Novel Rare SORL1 Variants in Early-Onset Dementia

Background: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer’s disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. Objective: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). Methods: The rare SORL1variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46–65 years) by using the whole-exome sequencing. Results: We found one novel nonsense variant (p.Gln290 *) and eight missense variants in SORL1. This is the first study reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. Conclusion: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD.

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Atrial Fibrillation Increases the Risk of Early-Onset Dementia in the General Population: Data from a Population-Based Cohort

Journal of Clinical Medicine ◽

10.3390/jcm9113665 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3665

Author(s):

Dongmin Kim ◽

Pil-Sung Yang ◽

Gregory Y.H. Lip ◽

Boyoung Joung

Keyword(s):

Atrial Fibrillation ◽

Early Onset ◽

Late Onset ◽

Population Data ◽

The Elderly ◽

Population Based ◽

Early Onset Dementia ◽

Increased Risk ◽

Late Onset Dementia

Atrial fibrillation (AF) is considered a risk factor for dementia, especially in the elderly. However, the association between the two diseases is not well identified in different age subgroups. The association of incident AF with the development of dementia was assessed from 1 January 2005, to 31 December 2013, in 428,262 participants from a longitudinal cohort (the Korea National Health Insurance Service-Health Screening cohort). In total, 10,983 participants were diagnosed with incident AF during the follow-up period. The incidence of dementia was 11.3 and 3.0 per 1000 person-years in the incident-AF and without-AF groups, respectively. After adjustment for clinical variables, the risk of dementia was significantly elevated by incident AF, with a hazard ratio (HR) of 1.98 (95% confidence interval [CI]: 1.80–2.17, p < 0.001), even after censoring for stroke (HR: 1.74, 95% CI: 1.55–1.94, p < 0.001). The HRs of incident AF for dementia onset before the age of 65 (early-onset dementia) and for onset after the age of 65 (late-onset dementia) were 2.91 (95% CI: 1.93–4.41) and 1.67 (95% CI: 1.49–1.87), respectively. Younger participants with AF were more prone to dementia development than older participants with AF (p for trend < 0.001). AF was associated with an increased risk of both early- and late-onset dementia, independent of clinical stroke.

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P2-131: WHOLE-EXOME SEQUENCING OF HISPANIC EARLY-ONSET ALZHEIMER DISEASE FAMILIES IDENTIFIES RARE VARIANTS IN MULTIPLE ALZHEIMER'S-RELATED GENES

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.05.806 ◽

2014 ◽

Vol 10 ◽

pp. P518-P519

Author(s):

Margaret Pericak-Vance ◽

Christiane Reitz ◽

Brian W. Kunkle ◽

Badri N. Vardarajan ◽

Martin A. Kohli ◽

...

Keyword(s):

Alzheimer Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Rare Variants ◽

Whole Exome

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Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

10.1101/2020.06.06.137299 ◽

2020 ◽

Cited By ~ 1

Author(s):

Bernabe I. Bustos ◽

Dimitri Krainc ◽

Steven J. Lubbe ◽

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Rare Variants ◽

Neurodegenerative Disorder ◽

Age Of Onset ◽

Late Onset ◽

Genetic Component ◽

Genetic Risk Assessment ◽

Whole Exome

ABSTRACTParkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95×10−26, beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease- and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

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Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

Frontiers in Genetics ◽

10.3389/fgene.2021.740052 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaojing Gu ◽

Yongping Chen ◽

Qianqian Wei ◽

Yanbing Hou ◽

Bei Cao ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rare Variants ◽

Chinese Patients ◽

Causative Gene ◽

Missense Variants ◽

Whole Exome ◽

Sporadic Als ◽

Als Patients ◽

Lateral Sclerosis

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%.Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS.Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed.

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P3-115: WHOLE EXOME SEQUENCING ANALYSIS OF KOREAN PATIENTS WITH EARLY ONSET DEMENTIA

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.3143 ◽

2019 ◽

Vol 15 ◽

pp. P974-P974

Author(s):

Seong Soo An ◽

Eva Bagyinszky ◽

Giau Van Vo ◽

Kyu Hwan Shim ◽

Jung Min Pyun ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Sequencing Analysis ◽

Early Onset Dementia ◽

Korean Patients ◽

Whole Exome

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Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2020.02.008 ◽

2020 ◽

Vol 93 ◽

pp. e1-e9

Author(s):

Oscar Ramos-Campoy ◽

Anna Antonell ◽

Neus Falgàs ◽

Mircea Balasa ◽

Sergi Borrego-Écija ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Early Onset Dementia ◽

Risk Variants ◽

Whole Exome ◽

Uncertain Significance

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Rare Variants Analysis of Lysosomal Related Genes in Early-Onset and Familial Parkinson’s Disease in a Chinese Cohort

Journal of Parkinson s Disease ◽

10.3233/jpd-212658 ◽

2021 ◽

pp. 1-11

Author(s):

Yong-Ping Chen ◽

Xiao-Jing Gu ◽

Wei Song ◽

Yan-Bing Hou ◽

Ru-Wei Ou ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Rare Variants ◽

Lysosomal Storage ◽

Asian Populations ◽

Whole Exome ◽

Gene Level ◽

Chinese Cohort

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

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Age at Onset, Sex, and Familial Psychiatric Morbidity in Schizophrenia

The British Journal of Psychiatry ◽

10.1192/bjp.165.4.466 ◽

1994 ◽

Vol 165 (4) ◽

pp. 466-473 ◽

Cited By ~ 78

Author(s):

Pak Chung Sham ◽

Peter Jones ◽

Ailsa Russell ◽

Karyna Gilvarry ◽

Paul Bebbington ◽

...

Keyword(s):

Diagnostic Criteria ◽

Early Onset ◽

Late Onset ◽

Psychiatric Morbidity ◽

Age At Onset ◽

First Degree Relatives ◽

Functional Psychosis ◽

Increased Risk ◽

Schizophrenic Patients ◽

Research Diagnostic Criteria

BackgroundAlthough a genetic component in schizophrenia is well established, it is likely that the contribution of genetic factors is not constant for all cases. Several recent studies have found that the relatives of female or early onset schizophrenic patients have an increased risk of schizophrenia, compared to relatives of male or late onset cases. These hypotheses are tested in the current study.MethodA family study design was employed; the probands were 195 patients with functional psychosis admitted to three south London hospitals, diagnosed using Research Diagnostic Criteria (RDC), and assessed using the Present State Examination (PSE). Information on their relatives was obtained by personal interview of the mother of the proband, and from medical records. Psychiatric diagnoses were made using Family History – Research Diagnostic Criteria (FH-RDC), blind to proband information.ResultsThere was a tendency for homotypia in the form of psychosis within families. The lifetime risk of schizophrenia in the first degree relatives of schizophrenic probands, and the risk of bipolar disorder in the first degree relatives of bipolar probands, were 5–10 times higher than reported population risks. Relatives of female and early onset (<22 years) schizophrenic probands had higher risk of schizophrenia than relatives of male and late onset schizophrenic probands. However, this effect was compensated in part by an excess of non-schizophrenic psychoses in the relatives of male probands.ConclusionsThese results suggest a high familial, possibly genetic, loading in female and early onset schizophrenia, but do not resolve the question of heterogeneity within schizophrenia.

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Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-318568 ◽

2018 ◽

Vol 90 (5) ◽

pp. 537-542 ◽

Cited By ~ 13

Author(s):

Hiroya Naruse ◽

Hiroyuki Ishiura ◽

Jun Mitsui ◽

Yuji Takahashi ◽

Takashi Matsukawa ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Age At Onset ◽

Sequencing Analysis ◽

Pathogenic Mutations ◽

Multiple Genes ◽

Whole Exome ◽

Lateral Sclerosis

ObjectivesTo evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series.MethodsWe conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups.ResultsWhole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants.ConclusionsA substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.

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