Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease

Guerreiro, Rita; Lohmann, Ebba; Kinsella, Emma; Brás, José; Luu, Nga; Gurunlian, Nicole; Dursun, Burcu; Bılgıç, Başar; Santana, Isabel; Hanağası, Haşmet; Gürvıt, Hakan; Gibbs, J. Raphael; Oliveira, Catarina R.; Emre, Murat; Singleton, Andrew B.

doi:10.1016/j.neurobiolaging.2011.10.009

Cited by 90 publications

(68 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A major susceptibility gene, ApoE, is commonly associated with sporadic late-onset AD [35]. Our results with the MTHFR gene are in agreement with other studies suggesting that polymorphisms in other genes, such as genes for the amyloid precursor protein (APP, MIM 104760), presenilin 1 (PSEN1, MIM 104311), and presenilin 2 (PSEN2, MIM 600759), account for less than 5% of AD cases [35,36].…”

Section: Discussionsupporting

confidence: 91%

The Mthfr 677t Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer'Sdisease in an Egyptian Population

Hewedi

Elhawary

2015

European Psychiatry

View full text Add to dashboard Cite

Objective. We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimer's disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Methods. Forty-three Alzheimer's cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. Results. No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls ( = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. Conclusions. The MTHFR 677C>T polymorphism-especially the presence of one copy of the T allele-appears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker.

show abstract

Section: Discussionsupporting

confidence: 91%

The Mthfr 677t Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer'Sdisease in an Egyptian Population

Hewedi

Elhawary

2015

European Psychiatry

View full text Add to dashboard Cite

show abstract

“…The variability seems to be by and large independent of the type of mutation [22,23,24,25,26,27]. This variability in genetic, clinic and radiological features were also reported in a few studies from Turkey [28,29,30]. In addition to weak correlations among clinical, radiological and genetic manifestations, no mutation in NOTCH3 gene could be demonstrated in some patients with very demonstrative features of CADASIL ( NOTCH3 -negative patients).…”

Section: Discussionmentioning

confidence: 73%

Clinical and Radiological Features in CADASIL and <b><i>NOTCH3</i></b>-Negative Patients: A Multicenter Study from Turkey

İnce

Benbir²,

Síva³

et al. 2014

Eur Neurol

View full text Add to dashboard Cite

Background: The diversity of clinical presentation and neuroimaging findings of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) from different regions of the world has not yet been studied in depth. Here we investigated the variability of clinical, radiological and genetic data of 48 patients analyzed for NOTCH3 mutation in Turkey. Methods: Clinical evaluation was made according to a preformed questionnaire. Cranial neuroimaging findings were determined on the basis of T1, T2, FLAIR and proton-density magnetic resonance scans. For genetic analysis, polymerase chain reaction was performed with primers flanking exons 2-6 and 11 of NOTCH3 gene. Results: Twenty-five patients (52.1%) were diagnosed as CADASIL with NOTCH3 mutation, while 23 patients (47.9%) had no mutation (NOTCH3-negative patients). The mean age and age at stroke onset were lower in male CADASIL patients (p < 0.03). A family history of migraine (p = 0.012), stroke (p < 0.001), recurrent strokes (p = 0.020) and dementia (p = 0.012) was more common in CADASIL patients. Temporal pole involvement was more common in CADASIL patients (p = 0.004). Conclusion: It is of clinical importance to identify the heterogeneity of CADASIL from different countries due to a low correlation of clinical and radiological data with respect to NOTCH3 mutation.

show abstract

“…It was found to be highly polymorphic and contains variants under strong positive selection in humans [35] . NOTCH3 has been implicated in small vessel disease [36] ; and a pathogenic variant (not present in our data) has recently been found in a consanguineous family with a high prevalence of AD [37] . MED18 is a component of the Mediator complex, which is a co-activator for DNA-binding factors that activate transcription via RNA polymerase II [38] .…”

Section: Non-apoe Resultsmentioning

confidence: 59%

Rare Variant Testing of Imputed Data: An Analysis Pipeline Typified

et al. 2014

View full text Add to dashboard Cite

Important methodological advancements in rare variant association testing have been made recently, among them collapsing tests, kernel methods and the variable threshold (VT) technique. Typically, rare variants from a region of interest are tested for association as a group (‘bin'). Rare variant studies are already routinely performed as whole-exome sequencing studies. As an alternative approach, we propose a pipeline for rare variant analysis of imputed data and develop respective quality control criteria. We provide suggestions for the choice and construction of analysis bins in whole-genome application and support the analysis with implementations of standard burden tests (COLL, CMAT) in our INTERSNP-RARE software. In addition, three rare variant regression tests (REG, FRACREG and COLLREG) are implemented. All tests are accompanied with the VT approach which optimizes the definition of ‘rareness'. We integrate kernel tests as implemented in SKAT/SKAT-O into the suggested strategies. Then, we apply our analysis scheme to a genome-wide association study of Alzheimer's disease. Further, we show that our pipeline leads to valid significance testing procedures with controlled type I error rates. Strong association signals surrounding the known APOE locus demonstrate statistical power. In addition, we highlight several suggestive rare variant association findings for follow-up studies, including genomic regions overlapping MCPH1, MED18 and NOTCH3. In summary, we describe and support a straightforward and cost-efficient rare variant analysis pipeline for imputed data and demonstrate its feasibility and validity. The strategy can complement rare variant studies with next generation sequencing data.

show abstract

Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease

Cited by 90 publications

References 25 publications

The Mthfr 677t Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer'Sdisease in an Egyptian Population

The Mthfr 677t Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer'Sdisease in an Egyptian Population

Clinical and Radiological Features in CADASIL and <b><i>NOTCH3</i></b>-Negative Patients: A Multicenter Study from Turkey

Rare Variant Testing of Imputed Data: An Analysis Pipeline Typified

Contact Info

Product

Resources

About