Clinical heterogeneity of LRRK2 p.I2012T mutation

Fan, Tian-Sin; Wu, Ruey‐Meei; Chen, Pei‐Lung; Chen, Ta‐Fu; Li, Huei-Ying; Lin, Yin-Hung; Chen, Chien‐Yu; Chen, Meng‐Ling; Tai, Chun‐Hwei; Lin, Hang-I; Lin, Chin‐Hsien

doi:10.1016/j.parkreldis.2016.09.008

Cited by 18 publications

(21 citation statements)

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“…19,20 Targeted NGS Panel A custom-designed NGS panel, including 40 genes associated with parkinsonism (Supplementary Table 1), was performed as previously described. 21 Figure 1 depicts the criteria for identifying causative variants in the affected families, including target enrichment, variant calling, and data filtering. The details are described in the Supplementary Methods.…”

Section: Repeat-primed Pcrmentioning

confidence: 99%

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A clinical and genetic study of early‐onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next‐generation sequencing

et al. 2019

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Background Recent genetic progress has allowed for the molecular diagnosis of Parkinson's disease. However, genetic causes of PD vary widely in different ethnicities. Mutational frequencies and clinical phenotypes of genes associated with PD in Asian populations are largely unknown. The objective of this study was to identify the mutational frequencies and clinical spectrums of multiple PD‐causative genes in a Taiwanese PD cohort. Methods A total of 571 participants including 324 patients with early‐onset parkinsonism (onset age, <50 years) and 247 parkinsonism pedigrees were recruited at a tertiary referral center in Taiwan from 2002 to 2017. Genetic causes were identified by an integrated approach including gene dosage analysis, a targeted next‐generation sequencing panel containing 40 known PD‐causative genes, repeat‐primed polymerase chain reaction, and whole‐exome sequencing analysis. Results Thirty of the 324 patients with early‐onset parkinsonism (9.3%) were found to carry mutations in Parkin , PINK1 , or PLA2G6 or had increased trinucleotide repeats in SCA8 . Twenty‐nine of 109 probands with autosomal‐recessive inheritance of parkinsonism (26.6%) were found to carry mutations in Parkin , PINK1 , GBA , or HTRA2 . The genetic causes for the 138 probands with an autosomal‐dominant inheritance pattern of parkinsonism were more heterogeneous. Seventeen probands (12.3%) carried pathogenic mutations in LRRK2 , VPS35 , MAPT , GBA , DNAJC13 , C9orf72 , SCA3, or SCA17 . A novel missense mutation in the UQCRC1 gene was found in a family with autosomal‐dominant inheritance parkinsonism via whole‐exome sequencing analysis. Conclusions Our findings provide a better understanding of the genetic architecture of PD in eastern Asia and broaden the clinical spectrum of PD‐causing mutations. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Repeat-primed Pcrmentioning

confidence: 99%

“…3A). 21 These variants are all known pathogenic mutations and segregated with the parkinsonism phenotype within the families. On the LRRK2 protein, the p.I1371V and p. R1441H substitutions are both on the Ras of complex protein (ROC) domain, and p.I2012T is on the kinase domain of the LRRK2 protein ( Fig.…”

Section: Genetic Analysesmentioning

confidence: 99%

A clinical and genetic study of early‐onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next‐generation sequencing

et al. 2019

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“…Next generation sequencing (NGS) allows for the comprehensive genetic analysis of familial neurodegenerative syndromes, as seen in FTD with parkinsonism [ 1 ]. Since the clinical picture in this case indicated an autosomal dominant inheritance form of FTD with neuropsychiatric disorder, we applied genetic analysis using targeted NGS and covering candidate genes known to cause familial forms of FTD and ALS to the proband [ 15 ]. We extracted variants within the genes of interest for further analysis, including MAPT (NM_001123066.3), GRN (NM_002087.2), FUS (NM_001170937), TARDBP (NM_007375), VCP (NM_007126) and CHMP2B (NM_014043).…”

Section: Case Presentationmentioning

confidence: 99%

Intrafamilial phenotypic heterogeneity in a Taiwanese family with a MAPT p.R5H mutation: a case report and literature review

Lin

Chen

et al. 2017

BMC Neurol

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BackgroundFrontotemporal degeneration (FTD) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by deficits in executive function that frequently overlaps with parkinsonism and motor neuron disorders. Several genes have been identified to cause autosomal dominant forms of FTD, including the gene coding for the protein associated with microtubule tau (MAPT). While most reported pathogenic mutations in MAPT occur in exons 9–13, few families have been reported with mutations outside of this region. Herein, we report a first Taiwanese family having the exon 1 p.Arg5His mutation in MAPT with intrafamilial phenotype heterogeneity.Case presentationA 63-year-old man presented with progressive non-fluent speech and impaired memory for 3 years. He then developed apraxia, myoclonus and parkinsonism feature at his right hand. Extensive neurologic and neurocognitive examination lead to a diagnosis of FTD mixed with corticobasal syndrome. Magnetic resonance imaging revealed asymmetric atrophy in the left frontal and temporal lobes and single-photon emission computed tomography indicated decreased metabolism in the same areas as well as the left basal ganglia. The patient’s mother had been diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 60 and was deceased 10 years later due to respiratory failure. The patient’s younger sister had persistent depressive disorder in her early forties and did not have any prominent cognitive or motor dysfunctions. We performed genetic analysis applying a targeted next generation sequencing (NGS) panel covering MAPT, GRN, VCP, FUS, CHMP2B, and TARDBP on the proband, followed by Sanger sequencing of candidate genes in eight family members. Hexanucleotide repeat expansion of C9Orf72 was determined by repeat-primed PCR. We identified a missense mutation in exon 1 of MAPT gene, c.14G > A (p.R5H), which was previously reported in only two Japanese patients in a literature review. This substitution co-segregated with the disease phenotypes in the family.ConclusionsThis is the first report of the occurrence of the MAPT p.R5H mutation in the Taiwanese population. Our findings extend the current knowledge of phenotypic heterogeneity among family members carrying the MAPT p.R5H mutation.

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“…32,33 The clinical spectrum of I2012T mutation carriers varies widely, ranges from typical late-onset levodopa-responsive PD to FTD with parkinsonism. 34 To date, dementia without parkinsonism phenotype has not been reported in I2012T mutation carriers. In the study, we detected I2012T mutation of LRRK2 in an EOAD family.…”

Section: Discussionmentioning

confidence: 99%

Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

Zhang

Jiao

Xiao

et al. 2020

Ann Clin Transl Neurol

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Objective: To investigate the impact of rare variants underlying neurodegenerative-related genes to familial Alzheimer's disease (AD). Methods: We performed targeted sequencing of 277 neurodegenerative-related genes on probands from 75 Chinese AD families non-carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control. Results: A novel rare variant, P410S of PLD3 was found in an early-onset AD family. LRRK2 I2012T, a causative mutation of Parkinson's disease, was identified in another early-onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1 (T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non-frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008). Interpretation: Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative-related genes is necessary for genetically unclear AD families.

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Clinical heterogeneity of LRRK2 p.I2012T mutation

Cited by 18 publications

References 30 publications

A clinical and genetic study of early‐onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next‐generation sequencing

A clinical and genetic study of early‐onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next‐generation sequencing

Intrafamilial phenotypic heterogeneity in a Taiwanese family with a MAPT p.R5H mutation: a case report and literature review

Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

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