Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.
Genet Med
; 26(5): 101082, 2024 05.
Article
in En
| MEDLINE
| ID: mdl-38281098
ABSTRACT
PURPOSE:
To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).METHODS:
We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92).RESULTS:
Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees.CONCLUSION:
We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.Key words
Full text:
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Membrane Glycoproteins
/
Receptors, Immunologic
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Genetic Testing
/
Genetic Predisposition to Disease
/
Presenilin-2
/
Alzheimer Disease
/
Exome Sequencing
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Guideline
/
Observational_studies
/
Risk_factors_studies
/
Screening_studies
Aspects:
Patient_preference
Limits:
Aged
/
Aged80
/
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Genet Med
Journal subject:
GENETICA MEDICA
Year:
2024
Document type:
Article
Country of publication: