Genetic characterization of a Turkish dementia cohort: a focus on leukodystrophy genes. (20th December 2022)

• Record Type: Journal Article
• Authors: Dehghani, Nadia; Guven, Gamze; Westra, Kaitlyn; Gardner, Eve; Paquette, Kimberly; Gibbons, Elizabeth; Hanagasi, Hasmet; Lohmann, Ebba; Samancı, Bedia; Gurvit, Hakan; Bilgiç, Başar; Bras, Jose; Guerreiro, Rita
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.067940
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Leukodystrophies broadly affect the brain white matter. As such, diseases including cerebral autosomal dominant/ recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL/CARASIL) are included in this group. NOTCH3 and HTRA1 variants are a known cause of CADASIL and CARASIL, respectively. Studies have reported NOTCH3 variants in Alzheimer's disease, and heterozygous HTRA1 variants in cerebral small vessel disease. Therefore, there is growing evidence of leukodystrophy gene variants in neurodegenerative diseases. Method: We screened a whole‐exome sequenced Turkish dementia cohort for rare variants in a panel of leukodystrophy genes. Where familial samples were available, we tested for segregation. We also consulted the exome data available from the Turkish Variome to gauge a better estimate of population frequency for candidate variants. Result: We identified rare variants in leukodystrophy genes in individuals from this Turkish dementia cohort. Variants in NOTCH3 include a known pathogenic gain‐of‐cysteine variant in a family presenting with CADASIL (NOTCH3 p.Arg133Cys); a novel loss‐of‐cysteine variant (NOTCH3 p.Cys65Tyr) in an atypic dementia case, and a novel cysteine‐sparing missense variant (NOTCH3 p.Ala818Thr) in a family with Alzheimer's disease and mild cognitive impairment. Conclusion: Considering the increased consanguinity of the Turkish population we were expecting to identify bi‐allelic variants in HTRA1 with potential roles in disease. Instead, NOTCH3 presented a higher burden of variability, including known and novel variants expected to be involved in disease.