity, rate of novel expansions and the clinical correlates vary across populations.

Objective:

We analyzed the diversity of alleles and their clinical correlates and examined the inheritance patterns and the pattern of instability of CAG repeats in a few families.

Methods:

Clinical history and pedigree structure were collected from records or through interviews between 2016 and 2019. Genetic testing at the HD locus was done on clinical suspicion, or relatedness, after counseling. Descriptive statistics and correlation analysis were used.

Results:

Expanded repeats were detected in 239 individuals, including 232 who were symptomatic and 7 presymptomatic relatives. The number of CAG repeats (mean = 45.6) and age at onset (mean = 39.2 years) showed a strong inverse correlation (r = -0.67). We found atypical alleles such as 8 intermediate alleles (IA), 12 reduced penetrance alleles and 14 large (>60) expansion alleles corresponding to juvenile HD. Three individuals carried biallelic expansions. Paternal inheritance was more common, and the mean increase in repeats in the available parent-child pairs was 14. Thirty-seven individuals had no family history of HD, with de novo expansion confirmed in three cases.

Conclusions:

Novel mutations at the HTT locus may not be rare in India. A lack of family history should not exclude appropriate testing. The prevalence of IA and incidence of de novo expansions suggest that there may be a reservoir of alleles prone to expansion.

Résumé

RÉSUMÉ

Diversité allélique, expansions de novo de type CAG et instabilité intergénérationnelle du locus HTT dans un échantillon de l’Inde.

Contexte :

La maladie de Huntington (MH) est une maladie neurodégénérative héréditaire causée par l’expansion d’une séquence répétitive instable de type CAG dans le gène HTT. La prévalence de la MH, la diversité allélique, le taux de nouvelles expansions et les corrélats cliniques varient d’une population à l’autre.

Objectif :

Nous avons analysé la diversité des allèles et leurs corrélats cliniques et examiné les schémas de transmission et d’instabilité des répétitions de type CAG au sein de quelques familles.

Méthodes :

Leurs antécédents cliniques et la structure de leur arbre généalogique ont été recueillis à partir de dossiers ou au moyen d’entretiens menés entre 2016 et 2019. Les tests génétiques au locus HD ont été effectués sur la base d’une suspicion clinique ou d’un lien de parenté après conseil. Des statistiques descriptives et des analyses de corrélation ont également été utilisées.

Résultats :

Des répétitions étendues ont été détectées chez 239 personnes, dont 232 étaient symptomatiques et 7 concernaient des parents présymptomatiques. Le nombre de répétitions de type CAG (moyenne = 45,6) et l’âge d’apparition de la maladie (moyenne = 39,2 ans) ont montré une forte corrélation inverse (r = 0,67). Nous avons trouvé des allèles atypiques tels que 8 allèles intermédiaires (AI), 12 allèles à faible pénétrance (AFP) et 14 allèles d’expansion de grande taille (> 60) correspondant à une forme juvénile de la MH. Trois individus étaient porteurs d’expansions bi-alléliques. L’hérédité paternelle était plus fréquente et l’augmentation moyenne des répétitions dans les paires parent-enfant disponibles était de 14. À noter que 37 individus n’avaient pas d’antécédents familiaux de MH, une expansion de novo ayant été confirmée dans trois cas.

Conclusion :

Les nouvelles mutations du locus HTT ne sont peut-être pas rares en Inde. De plus, l’absence d’antécédents familiaux ne doit pas exclure un dépistage approprié. La prévalence des allèles intermédiaires et l’incidence des expansions de novo suggèrent qu’il pourrait y avoir un réservoir d’allèles susceptibles d’expansion.

Keywords

clinical neurogeneticsgenetics – humanHuntington’s diseasemovement disordersneurogeneticsneuroepidemiology

Information

Type
Original Article
Information
Canadian Journal of Neurological Sciences , First View , pp. 1 - 7
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation

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