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Pi BK, Chung YH, Kim HS, Nam SH, Lee AJ, Nam DE, Park HJ, Kim SB, Chung KW, Choi BO. Compound Heterozygous Mutations of SACS in a Korean Cohort Study of Charcot-Marie-Tooth Disease Concurrent Cerebellar Ataxia and Spasticity. Int J Mol Sci 2024; 25:6378. [PMID: 38928084 PMCID: PMC11204044 DOI: 10.3390/ijms25126378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/03/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity.
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Affiliation(s)
- Byung Kwon Pi
- Department of Biological Sciences, Kongju National University, Gongju 32588, Republic of Korea; (B.K.P.); (A.J.L.)
| | - Yeon Hak Chung
- Department of Neurology, Korea University Guro Hospital, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea;
| | - Hyun Su Kim
- Department of Radiology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea;
| | - Soo Hyun Nam
- Cell and Gene Therapy Institute, Samsung Medical Center, Gangnam-gu, Seoul 06351, Republic of Korea;
| | - Ah Jin Lee
- Department of Biological Sciences, Kongju National University, Gongju 32588, Republic of Korea; (B.K.P.); (A.J.L.)
| | - Da Eun Nam
- Department of Domestic Business, Macrogen, Inc., 238 Teheran-ro, Gangnam-gu, Seoul 06221, Republic of Korea;
| | - Hyung Jun Park
- Department of Neurology, Gangnam Severance Hospital, College of Medicine, Yonsei University, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea;
| | - Sang Beom Kim
- Department of Neurology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Republic of Korea;
| | - Ki Wha Chung
- Department of Biological Sciences, Kongju National University, Gongju 32588, Republic of Korea; (B.K.P.); (A.J.L.)
| | - Byung-Ok Choi
- Cell and Gene Therapy Institute, Samsung Medical Center, Gangnam-gu, Seoul 06351, Republic of Korea;
- Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, 81 Irwonr-ro, Gangnam-gu, Seoul 06351, Republic of Korea
- Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences and Technology, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
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Ashrafi MR, Mohammadi P, Tavasoli AR, Heidari M, Hosseinpour S, Rasulinejad M, Rohani M, Akbari MG, Malamiri RA, Badv RS, Fathi D, Dehnavi AZ, Savad S, Rabbani A, Synofzik M, Mahdieh N, Rezaei Z. Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: an Iranian Case Series Expanding the Genetic and Neuroimaging Spectra. CEREBELLUM (LONDON, ENGLAND) 2022:10.1007/s12311-022-01430-3. [PMID: 35731353 DOI: 10.1007/s12311-022-01430-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/06/2022] [Indexed: 06/15/2023]
Abstract
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.
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Affiliation(s)
- Mahmoud Reza Ashrafi
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pediatrics Center, Growth and Development Research Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Pouria Mohammadi
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran
| | - Ali Reza Tavasoli
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Myelin Disorders Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, USA
| | - Morteza Heidari
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Myelin Disorders Clinic, Tehran University of Medical Sciences, Tehran, Iran
| | - Sareh Hosseinpour
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pediatric Neurology, Vali-E-Asr Hospital, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Rasulinejad
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Rohani
- Department of Neurology, School of Medicine, Hazrat Rasool-E Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Masoud Ghahvechi Akbari
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Physical Medicine and Rehabilitation Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Azizi Malamiri
- Division of Pediatric Neurology, Department of Pediatrics, Golestan Medical, Educational and Research Center, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
| | - Reza Shervin Badv
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Fathi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- Neurology Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Zare Dehnavi
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahram Savad
- Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Rabbani
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pediatrics Center, Growth and Development Research Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Matthis Synofzik
- Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany
- Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Nejat Mahdieh
- Cardiogenetic Research Center, Rajaei Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Zahra Rezaei
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran.
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Bagaria J, Bagyinszky E, An SSA. Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration. Int J Mol Sci 2022; 23:552. [PMID: 35008978 PMCID: PMC8745260 DOI: 10.3390/ijms23010552] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/30/2021] [Accepted: 12/30/2021] [Indexed: 12/14/2022] Open
Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.
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Affiliation(s)
- Jaya Bagaria
- Department of Bionano Technology, Gachon University, Seongnam 13120, Korea;
| | - Eva Bagyinszky
- Department of Industrial and Environmental Engineering, Graduate School of Environment, Gachon University, Seongnam 13120, Korea
| | - Seong Soo A. An
- Department of Bionano Technology, Gachon University, Seongnam 13120, Korea;
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Dragašević-Mišković N, Stanković I, Milovanović A, Kostić VS. Autosomal recessive adult onset ataxia. J Neurol 2021; 269:504-533. [PMID: 34499204 DOI: 10.1007/s00415-021-10763-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 11/24/2022]
Abstract
Autosomal recessive ataxias (ARCA) represent a complex group of diseases ranging from primary ataxias to rare and complex metabolic disorders in which ataxia is a part of the clinical picture. Small number of ARCA manifest exclusively in adulthood, while majority of typical childhood onset ARCA may also start later with atypical clinical presentation. We have systematically searched the literature for ARCA with adult onset, both in the group of primary ataxias including those that are less frequently described in isolated or in a small number of families, and also in the group of complex and metabolic diseases in which ataxia is only part of the clinical picture. We propose an algorithm that could be used when encountering a patient with adult onset sporadic or recessive ataxia in whom the acquired causes are excluded. ARCA are frequently neglected in the differential diagnosis of adult-onset ataxias. Rising awareness of their clinical significance is important, not only because some of these disorders may be potentially treatable, but also for prognostic implications and inclusion of patients to future clinical trials with disease modifying agents.
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Affiliation(s)
- Nataša Dragašević-Mišković
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia.
| | - Iva Stanković
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Andona Milovanović
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Vladimir S Kostić
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
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Xiromerisiou G, Dadouli K, Marogianni C, Provatas A, Ntellas P, Rikos D, Stathis P, Georgouli D, Loules G, Zamanakou M, Hadjigeorgiou GM. A novel homozygous SACS mutation identified by whole exome sequencing-genotype phenotype correlations of all published cases. J Mol Neurosci 2019; 70:131-141. [PMID: 31701440 DOI: 10.1007/s12031-019-01410-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023]
Abstract
ARSACS is an autosomal recessive disorder characterized by ataxia, spasticity, and polyneuropathy. A plethora of worldwide distributed mutations have been described so far. Here, we report two brothers, born to non-consanguineous parents, presenting with cerebellar ataxia and peripheral neuropathy. Whole-exome sequencing revealed the presence of a novel homozygous variant in the SACS gene. The variant was confirmed by Sanger sequencing and found at heterozygous state in both parents. This is the first reported mutation in this gene, in Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide. Additionally, we performed a systematic review of all published cases with SACs mutations. ARSACS seems to be an important cause of ataxia and many different types of mutations have been identified, mainly located in exon 10. We evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age of onset of ARSACS. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various ARSACS variants.
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Affiliation(s)
- Georgia Xiromerisiou
- Department of Neurology, University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
| | - Katerina Dadouli
- Department of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Chrysoula Marogianni
- Department of Neurology, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Antonios Provatas
- Department of Neurology, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Panagiotis Ntellas
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Dimitrios Rikos
- Department of Neurology, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Pantelis Stathis
- Department of Neurology, Mediterraneo Hospital, Glyfada, Athens, Greece
| | - Despina Georgouli
- Department of Neurology, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | | | | | - Georgios M Hadjigeorgiou
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.,Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus
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Suratanee A, Plaimas K. Network-based association analysis to infer new disease-gene relationships using large-scale protein interactions. PLoS One 2018; 13:e0199435. [PMID: 29949603 PMCID: PMC6021074 DOI: 10.1371/journal.pone.0199435] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 06/07/2018] [Indexed: 01/02/2023] Open
Abstract
Protein-protein interactions integrated with disease-gene associations represent important information for revealing protein functions under disease conditions to improve the prevention, diagnosis, and treatment of complex diseases. Although several studies have attempted to identify disease-gene associations, the number of possible disease-gene associations is very small. High-throughput technologies have been established experimentally to identify the association between genes and diseases. However, these techniques are still quite expensive, time consuming, and even difficult to perform. Thus, based on currently available data and knowledge, computational methods have served as alternatives to provide more possible associations to increase our understanding of disease mechanisms. Here, a new network-based algorithm, namely, Disease-Gene Association (DGA), was developed to calculate the association score of a query gene to a new possible set of diseases. First, a large-scale protein interaction network was constructed, and the relationship between two interacting proteins was calculated with regard to the disease relationship. Novel plausible disease-gene pairs were identified and statistically scored by our algorithm using neighboring protein information. The results yielded high performance for disease-gene prediction, with an F-measure of 0.78 and an AUC of 0.86. To identify promising candidates of disease-gene associations, the association coverage of genes and diseases were calculated and used with the association score to perform gene and disease selection. Based on gene selection, we identified promising pairs that exhibited evidence related to several important diseases, e.g., inflammation, lipid metabolism, inborn errors, xanthomatosis, cerebellar ataxia, cognitive deterioration, malignant neoplasms of the skin and malignant tumors of the cervix. Focusing on disease selection, we identified target genes that were important to blistering skin diseases and muscular dystrophy. In summary, our developed algorithm is simple, efficiently identifies disease–gene associations in the protein-protein interaction network and provides additional knowledge regarding disease-gene associations. This method can be generalized to other association studies to further advance biomedical science.
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Affiliation(s)
- Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut’s University of Technology North Bangkok, Bangkok, Thailand
- * E-mail: (AS); (KP)
| | - Kitiporn Plaimas
- Advanced Virtual and Intelligent Computing (AVIC) Center, Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- * E-mail: (AS); (KP)
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Doi H, Koyano S, Miyatake S, Nakajima S, Nakazawa Y, Kunii M, Tomita-Katsumoto A, Oda K, Yamaguchi Y, Fukai R, Ikeda S, Kato R, Ogata K, Kubota S, Hayashi N, Takahashi K, Tada M, Tanaka K, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Ogi T, Aihara M, Takeuchi H, Matsumoto N, Tanaka F. Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations. J Hum Genet 2018; 63:417-423. [DOI: 10.1038/s10038-017-0408-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 12/05/2017] [Accepted: 12/22/2017] [Indexed: 01/05/2023]
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Lin D, Liang Y, Jing X, Chen Y, Lei M, Zeng Z, Zhou T, Wu X, Peng S, Zheng D, Huang K, Yang L, Xiao S, Liu J, Tao E. Microarray analysis of an synthetic α-synuclein induced cellular model reveals the expression profile of long non-coding RNA in Parkinson's disease. Brain Res 2017; 1678:384-396. [PMID: 29137975 DOI: 10.1016/j.brainres.2017.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 11/07/2017] [Accepted: 11/08/2017] [Indexed: 01/10/2023]
Abstract
Long non-coding RNAs (lncRNAs) are a new research focus that are reported to influence the pathogenetic process of neurodegenerative disorders. To uncover new disease-associated genes and their relevant mechanisms, we carried out a gene microarray analysis based on a Parkinson's disease (PD) in vitro model induced by α-synuclein oligomers. This cellular model induced by 25 μmol/L α-synuclein oligomers has been confirmed to show the stable, transmissible neurotoxicity of α-synuclein, a typical PD pathological marker. And several differentially expressed lncRNAs and mRNAs were identified in this model, such as G046036, G030771, AC009365.4, RPS14P3, CTB-11I22.1, and G007549. Subsequent ceRNA analysis determined the potential relationships between these lncRNAs and their associated mRNAs and microRNAs. The results of the present study widen our horizon of PD susceptibility genes and provide new pathways towards efficient diagnostic biomarkers and therapeutic targets for PD.
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Affiliation(s)
- D Lin
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - Y Liang
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - X Jing
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - Y Chen
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - M Lei
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - Z Zeng
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - T Zhou
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - X Wu
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - S Peng
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - D Zheng
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - K Huang
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - L Yang
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - S Xiao
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - J Liu
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China
| | - E Tao
- Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
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9
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Han YY, Zhao LJ, Lin Y, He H, Tian Q, Zhu W, Shen H, Chen XD, Deng HW. Multiple analyses indicate the specific association of NR1I3, C6 and TNN with low hip BMD risk. J Genet Genomics 2017; 44:327-330. [PMID: 28629900 PMCID: PMC5822710 DOI: 10.1016/j.jgg.2017.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 04/17/2017] [Accepted: 05/04/2017] [Indexed: 01/20/2023]
Affiliation(s)
- Ying-Ying Han
- Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Lan-Juan Zhao
- Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Yong Lin
- Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Hao He
- Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Qing Tian
- Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Wei Zhu
- Laboratory of Molecular and Statistical Genetics and the Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Hui Shen
- Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Xiang-Ding Chen
- Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Hong-Wen Deng
- Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, China; Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA.
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10
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Hammer MB, Ding J, Mochel F, Eleuch-Fayache G, Charles P, Coutelier M, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Majounie E, Clipman S, Bouhlal Y, Nehdi H, Brice A, Hentati F, Stevanin G, Amouri R, Durr A, Singleton AB. SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families. NEURODEGENER DIS 2017; 17:208-212. [PMID: 28558379 DOI: 10.1159/000464445] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 02/20/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with high clinical and genetic heterogeneity. In most cases, the cerebellar ataxia is not pure, and complicating clinical features such as pyramidal signs or extraneurological features are found. OBJECTIVE To identify the genetic origin of the cerebellar ataxia for 3 consanguineous North African families presenting with ARCA. METHODS Genome-wide high-density SNP genotyping and whole-exome sequencing were performed followed by Sanger sequencing for mutation confirmation. RESULTS Two variants were identified in SLC25A46. Mutations in this gene have been previously associated with Charcot-Marie-Tooth type 2 and optic atrophy. While the previously reported variant p.Arg340Cys seems to be consistently associated with the same clinical features such as childhood onset, optic atrophy, gait and speech difficulties, and wasting of the lower limbs, the patient with the novel mutation p.Trp160Ser did not present with optic atrophy and his ocular abnormalities were limited to nystagmus and saccadic pursuit. CONCLUSION In this study, we report a novel variant (p.Trp160Ser) in SLC25A46 and we broaden the phenotypic spectrum associated with mutations in SLC25A46.
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Affiliation(s)
- Monia B Hammer
- Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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11
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Hsu JS, Kwan JSH, Pan Z, Garcia-Barcelo MM, Sham PC, Li M. Inheritance-mode specific pathogenicity prioritization (ISPP) for human protein coding genes. Bioinformatics 2016; 32:3065-3071. [PMID: 27354691 DOI: 10.1093/bioinformatics/btw381] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 06/14/2016] [Indexed: 11/13/2022] Open
Abstract
MOTIVATION Exome sequencing studies have facilitated the detection of causal genetic variants in yet-unsolved Mendelian diseases. However, the identification of disease causal genes among a list of candidates in an exome sequencing study is still not fully settled, and it is often difficult to prioritize candidate genes for follow-up studies. The inheritance mode provides crucial information for understanding Mendelian diseases, but none of the existing gene prioritization tools fully utilize this information. RESULTS We examined the characteristics of Mendelian disease genes under different inheritance modes. The results suggest that Mendelian disease genes with autosomal dominant (AD) inheritance mode are more haploinsufficiency and de novo mutation sensitive, whereas those autosomal recessive (AR) genes have significantly more non-synonymous variants and regulatory transcript isoforms. In addition, the X-linked (XL) Mendelian disease genes have fewer non-synonymous and synonymous variants. As a result, we derived a new scoring system for prioritizing candidate genes for Mendelian diseases according to the inheritance mode. Our scoring system assigned to each annotated protein-coding gene (N = 18 859) three pathogenic scores according to the inheritance mode (AD, AR and XL). This inheritance mode-specific framework achieved higher accuracy (area under curve = 0.84) in XL mode. CONCLUSION The inheritance-mode specific pathogenicity prioritization (ISPP) outperformed other well-known methods including Haploinsufficiency, Recessive, Network centrality, Genic Intolerance, Gene Damage Index and Gene Constraint scores. This systematic study suggests that genes manifesting disease inheritance modes tend to have unique characteristics. AVAILABILITY AND IMPLEMENTATION ISPP is included in KGGSeq v1.0 (http://grass.cgs.hku.hk/limx/kggseq/), and source code is available from (https://github.com/jacobhsu35/ISPP.git). CONTACT mxli@hku.hkSupplementary information: Supplementary data are available at Bioinformatics online.
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Affiliation(s)
| | | | | | | | - Pak Chung Sham
- Department of Psychiatry Centre for Genomics Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Miaoxin Li
- Department of Psychiatry Centre for Genomics Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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12
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Shi C, Shang D, Sun S, Mao C, Qin J, Luo H, Shao M, Chen Z, Liu Y, Liu X, Song B, Xu Y. MMACHC gene mutation in familial hypogonadism with neurological symptoms. Gene 2015; 574:380-4. [PMID: 26283149 DOI: 10.1016/j.gene.2015.08.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 08/12/2015] [Accepted: 08/13/2015] [Indexed: 10/23/2022]
Abstract
Recent studies have convincingly documented that hypogonadism is a component of various hereditary disorders and is often recognized as an important clinical feature in combination with various neurological symptoms, yet, the causative genes in a few related families are still unknown. High-throughput sequencing has become an efficient method to identify causative genes in related complex hereditary disorders. In this study, we performed exome sequencing in a family presenting hypergonadotropic hypogonadism with neurological presentations of mental retardation, epilepsy, ataxia, and leukodystrophy. After bioinformatic analysis and Sanger sequencing validation, we identified compound heterozygous mutations: c.482G>A (p.R161Q) and c.609G>A (p.W203X) in MMACHC gene in this pedigree. MMACHC was previously confirmed to be responsible for methylmalonic aciduria (MMA) combined with homocystinuria, cblC type (cblC disease), a hereditary vitamin B12 metabolic disorder. Biochemical and gas chromatography-mass spectrometry (GC-MS) examinations in this pedigree further supported the cblC disease diagnosis. These results indicated that hypergonadotropic hypogonadism may be a novel clinical manifestation of cblC disease, but more reports on additional patients are needed to support this hypothesis.
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Affiliation(s)
- Changhe Shi
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Dandan Shang
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Shilei Sun
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Chengyuan Mao
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Jie Qin
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Haiyang Luo
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Mingwei Shao
- Department of Endocrinology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Zhengguang Chen
- Department of Ultrasound, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Yutao Liu
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Xinjing Liu
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Bo Song
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China
| | - Yuming Xu
- Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University. 1 Jian-she East Road, Zhengzhou 450000, Henan, China.
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13
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Mao CY, Yang J, Zhang SY, Luo HY, Song B, Liu YT, Wu J, Sun SL, Yang ZH, Du P, Wang YH, Shi CH, Xu YM. Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations. Int J Neurosci 2015; 126:1071-6. [PMID: 26643368 DOI: 10.3109/00207454.2015.1118628] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novel CCM1 gene mutation. MATERIALS AND METHODS We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. The CCM1 mRNA expression level in three patients of the family and 10 wild-type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR). RESULTS Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in the CCM1 gene in the pedigree. Based on real-time RT-PCR results, we have found that the CCM1 mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals. CONCLUSIONS Our finding suggests that the novel nonsense mutation c.1159G>T in CCM1 gene is associated with FCCM, and that CCM1 haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases.
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Affiliation(s)
- Cheng-Yuan Mao
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.,b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Jing Yang
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Shu-Yu Zhang
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.,b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Hai-Yang Luo
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.,b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Bo Song
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Yu-Tao Liu
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Jun Wu
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Shi-Lei Sun
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Zhi-Hua Yang
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.,b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Pan Du
- c 3 International Joint Research Laboratory for Cell and Gene Therapy of Henan Province , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Yao-He Wang
- c 3 International Joint Research Laboratory for Cell and Gene Therapy of Henan Province , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Chang-He Shi
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.,b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
| | - Yu-Ming Xu
- a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.,b 2 Institute of Clinical Medicine , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China
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14
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Li YS, Mao CY, Shi CH, Song B, Wu J, Qin J, Ji Y, Niu HX, Luo HY, Shang DD, Sun SL, Xu YM. Exome sequencing reveals novel SPG11 mutation in hereditary spastic paraplegia with complicated phenotypes. J Clin Neurosci 2015; 22:1150-4. [DOI: 10.1016/j.jocn.2015.01.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 12/29/2014] [Accepted: 01/03/2015] [Indexed: 12/12/2022]
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15
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Tacik P, Guthrie KJ, Strongosky AJ, Broderick DF, Riegert-Johnson DL, Tang S, El-Khechen D, Parker AS, Ross OA, Wszolek ZK. Whole-exome sequencing as a diagnostic tool in a family with episodic ataxia type 1. Mayo Clin Proc 2015; 90:366-71. [PMID: 25659636 PMCID: PMC4354704 DOI: 10.1016/j.mayocp.2015.01.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 12/18/2014] [Accepted: 01/02/2015] [Indexed: 11/23/2022]
Abstract
Complex neurologic phenotypes are inherently difficult to diagnose. Whole-exome sequencing (WES) is a new tool in the neurologist's diagnostic armamentarium. Whole-exome sequencing can be applied to investigate the "diagnostic odyssey" cases. These cases involve patients with rare diseases that likely have a genetic etiology but have failed to be diagnosed by clinical evaluation and targeted gene testing. We describe such a case, a 22-year-old man who had mild intellectual developmental disability and episodes of jerking ataxic movements that affected his whole body. He underwent numerous multidisciplinary and multicentric evaluations throughout his life that failed to establish a clear diagnosis. Following his visit to Mayo Clinic in Jacksonville, Florida, WES was applied for genetic determination of the unknown disorder in the proband and his biological parents and sister. Additional clinical evaluation, magnetic resonance neuroimaging, electromyography, and electroencephalography of the proband were performed to verify the phenotype after the WES results were available. To our knowledge, this is the first report of the application of WES to facilitate the diagnosis of episodic ataxia type 1. This case illustrates that WES supported by clinical data is a useful and time-saving tool in the evaluation of patients with rare and complex hereditary disorders.
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Affiliation(s)
- Pawel Tacik
- Department of Neurology, Mayo Clinic, Jacksonville, FL
| | | | | | | | | | - Sha Tang
- Ambry Genetics Corp, Aliso Viejo, CA
| | | | | | - Owen A Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL
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16
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Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation. Sci Rep 2014; 4:7132. [PMID: 25417924 PMCID: PMC5384088 DOI: 10.1038/srep07132] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 11/04/2014] [Indexed: 11/08/2022] Open
Abstract
Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.
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17
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Affiliation(s)
- A H V Schapira
- Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.
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18
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Sun ZF, Zhang YH, Guo JF, Sun QY, Mei JP, Zhou HL, Guan LP, Tian JY, Hu ZM, Li JD, Xia K, Yan XX, Tang BS. Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing. PLoS One 2014; 9:e106388. [PMID: 25181484 PMCID: PMC4152247 DOI: 10.1371/journal.pone.0106388] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 08/06/2014] [Indexed: 11/18/2022] Open
Abstract
Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.
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Affiliation(s)
- Zhan-fang Sun
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Yu-han Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Ji-feng Guo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Qi-ying Sun
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | | | | | | | - Jin-yong Tian
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Zheng-mao Hu
- State Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Jia-da Li
- State Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Kun Xia
- State Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Xin-xiang Yan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Bei-sha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
- State Key Laboratory of Medical Genetics, Central South University, Changsha, China
- * E-mail:
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Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N, Ragusa N, Mancini C, Gaussen M, Calcia A, Mitro N, Hoxha E, Mura I, Coviello DA, Moon YA, Tesson C, Vaula G, Couarch P, Orsi L, Duregon E, Papotti MG, Deleuze JF, Imbert J, Costanzi C, Padovani A, Giunti P, Maillet-Vioud M, Durr A, Brice A, Tempia F, Funaro A, Boccone L, Caruso D, Stevanin G, Brusco A. ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet 2014; 95:209-17. [PMID: 25065913 DOI: 10.1016/j.ajhg.2014.07.001] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 07/02/2014] [Indexed: 12/18/2022] Open
Abstract
Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.
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Affiliation(s)
- Eleonora Di Gregorio
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy; Medical Genetics Unit, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy
| | - Barbara Borroni
- Department of Neurology, University of Brescia, 25100 Brescia, Italy
| | - Elisa Giorgio
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Daniela Lacerenza
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Marta Ferrero
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Nicola Lo Buono
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Neftj Ragusa
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Cecilia Mancini
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Marion Gaussen
- Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Neurogenetics team, École Pratique des Hautes Études, HéSam Université, 75013 Paris, France
| | - Alessandro Calcia
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Nico Mitro
- Department of Pharmacological and Biomolecular Sciences, University of Milano, 20133 Milano, Italy
| | - Eriola Hoxha
- Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10043 Orbassano, Italy
| | - Isabella Mura
- Laboratory of Human Genetics, Galliera Hospital, 16128 Genova, Italy
| | | | - Young-Ah Moon
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Christelle Tesson
- Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Neurogenetics team, École Pratique des Hautes Études, HéSam Université, 75013 Paris, France
| | - Giovanna Vaula
- Neurologic Division 1, Department of Neuroscience and Mental Health, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy
| | - Philippe Couarch
- Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France
| | - Laura Orsi
- Neurologic Division 1, Department of Neuroscience and Mental Health, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy
| | - Eleonora Duregon
- Department of Oncology, University of Torino at San Luigi Hospital, 10043 Orbassano, Italy
| | - Mauro Giulio Papotti
- Department of Oncology, University of Torino at San Luigi Hospital, 10043 Orbassano, Italy
| | | | - Jean Imbert
- Transcriptomic and Genomic Marseille-Luminy platform, Technological Advances for Genomics and Clinics Laboratory, Institut National de la Santé et de la Recherche Médicale UMR_S 1090, Aix-Marseille University, 13009 Marseille, France
| | - Chiara Costanzi
- Department of Neurology, University of Brescia, 25100 Brescia, Italy
| | | | - Paola Giunti
- Department of Molecular Neuroscience, University College London Institute of Neurology, WC1 N3BG London, UK
| | | | - Alexandra Durr
- Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Fédération de Génétique, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France
| | - Alexis Brice
- Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Fédération de Génétique, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France
| | - Filippo Tempia
- Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10043 Orbassano, Italy
| | - Ada Funaro
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Loredana Boccone
- Ospedale Regionale Microcitemie, Azienda Unità Sanitaria Locale 8, 09121 Cagliari, Italy
| | - Donatella Caruso
- Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10043 Orbassano, Italy
| | - Giovanni Stevanin
- Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Neurogenetics team, École Pratique des Hautes Études, HéSam Université, 75013 Paris, France; Fédération de Génétique, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France
| | - Alfredo Brusco
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy; Medical Genetics Unit, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy.
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20
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Sawyer SL, Schwartzentruber J, Beaulieu CL, Dyment D, Smith A, Chardon JW, Yoon G, Rouleau GA, Suchowersky O, Siu V, Murphy L, Hegele RA, Marshall CR, Bulman DE, Majewski J, Tarnopolsky M, Boycott KM. Exome sequencing as a diagnostic tool for pediatric-onset ataxia. Hum Mutat 2014; 35:45-9. [PMID: 24108619 PMCID: PMC4255313 DOI: 10.1002/humu.22451] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/20/2013] [Accepted: 09/22/2013] [Indexed: 12/30/2022]
Abstract
Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative.
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Affiliation(s)
- Sarah L Sawyer
- Children's Hospital of Eastern Ontario Research Institute, University of OttawaOttawa, Ontario, Canada
| | | | - Chandree L Beaulieu
- Children's Hospital of Eastern Ontario Research Institute, University of OttawaOttawa, Ontario, Canada
| | - David Dyment
- Children's Hospital of Eastern Ontario Research Institute, University of OttawaOttawa, Ontario, Canada
| | - Amanda Smith
- Children's Hospital of Eastern Ontario Research Institute, University of OttawaOttawa, Ontario, Canada
| | - Jodi Warman Chardon
- Children's Hospital of Eastern Ontario Research Institute, University of OttawaOttawa, Ontario, Canada
| | - Grace Yoon
- Divisions of Neurology and Clinical and Metabolic Genetics, Hospital for Sick Children, University of TorontoToronto, Ontario, Canada
| | - Guy A Rouleau
- Montreal Neurological Institute and Hospital, McGill University MontrealQuebec, Canada
| | - Oksana Suchowersky
- Departments of Medicine (Neurology) and Medical Genetics, University of AlbertaEdmonton, Alberta, Canada
| | - Victoria Siu
- Department of Pediatrics, Division of Medical Genetics, Western UniversityLondon, Ontario, Canada
| | - Lisa Murphy
- Department of Pediatrics, Division of Medical Genetics, Western UniversityLondon, Ontario, Canada
| | - Robert A Hegele
- Robarts Research Institute, University of Western OntarioLondon, Canada
| | - Christian R Marshall
- Program in Genetics and Genome Biology, Hospital for Sick Children and McLaughlin Centre, University of TorontoToronto, Ontario, Canada
| | | | - Jacek Majewski
- Department of Human Genetics, McGill UniversityMontréal, Quebec, Canada
| | - Mark Tarnopolsky
- Department of Pediatrics, McMaster Children's HospitalHamilton, Ontario, Canada
| | - Kym M Boycott
- Children's Hospital of Eastern Ontario Research Institute, University of OttawaOttawa, Ontario, Canada
- *Correspondence to: Kym M Boycott, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada. E-mail:
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21
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De Silva DR, Nichols R, Elgar G. Purifying selection in deeply conserved human enhancers is more consistent than in coding sequences. PLoS One 2014; 9:e103357. [PMID: 25062004 PMCID: PMC4111549 DOI: 10.1371/journal.pone.0103357] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 07/01/2014] [Indexed: 12/30/2022] Open
Abstract
Comparison of polymorphism at synonymous and non-synonymous sites in protein-coding DNA can provide evidence for selective constraint. Non-coding DNA that forms part of the regulatory landscape presents more of a challenge since there is not such a clear-cut distinction between sites under stronger and weaker selective constraint. Here, we consider putative regulatory elements termed Conserved Non-coding Elements (CNEs) defined by their high level of sequence identity across all vertebrates. Some mutations in these regions have been implicated in developmental disorders; we analyse CNE polymorphism data to investigate whether such deleterious effects are widespread in humans. Single nucleotide variants from the HapMap and 1000 Genomes Projects were mapped across nearly 2000 CNEs. In the 1000 Genomes data we find a significant excess of rare derived alleles in CNEs relative to coding sequences; this pattern is absent in HapMap data, apparently obscured by ascertainment bias. The distribution of polymorphism within CNEs is not uniform; we could identify two categories of sites by exploiting deep vertebrate alignments: stretches that are non-variant, and those that have at least one substitution. The conserved category has fewer polymorphic sites and a greater excess of rare derived alleles, which can be explained by a large proportion of sites under strong purifying selection within humans--higher than that for non-synonymous sites in most protein coding regions, and comparable to that at the strongly conserved trans-dev genes. Conversely, the more evolutionarily labile CNE sites have an allele frequency distribution not significantly different from non-synonymous sites. Future studies should exploit genome-wide re-sequencing to obtain better coverage in selected non-coding regions, given the likelihood that mutations in evolutionarily conserved enhancer sequences are deleterious. Discovery pipelines should validate non-coding variants to aid in identifying causal and risk-enhancing variants in complex disorders, in contrast to the current focus on exome sequencing.
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Affiliation(s)
- Dilrini R. De Silva
- Systems Biology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom
- School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom
| | - Richard Nichols
- School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom
| | - Greg Elgar
- Systems Biology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom
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22
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Sandford E, Burmeister M. Genes and genetic testing in hereditary ataxias. Genes (Basel) 2014; 5:586-603. [PMID: 25055202 PMCID: PMC4198919 DOI: 10.3390/genes5030586] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 06/25/2014] [Accepted: 07/01/2014] [Indexed: 12/19/2022] Open
Abstract
Ataxia is a neurological cerebellar disorder characterized by loss of coordination during muscle movements affecting walking, vision, and speech. Genetic ataxias are very heterogeneous, with causative variants reported in over 50 genes, which can be inherited in classical dominant, recessive, X-linked, or mitochondrial fashion. A common mechanism of dominant ataxias is repeat expansions, where increasing lengths of repeated DNA sequences result in non-functional proteins that accumulate in the body causing disease. Greater understanding of all ataxia genes has helped identify several different pathways, such as DNA repair, ubiquitination, and ion transport, which can be used to help further identify new genes and potential treatments. Testing for the most common mutations in these genes is now clinically routine to help with prognosis and treatment decisions, but next generation sequencing will revolutionize how genetic testing will be done. Despite the large number of known ataxia causing genes, however, many individuals with ataxia are unable to obtain a genetic diagnosis, suggesting that more genes need to be discovered. Utilization of next generation sequencing technologies, expression studies, and increased knowledge of ataxia pathways will aid in the identification of new ataxia genes.
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Affiliation(s)
- Erin Sandford
- Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Margit Burmeister
- Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
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Schuster J, Khan TN, Tariq M, Shaiq PA, Mäbert K, Baig SM, Klar J. Exome sequencing circumvents missing clinical data and identifies a BSCL2 mutation in congenital lipodystrophy. BMC MEDICAL GENETICS 2014; 15:71. [PMID: 24961962 PMCID: PMC4076434 DOI: 10.1186/1471-2350-15-71] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 06/10/2014] [Indexed: 11/10/2022]
Abstract
Background Exome sequencing has become more and more affordable and the technique has emerged as an important diagnostic tool for monogenic disorders at early stages of investigations, in particular when clinical information is limited or unspecific as well as in cases of genetic heterogeneity. Methods We identified a consanguineous Pakistani family segregating an autosomal recessive phenotype characterized by muscular hypertrophy, mild mental retardation and skeletal abnormalities. The available clinical information was incomplete and we applied whole exome sequencing in an affected family member for the identification of candidate gene variants. Results Exome sequencing identified a previously unreported homozygous mutation in the acceptor splice site of intron 5 in the BSCL2 gene (c.574-2A > G). Expression analysis revealed that the mutation was associated with skipping of exon 6. BSCL2 mutations are associated with Berardinelli-Seip congenital lipodystrophy and a clinical re-evaluation of affected individuals confirmed the diagnosis. Conclusions Exome sequencing is a powerful technique for the identification of candidate gene variants in Mendelian traits. We applied this technique on a single individual affected by a likely autosomal recessive disorder without access to complete clinical details. A homozygous and truncating mutation was identified in the BSCL2 gene suggesting congenital generalized lipodystrophy. Incomplete phenotypic delineations are frequent limiting factors in search for a diagnosis and may lead to inappropriate care and follow-up. Our study exemplifies exome sequencing as a powerful diagnostic tool in Mendelian disorders that may complement missing clinical information and accelerate clinical diagnosis.
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Affiliation(s)
| | | | | | | | | | | | - Joakim Klar
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden.
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Votsi C, Christodoulou K. Molecular diagnosis of autosomal recessive cerebellar ataxia in the whole exome/genome sequencing era. World J Neurol 2013; 3:115-128. [DOI: 10.5316/wjn.v3.i4.115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 08/30/2013] [Accepted: 10/16/2013] [Indexed: 02/06/2023] Open
Abstract
Autosomal recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich’s ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore, an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of whole-exome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.
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25
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Next-generation sequencing diagnostics for neurological diseases/disorders: from a clinical perspective. Hum Genet 2013; 132:721-34. [PMID: 23525706 DOI: 10.1007/s00439-013-1287-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 03/02/2013] [Indexed: 12/13/2022]
Abstract
Neurological diseases encompass a broad, heterogeneous group of disorders ranging from pediatric neurodevelopmental diseases to late-onset neurodegenerative diseases, most of which are poorly understood and few of which are curable. Most of these diseases have a genetic basis and thus are expected to be amenable to genetic or genomic analysis by next-generation sequencing (NGS). While the advancement of contemporary technologies (such as NGS) is exciting, translating this tool into actual benefit for patients and clinicians can be challenging. In a clinical setting, a sequencing test that is fast, non-invasive, cheap and with perfect specificity would be ideal. However, in practice, there are several hurdles and caveats to consider even before a NGS diagnostic testing can be optimally applied. Proper definition of clinical phenotype, selection of the most appropriate subjects and the clinical setting, optimization of both sensitivity and specificity of the test, evaluation of the availability of the infrastructure and expertise, and consideration of economic, ethical and legal issues are vital in the final application of NGS diagnostic screening in the clinics.
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