Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Ciliary Defects and Hyperammoniemia as Possible Causes of Dementia Not Classified as Alzheimer’s Disease or Frontomteporal Dementia

Sena Karachanak-Yankova
* ORCID logo ,
Dimitar Serbezov
,
Mikaela Stancheva
ORCID logo ,
Savina Hadjidekova
,
Draga Toncheva
ORCID logo ,
Diana Belezhanska
,
Mariya Petrova
,
Shima Mehrabian
,
Latchezar Traykov
Version 1 : Received: 14 March 2024 / Approved: 14 March 2024 / Online: 14 March 2024 (15:18:08 CET)

How to cite: Karachanak-Yankova, S.; Serbezov, D.; Stancheva, M.; Hadjidekova, S.; Toncheva, D.; Belezhanska, D.; Petrova, M.; Mehrabian, S.; Traykov, L. Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Ciliary Defects and Hyperammoniemia as Possible Causes of Dementia Not Classified as Alzheimer’s Disease or Frontomteporal Dementia. Preprints 2024, 2024030851. https://doi.org/10.20944/preprints202403.0851.v1 Karachanak-Yankova, S.; Serbezov, D.; Stancheva, M.; Hadjidekova, S.; Toncheva, D.; Belezhanska, D.; Petrova, M.; Mehrabian, S.; Traykov, L. Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Ciliary Defects and Hyperammoniemia as Possible Causes of Dementia Not Classified as Alzheimer’s Disease or Frontomteporal Dementia. Preprints 2024, 2024030851. https://doi.org/10.20944/preprints202403.0851.v1

Abstract

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia by surveying rare pathogenic variants. The analysis was performed on 91 patients, the DNA samples of which were pooled and then subjected to whole exome sequencing. Among detected variants two are rare pathogenic and show significant difference in frequency between the analyzed pool and gnomAD Bulgarian control exomes. The rs373478202, G>T, B9D1 variant, most likely present in heterozygous state; is causative for the autosomal recessive ciliopathy- Joubert syndrome, which involves specific CNS malformation. The rs148918985, C>T, ASS1 variant leads to arginosuccinate enzyme deficiency and in compound heterozygosity with other rare pathogenic variant detected in the same gene causes the late-onset form of citrullinemia type I. This disorder causes high ammonia levels, which can lead to cerebral dysfunction. In conclusion, the detected rare pathogenic variants suggest that, in certain cases, the development of non-AD and non-FTD dementia can be mediated by structural alterations in neuronal cilia or by hyperammoniemia.

Keywords

dementia; whole exome sequencing; rare pathogenic variants; ciliary defects; argininosuccinate synthase deficiency

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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