Publications by authors named "Brent L Fogel"

57 Publications

miR-142-3p regulates cortical oligodendrocyte gene co-expression networks associated with tauopathy.

Hum Mol Genet 2021 Mar;30(1):103-118

Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.

Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system. Weighted gene co-expression network analysis reveals distinct region-specific gene networks. Two of these mature myelinating oligodendrocyte gene networks uniquely define cortical oligodendrocytes and differentially regulate cortical myelination (M8) and synaptic signaling (M4). These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia including MAPT and include multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both the M8 and M4 cortical oligodendrocyte gene networks identified from normal cortex. We further demonstrate overlapping gene networks in mature oligodendrocytes present in normal cortex, rTg4510 and miR-142-null mice, and existing datasets from human tauopathies to provide evidence for a critical role of miR-142-3p-regulated cortical myelination and oligodendrocyte-mediated synaptic signaling in neurodegeneration.
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http://dx.doi.org/10.1093/hmg/ddaa252DOI Listing
March 2021

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Authors:
Laura Cif Diane Demailly Jean-Pierre Lin Katy E Barwick Mario Sa Lucia Abela Sony Malhotra Wui K Chong Dora Steel Alba Sanchis-Juan Adeline Ngoh Natalie Trump Esther Meyer Xavier Vasques Julia Rankin Meredith W Allain Carolyn D Applegate Sanaz Attaripour Isfahani Julien Baleine Bettina Balint Jennifer A Bassetti Emma L Baple Kailash P Bhatia Catherine Blanchet Lydie Burglen Gilles Cambonie Emilie Chan Seng Sandra Chantot Bastaraud Fabienne Cyprien Christine Coubes Vincent d'Hardemare Asif Doja Nathalie Dorison Diane Doummar Marisela E Dy-Hollins Ellyn Farrelly David R Fitzpatrick Conor Fearon Elizabeth L Fieg Brent L Fogel Eva B Forman Rachel G Fox William A Gahl Serena Galosi Victoria Gonzalez Tracey D Graves Allison Gregory Mark Hallett Harutomo Hasegawa Susan J Hayflick Ada Hamosh Marie Hully Sandra Jansen Suh Young Jeong Joel B Krier Sidney Krystal Kishore R Kumar Chloé Laurencin Hane Lee Gaetan Lesca Laurence Lion François Timothy Lynch Neil Mahant Julian A Martinez-Agosto Christophe Milesi Kelly A Mills Michel Mondain Hugo Morales-Briceno John R Ostergaard Swasti Pal Juan C Pallais Frédérique Pavillard Pierre-Francois Perrigault Andrea K Petersen Gustavo Polo Gaetan Poulen Tuula Rinne Thomas Roujeau Caleb Rogers Agathe Roubertie Michelle Sahagian Elise Schaefer Laila Selim Richard Selway Nutan Sharma Rebecca Signer Ariane G Soldatos David A Stevenson Fiona Stewart Michel Tchan Ishwar C Verma Bert B A de Vries Jenny L Wilson Derek A Wong Raghda Zaitoun Dolly Zhen Anna Znaczko Russell C Dale Claudio M de Gusmão Jennifer Friedman Victor S C Fung Mary D King Shekeeb S Mohammad Luis Rohena Jeff L Waugh Camilo Toro F Lucy Raymond Maya Topf Philippe Coubes Kathleen M Gorman Manju A Kurian

Brain 2020 12;143(11):3242-3261

Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
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http://dx.doi.org/10.1093/brain/awaa304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719027PMC
December 2020

Novel NUDT2 variant causes intellectual disability and polyneuropathy.

Ann Clin Transl Neurol 2020 11 15;7(11):2320-2325. Epub 2020 Oct 15.

Department of Neurology, Olive View-UCLA Medical Center, Sylmar, California, USA.

Exome or genome sequencing was performed to identify the genetic etiology for the clinical presentation of global developmental delay, intellectual disability, and sensorimotor neuropathy with associated distal weakness in two unrelated families. A homozygous frameshift variant c.186delA (p.A63Qfs*3) in the NUDT2 gene was identified in cases 1 and 2 from one family and a third case from another family. Variants in NUDT2 were previously shown to cause intellectual disability, but here we expand the phenotype by demonstrating its association with distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features.
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http://dx.doi.org/10.1002/acn3.51209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664258PMC
November 2020

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240).

J Child Neurol 2020 12 24;35(14):953-962. Epub 2020 Jul 24.

Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.

Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) is a rare form of cerebellar ataxia that commonly presents with motor, cognitive, and behavioral impairments. Although these features have been identified as part of the clinical manifestations of SCA21, the neurodevelopmental disorders associated with SCA21 have not been well studied or described. Here we present extensive phenotypic data for 3 subjects from an SCA21 family in the United States. Genetic testing demonstrated the c.196 G>A (p.Gly66Arg) variant to be a second recurrent mutation associated with the disorder. Standardized developmental assessment revealed significant deficits in cognition, adaptive function, motor skills, and social communication with 2 of the subjects having diagnoses of autism spectrum disorder, which has never been described in SCA21. Quantitative gait analysis showed markedly abnormal spatiotemporal gait variables indicative of poor gait control and cerebellar as well as noncerebellar dysfunction. Clinical evaluation also highlighted a striking variability in clinical symptoms, with greater ataxia correlating with greater severity of neurodevelopmental disorder diagnoses. Notably, neurodevelopmental outcomes have improved with intervention over time. Taken together, this case series identifies that the manifestation of neurodevelopmental disorders is a key feature of SCA21 and may precede the presence of motor abnormalities. Furthermore, the coexistence of ataxia and neurodevelopmental disorders in these subjects suggests a role for spinocerebellar pathways in both outcomes. The findings in this study highlight the importance of evaluation of neurodevelopmental concerns in the context of progressive motor abnormalities and the need for timely intervention to ultimately improve quality of life for individuals with SCA21.
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http://dx.doi.org/10.1177/0883073820943488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674185PMC
December 2020

Prevalence of -mediated spinocerebellar ataxia in a North American ataxia cohort.

Neurol Genet 2020 Jun 20;6(3):e440. Epub 2020 May 20.

Department of Neurology (D.A.S., D.W., Y.M., S.P., B.L.F.), Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles; Department of Neurology (D.W., B.L.F.), Clinical Neurogenomics Research Center, David Geffen School of Medicine, University of California, Los Angeles; Department of Human Genetics (S.A., M.S., S.D.), University of Chicago, IL; Department of Neurology (C.M.D.G., V.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Neurology (G.G., C.M.G.), University of Chicago, IL; Bruce Lefroy Centre (P.J.L.), Murdoch Children's Research Institute; Department of Paediatrics (P.J.L.), University of Melbourne, Parkville, Australia; Sackler Faculty of Medicine (S.H.-B.), Tel-Aviv University, Tel-Aviv, Israel; and Department of Human Genetics (B.L.F.), David Geffen School of Medicine, University of California, Los Angeles.

Objective: We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 () and disabled adaptor protein 1 in an undiagnosed ataxia cohort from North America.

Methods: A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in (AAGGG) and (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for , resulting in a combined 911 subjects tested.

Results: In the initial cohort, 41 samples were identified with 1 expanded allele in the gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the gene (spinocerebellar ataxia type 37).

Conclusions: In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.
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http://dx.doi.org/10.1212/NXG.0000000000000440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274910PMC
June 2020

Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36.

Neuron 2020 07 5;107(2):292-305.e6. Epub 2020 May 5.

Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA. Electronic address:

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.
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http://dx.doi.org/10.1016/j.neuron.2020.04.011DOI Listing
July 2020

A family with spinocerebellar ataxia and retinitis pigmentosa attributed to an mutation.

Neurol Genet 2019 10 23;5(5):e357. Epub 2019 Sep 23.

National Human Genome Research Institute (C.X.), Bethesda, MD; Department of Neurology (C.M.G.), University of Chicago Hospitals, IL; Department of Ophthalmology and Visual Sciences (E.M.B., E.M.S.), University of Iowa; Department Neurology (J.R., B.L.F.), David Geffen School of Medicine, University of California Los Angeles; Department of Genetics (A.K.-J., S.D.), University of Chicago, IL; and Department of Neurology (P.K.), UTSW Medical Center, Dallas, TX.

Objective: To identify the genetic cause of autosomal dominant spinocerebellar ataxia and retinitis pigmentosa in a large extended pedigree.

Methods: Clinical studies were done at 4 referral centers. Ten individuals in the same extended family participated in at least a portion of the study. Records were obtained from an 11th, deceased, individual. Neurologic and dermatological examinations were performed. Ophthalmologic evaluation including funduscopic examination and in some cases ocular coherence tomography were used to identify the presence of retinal disease. Whole exome sequencing (WES), in conjunction with Sanger sequencing and segregation analysis, was used to identify potential genetic mutation.

Results: Affected individuals reported slowly progressive cerebellar ataxia with age at onset between 38 and 57. Imaging demonstrated cerebellar atrophy (3/3). WES identified a novel heterozygous mutation in the elongation of very long chain fatty acids 4 () gene (c.512T>C, p.Ile171Thr) that segregated with ataxia in 7 members tested. Four of 8 members who underwent ophthalmologic evaluation were found to have retinitis pigmentosa. No skin findings were identified or reported. Ocular movement abnormalities and pyramidal tract signs were also present with incomplete penetrance.

Conclusions: We report a family with both spinocerebellar ataxia and retinal dystrophy associated with an mutation. In addition, to supporting prior reports that mutations can cause spinocerebellar ataxia, our findings further broaden the spectrum of clinical presentations associated with spinocerebellar ataxia 34.
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http://dx.doi.org/10.1212/NXG.0000000000000357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812731PMC
October 2019

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.

Hum Mutat 2020 02 25;41(2):487-501. Epub 2019 Nov 25.

Department of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.
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http://dx.doi.org/10.1002/humu.23946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182470PMC
February 2020

Progressive Ataxia with Elevated Alpha-Fetoprotein: Diagnostic Issues and Review of the Literature.

Tremor Other Hyperkinet Mov (N Y) 2019 10;9. Epub 2019 Oct 10.

Department of Neurology, Karolinska University Hospital, Stockholm, SE.

Background: Ataxias represent a challenging group of disorders due to significant clinical overlap. Here, we present a patient with early-onset progressive ataxia, polyneuropathy and discuss how elevation of alpha fetoprotein (AFP) narrows the differential diagnosis.

Case Report: Ataxia, polyneuropathy, and mild elevation of AFP are features compatible with ataxia with oculomotor apraxia type 2 (AOA2) but also with ataxia with oculomotor apraxia type 4 (AOA4). A genetic analysis demonstrated biallelic mutations in senataxin (), confirming the diagnosis of AOA2.

Discussion: Mild elevation of AFP is found in patients with AOA2 and AOA4, and higher levels are commonly seen in ataxia-telangiectasia. AFP is a useful diagnostic tool but not a biomarker for disease progression in AOA2.
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http://dx.doi.org/10.7916/tohm.v0.708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790008PMC
September 2020

Spinocerebellar Ataxia type 29 in a family of Māori descent.

Cerebellum Ataxias 2019 12;6:14. Epub 2019 Oct 12.

1Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Gonda Room 6554, Los Angeles, CA 90095 USA.

Background: Mutations in the Inositol 1,4,5-Trisphosphate Receptor Type 1 ( gene cause spinocerebellar ataxia type 29 (SCA29), a rare congenital-onset autosomal dominant non-progressive cerebellar ataxia. The Māori, indigenous to New Zealand, are an understudied population for genetic ataxias.

Case Presentation: We investigated the genetic origins of spinocerebellar ataxia in a family of Māori descent consisting of two affected sisters and their unaffected parents. Whole exome sequencing identified a pathogenic variant, p.Thr267Met, in in both sisters, establishing their diagnosis as SCA29.

Conclusions: We report the identification of a family of Māori descent with a mutation causing SCA29, extending the worldwide scope of this disease. Although this mutation has occurred de novo in other populations, suggesting a mutational hotspot, the children in this family inherited it from their unaffected mother who was germline mosaic.
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http://dx.doi.org/10.1186/s40673-019-0108-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790028PMC
October 2019

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

Genet Med 2020 03 14;22(3):490-499. Epub 2019 Oct 14.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.

Purpose: We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications.

Methods: From 234 subjects referred to the Undiagnosed Diseases Network, University of California-Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide.

Results: The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality.

Conclusion: In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.
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http://dx.doi.org/10.1038/s41436-019-0672-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405636PMC
March 2020

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Am J Hum Genet 2019 07 20;105(1):151-165. Epub 2019 Jun 20.

Bruce Lefroy Centre, Murdoch Children's Research Institute, Flemington Rd, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Rd, Parkville, VIC 3052, Australia. Electronic address:

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612533PMC
July 2019

Clinical application of next-generation sequencing to the practice of neurology.

Lancet Neurol 2019 05;18(5):492-503

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Clinical Neurogenomics Research Center, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address:

Next-generation sequencing technologies allow for rapid and inexpensive large-scale genomic analysis, creating unprecedented opportunities to integrate genomic data into the clinical diagnosis and management of neurological disorders. However, the scale and complexity of these data make them difficult to interpret and require the use of sophisticated bioinformatics applied to extensive datasets, including whole exome and genome sequences. Detailed analysis of genetic data has shown that accurate phenotype information is essential for correct interpretation of genetic variants and might necessitate re-evaluation of the patient in some cases. A multidisciplinary approach that incorporates bioinformatics, clinical evaluation, and human genetics can help to address these challenges. However, despite numerous studies that show the efficacy of next-generation sequencing in establishing molecular diagnoses, pathogenic mutations are generally identified in fewer than half of all patients with genetic neurological disorders, exposing considerable gaps in the understanding of the human genome and providing opportunities to focus research on improving the usefulness of genomics in clinical practice. Looking forward, the emergence of precision health in neurological care will increasingly apply genomic data analysis to pharmacogenetics, preventive medicine, and patient-targeted therapies.
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http://dx.doi.org/10.1016/S1474-4422(19)30033-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055532PMC
May 2019

Disruption of Spermatogenesis and Infertility in Ataxia with Oculomotor Apraxia Type 2 (AOA2).

Cerebellum 2019 Jun;18(3):448-456

Cancer and Neuroscience, UQ Centre for Clinical Research (UQCCR), The University of Queensland, Building 71/918, Royal Brisbane and Women's Hospital Campus, Brisbane, QLD, 4029, Australia.

Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia characterized by onset between 10 and 20 years of age and a range of neurological features that include progressive cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia in a majority of patients, and elevated serum alpha-fetoprotein (AFP). AOA2 is caused by mutation of the SETX gene which encodes senataxin, a DNA/RNA helicase involved in transcription regulation, RNA processing, and DNA maintenance. Disruption of senataxin in rodents led to defective spermatogenesis and sterility in males uncovering a key role for senataxin in male germ cell survival. Here, we report the first clinical and cellular evidence of impaired spermatogenesis in AOA2 patients. We assessed sperm production in three AOA2 patients and testicular pathology in one patient and compared the findings to those of Setx-knockout mice. Sperm production was impaired in all patients assessed (3/3, 100%). Analyses of testicular biopsies from an AOA2 patient recapitulate features of the histology seen in Setx-knockout mice, strongly suggesting an underlying mechanism centering on DNA-damage-mediated germ cell apoptosis. These findings support a role for senataxin in human reproductive function and highlight a novel clinical feature of AOA2 that extends the extra-neurological roles of senataxin. This raises an important reproductive counseling issue for clinicians, and fertility specialists should be aware of SETX mutations as a possible diagnosis in young male patients presenting with oligospermia or azoospermia since infertility may presage the later onset of neurological manifestations in some individuals.
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http://dx.doi.org/10.1007/s12311-019-01012-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520128PMC
June 2019

Successful treatment of a genetic childhood ataxia due to riboflavin transporter deficiency.

Cerebellum Ataxias 2018 20;5:12. Epub 2018 Oct 20.

1Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.

Background: Riboflavin transporter deficiency (Brown-Vialetto-Van Laere syndrome) is a rare recessive neurodegenerative disorder that can present with gait ataxia, primarily due to sensory neuropathy as well as cerebellar involvement. Although sensorineural hearing loss, bulbar palsy, and optic atrophy are typical, presentation may be variable and an atypical condition may be difficult to recognize clinically.

Case Presentation: Here we report a patient presenting at age 8 with progressive ataxia since the age of 2.5 years with cerebellar atrophy and peripheral polyneuropathy. Whole exome sequencing identified a known pathogenic mutation in the gene consistent with a diagnosis of Brown-Vialetto-Van Laere syndrome despite the absence of common symptoms including motor neuropathy, bulbar palsy, optic atrophy, and sensorineural hearing loss. High-dose riboflavin therapy was initiated, symptoms stabilized, metabolic abnormalities resolved, and the patient is doing well with a near-normal examination at age 15.

Conclusions: Riboflavin transporter deficiency can be fatal if left untreated. The excellent outcome of this case illustrates the importance of identifying this potentially treatable neurologic condition. In this patient, clinical diagnosis was limited by an atypical presentation lacking several common features which was overcome through the use of genomic sequencing identifying the pathogenic mutation enabling correct diagnosis and subsequent treatment. Riboflavin transporter deficiency should be considered early in the diagnostic evaluation as a treatable form of ataxia in children, even if patients lack typical features.
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http://dx.doi.org/10.1186/s40673-018-0091-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196015PMC
October 2018

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Eur J Hum Genet 2018 10 28;26(10):1462-1477. Epub 2018 Jun 28.

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
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http://dx.doi.org/10.1038/s41431-018-0185-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138755PMC
October 2018

Collaborative science unites researchers and a novel spastic ataxia gene.

Authors:
Brent L Fogel

Ann Neurol 2018 06;83(6):1072-1074

Departments of Neurology and Human Genetics David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA.

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http://dx.doi.org/10.1002/ana.25262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105536PMC
June 2018

Expanding the global prevalence of spinocerebellar ataxia type 42.

Neurol Genet 2018 Jun 5;4(3):e232. Epub 2018 Apr 5.

Department of Neurology (K.J.N., M.A., S.P., G.C., B.L.F.), Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles; Department of Medical Genetics (L.E.P., J.E.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Psychiatry and Biobehavioral Sciences (J.A.C., G.C.), University of California, Los Angeles, CA; Institute of Neurological Sciences (F.C., S.C.), Italian National Research Council, Mangone, Italy; Department of Neurology (A.B.N., M.D.G.), UCSF Memory and Aging Center, University of California, San Francisco; Sackler Faculty of Medicine (S.H.), Tel-Aviv University, Israel; Italian College of General Practitioners and Primary Care (D.I.), Department of Clinical and Experimental Medicine (A.L.), University of Messina, Italy; and the Department of Human Genetics (B.L.F.), David Geffen School of Medicine, University of California, Los Angeles.

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http://dx.doi.org/10.1212/NXG.0000000000000232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886831PMC
June 2018

Autosomal-recessive cerebellar ataxias.

Authors:
Brent L Fogel

Handb Clin Neurol 2018 ;147:187-209

Program in Neurogenetics, Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States. Electronic address:

The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50. In this review, the clinical neurogenetics of the recessive cerebellar ataxias will be discussed, including updates on recently identified novel ataxia genes, advancements in unraveling disease-specific molecular pathogenesis leading to ataxia, potential treatments under development, technologic improvements in diagnostic testing such as clinical exome sequencing, and what the future holds for clinicians and geneticists.
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http://dx.doi.org/10.1016/B978-0-444-63233-3.00013-0DOI Listing
July 2018

Genetic and genomic testing for neurologic disease in clinical practice.

Authors:
Brent L Fogel

Handb Clin Neurol 2018 ;147:11-22

Program in Neurogenetics, Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States. Electronic address:

The influence of genetics on neurologic disease is broad and it is becoming more common that clinicians are presented with a patient whose disease is likely of genetic origin. In the search for mutations causing Mendelian disorders, advances in genetic testing methodology have propelled modern neurologic practice beyond single-gene testing into the realm of genomic medicine, where routine evaluations encompass hundreds or thousands of genes, or even the entire exome, representing all protein-coding genes in the genome. The role of various single-gene, multigene, and genomic testing methods, including chromosomal microarray and next-generation sequencing, in the evaluation of neurologic disease is discussed here to provide a framework for their use in a modern neurologic practice. Understanding the inherent issues that arise during the interpretation of sequence variants as pathogenic or benign and the potential discovery of incidental medically relevant findings are important considerations for neurologists utilizing these tests clinically. Strategies for the evaluation of clinically heterogeneous disorders are presented to guide neurologists in the transition from single-gene to genomic considerations and toward the prospect of the widespread routine use of exome sequencing in the continuing goal to achieve more rapid and more precise diagnoses that will improve management and outcome in patients challenged by neurologic disease.
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http://dx.doi.org/10.1016/B978-0-444-63233-3.00002-6DOI Listing
July 2018

Prevalence of spinocerebellar ataxia 36 in a US population.

Neurol Genet 2017 Aug 18;3(4):e174. Epub 2017 Jul 18.

Program in Neurogenetics (J.M.V., T.D., D.H.G., S.P., B.L.F.), Department of Neurology and Department of Human Genetics (D.H.G., B.L.F.), David Geffen School of Medicine, University of California Los Angeles; The Human Genetics Center (L.E.P., J.E.B.), University of Texas School of Public Health, Houston; Fundación Pública Galega de Medicina Xenómica-SERGAS (B.Q., Z.Y., M.J.S.), Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela; Genomic Medicine Group (U711) (B.Q., Z.Y., M.J.S.), Centre for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain; Grupo del Investigación en Genética (Z.Y.), Universidad Simón Bolívar, Barranquilla, Colombia; Department of Molecular and Human Genetics (E.B., D.M., R.G., J.R.L.) and Human Genome Center (J.R.L.), Baylor College of Medicine, Houston, TX; and Department of Integrative Biology and Pharmacology (D.A., R.B.), Institute of Molecular Medicine Center for Metabolic and Degenerative Diseases (R.B.), and Cell and Regulatory Biology Program of The University of Texas Graduate School of Biomedical Sciences (R.B.), McGovern Medical School at The University of Texas Health Science Center at Houston.

Objective: To assess the prevalence and clinical features of individuals affected by spinocerebellar ataxia 36 (SCA36) at a large tertiary referral center in the United States.

Methods: A total of 577 patients with undiagnosed sporadic or familial cerebellar ataxia comprehensively evaluated at a tertiary referral ataxia center were molecularly evaluated for SCA36. Repeat primed PCR and fragment analysis were used to screen for the presence of a repeat expansion in the gene.

Results: Fragment analysis of triplet repeat primed PCR products identified a GGCCTG hexanucleotide repeat expansion in intron 1 of in 4 index cases. These 4 SCA36-positive families comprised 2 distinct ethnic groups: white (European) (2) and Asian (Japanese [1] and Vietnamese [1]). Individuals affected by SCA36 exhibited typical clinical features with gait ataxia and age at onset ranging between 35 and 50 years. Patients also suffered from ataxic or spastic limbs, altered reflexes, abnormal ocular movement, and cognitive impairment.

Conclusions: In a US population, SCA36 was observed to be a rare disorder, accounting for 0.7% (4/577 index cases) of disease in a large undiagnosed ataxia cohort.
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http://dx.doi.org/10.1212/NXG.0000000000000174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515602PMC
August 2017

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.

Orphanet J Rare Dis 2017 06 28;12(1):121. Epub 2017 Jun 28.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

Background: Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.

Results: Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.

Conclusions: Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.
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http://dx.doi.org/10.1186/s13023-017-0672-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490223PMC
June 2017

The need to develop a patient-centered precision medicine model for adults with chronic disability.

Expert Rev Mol Diagn 2017 05 3;17(5):415-418. Epub 2017 Apr 3.

c University of California-Los Angeles (UCLA) , Departments of Neurology and Human Genetics , Los Angeles , CA , USA.

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http://dx.doi.org/10.1080/14737159.2017.1309976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038920PMC
May 2017

ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism.

Hum Mol Genet 2016 06 3;25(12):2451-2464. Epub 2016 Jun 3.

Program in Neurogenetics and Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Gonda Room 1206, Los Angeles, CA 90095, USA

The role of post-transcriptional gene regulation in human brain development and neurodevelopmental disorders remains mostly uncharacterized. ELAV-like RNA-binding proteins (RNAbps) are a family of proteins that regulate several aspects of neuronal function including neuronal excitability and synaptic transmission, both critical to the normal function of the brain in cognition and behavior. Here, we identify the downstream neuronal transcriptional and splicing networks of ELAVL2, an RNAbp with previously unknown function in the brain. Expression of ELAVL2 was reduced in human neurons and RNA-sequencing was utilized to identify networks of differentially expressed and alternatively spliced genes resulting from haploinsufficient levels of ELAVL2. These networks contain a number of autism-relevant genes as well as previously identified targets of other important RNAbps implicated in autism spectrum disorder (ASD) including RBFOX1 and FMRP. ELAVL2-regulated co-expression networks are also enriched for neurodevelopmental and synaptic genes, and include genes with human-specific patterns of expression in the frontal pole. Together, these data suggest that ELAVL2 regulation of transcript expression is critical for neuronal function and clinically relevant to ASD.
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http://dx.doi.org/10.1093/hmg/ddw110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086562PMC
June 2016

Whole exome sequencing in patients with white matter abnormalities.

Ann Neurol 2016 06 9;79(6):1031-1037. Epub 2016 May 9.

School of Medicine and Health Sciences, George Washington University, Washington, DC.

Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031-1037.
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http://dx.doi.org/10.1002/ana.24650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354169PMC
June 2016

Clinical exome sequencing in neurologic disease.

Neurol Clin Pract 2016 Apr;6(2):164-176

Program in Neurogenetics and Departments of Neurology and Human Genetics (BLF), David Geffen School of Medicine, University of California Los Angeles; Health Policy Consultant (SS-M), Santa Maria, CA; and NeuroDevelopmental Science Center and the Department of Pediatrics (BHC), Akron Children's Hospital, OH.

Purpose Of Review: The landscape of genetic diagnostic testing has changed dramatically with the introduction of next-generation clinical exome sequencing (CES), which provides an unbiased analysis of all protein-coding sequences in the roughly 21,000 genes in the human genome. Use of this testing, however, is currently limited in clinical neurologic practice by the lack of a framework for appropriate use and payer coverage.

Recent Findings: CES can be cost-effective due to its high diagnostic yield in comparison to other genetic tests in current use and should be utilized as a routine diagnostic test in patients with heterogeneous neurologic phenotypes facing a broad genetic differential diagnosis. CES can eliminate the need for escalating sequences of conventional neurodiagnostic tests.

Summary: This review discusses the role of clinical exome sequencing in neurologic disease, including its benefits to patients, limitations, appropriate use, and billing. We also provide a reference template policy for payer use when considering testing requests.
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http://dx.doi.org/10.1212/CPJ.0000000000000239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828678PMC
April 2016

Emerging therapies in Friedreich's ataxia.

Neurodegener Dis Manag 2016 ;6(1):49-65

University of South Florida Ataxia Research Center, Department of Neurology, FL, USA.

Friedreich's ataxia (FRDA) is an inherited, progressive neurodegenerative disease that typically affects teenagers and young adults. Therapeutic strategies and disease insight have expanded rapidly over recent years, leading to hope for the FRDA population. There is currently no US FDA-approved treatment for FRDA, but advances in research of its pathogenesis have led to clinical trials of potential treatments. This article reviews emerging therapies and discusses future perspectives, including the need for more precise measures for detecting changes in neurologic symptoms as well as a disease-modifying agent.
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http://dx.doi.org/10.2217/nmt.15.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768799PMC
October 2016

Clinical exome sequencing in neurogenetic and neuropsychiatric disorders.

Ann N Y Acad Sci 2016 02 6;1366(1):49-60. Epub 2015 Aug 6.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.

Exome sequencing has recently been elevated to the standard of care for genetic diagnostic testing, particularly for genetically diverse and clinically heterogeneous disorders. This review provides a clinically oriented discussion of the next-generation sequencing technology that makes exome sequencing possible and how such technology is applied to the diagnosis of Mendelian disease, including clinically significant de novo variation, interpretation of variants of uncertain clinical significance, the future potential for genetic assessments of disease risk, and the substantial benefits in diagnostic efficiency. Important caveats are also discussed, including the implications of incidental or secondary findings detected during exome sequencing and the relationship of exome sequencing to other methods of clinical genomic testing, such as chromosomal microarray and genome sequencing. Overall, the widespread adoption and use of exome sequencing in routine clinical practice is expected to improve diagnosis rates and reduce test costs, while leading to improvements in patient outcomes and a renewed emphasis on disease management.
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http://dx.doi.org/10.1111/nyas.12850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744590PMC
February 2016