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P4‐039: APP , PSEN1 , AND PSEN2 MUTATIONS IN EARLY‐ONSET ALZHEIMER'S DISEASE DISCOVERED IN ASIAN COUNTRIES: A GENETIC SCREENING STUDY OF FAMILIAL AND SPORADIC CASES
Author(s) -
Van Vo Giau,
Ch'ng Gaik-Siew,
Senanarong Vorapun -,
Antonio D. Ligsay,
Shim Kyu Hwan,
Jamerlan Angelo,
Seo Eunhye,
Bagyinszky Eva,
Park Young-Ho,
An Seong Soo,
Kim SangYun
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2441
Subject(s) - psen1 , presenilin , genetics , sanger sequencing , amyloid precursor protein , early onset alzheimer's disease , biology , mutation , disease , gene , alzheimer's disease , medicine , pathology
Background:Recent studies reported that extremely rare genetic variants that affect SORL1 function are associated with increased AD risk. However, to prove that disruption of SORL1 is causative for autosomal dominant inheritance of AD, segregation of the SORL1 variant with disease needs to be demonstrated in large families. To estimate pathogenicity of SORL1 variants found in AD patients with no available pedigree, we previously suggested a pathogenicity screen based on SORL1 variant characteristics (Table). In our analysis, 2% of the AD cases carried a predicted (likely) pathogenic SORL1 variant. We reasoned that these carrier-cases have an increased probability to come from families genetically predisposed for AD. Here, we aimed to identify these patients and collect evidence for autosomal dominant inheritance of AD in their families.Methods:Using exome sequencing we identified 24 cases from the Amsterdam Dementia Cohort with a predicted (likely) pathogenic SORL1 mutation, based on our pathogenicity screen. We extracted family history from patient-files and constructed pedigrees when possible. Additionally, we summarized family history in SORL1 variant-carriers reported in 10 publications between 2012-2017. Results:Of 24 AD patients with a (likely) pathogenic SORL1 variant, 15 had at least one first-degree family member affected with dementia (unknown for 9 cases). For 7 patients, with an average age at onset of 56.1 years, large pedigrees could be constructed over several generations. In the affected lineages, w50% of the family members developed AD before 65 years, with no skipped generations, suggesting that affected familymembers carry a fully penetrant AD-causing allele. In literature, family history was reported for carriers of 90 unique SORL1 variants: a family history of AD occurred significantly more often in carriers of (likely) pathogenic SORL1 variants (83%) compared to carriers of uncertain/benign SORL1 variants (57%), p<0.01. For 10 variants, segregation with AD was shown, but pedigrees were small. Conclusions:By selecting AD patients with a predicted (likely) pathogenic SORL1 mutation we identified 7 large families with an inheritance pattern suggestive of autosomal dominant AD. Segregation analysis is ongoing; we hope to provide closing evidence that SORL1 is an autosomal dominant AD gene, next to PSEN1, PSEN2 and APP.