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• W2057509417 abstract "Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail. The study implicates mGluR1 in human hereditary ataxia. It also illustrates the potential of the Roma founder populations for mutation identification by exome sequencing. Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail. The study implicates mGluR1 in human hereditary ataxia. It also illustrates the potential of the Roma founder populations for mutation identification by exome sequencing. Autosomal-recessive cerebellar ataxias (ARCAs) are a clinically and genetically heterogeneous group of disorders whose clinical and genetic classifications are still evolving as the field progresses and novel phenotypes and genes are described.1Palau F. Espinós C. Autosomal recessive cerebellar ataxias.Orphanet J. Rare Dis. 2006; 1: 47Crossref PubMed Scopus (133) Google Scholar, 2Fogel B.L. Perlman S. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias.Lancet Neurol. 2007; 6: 245-257Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar Congenital cerebellar ataxias are a relatively small ARCA subset characterized by infantile onset of motor incoordination, developmental delay, and variable additional manifestations.3Norman R.M. Primary degeneration of the granular layer of the cerebellum: An unusual form of familial cerebellar atrophy occurring in early life.Brain. 1940; 63: 365-379Crossref Scopus (88) Google Scholar, 4Steinlin M. Non-progressive congenital ataxias.Brain Dev. 1998; 20: 199-208Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 5Mégarbané A. Delague V. Ruchoux M.M. Rizkallah E. Maurage C.A. Viollet L. Rouaix-Emery N. Urtizberea A. New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family.Am. J. Med. Genet. 2001; 101: 135-141Crossref PubMed Scopus (18) Google Scholar, 6Bomar J.M. Benke P.J. Slattery E.L. Puttagunta R. Taylor L.P. Seong E. Nystuen A. Chen W. Albin R.L. Patel P.D. et al.Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse.Nat. Genet. 2003; 35: 264-269Crossref PubMed Scopus (119) Google Scholar, 7Glass H.C. Boycott K.M. Adams C. Barlow K. Scott J.N. Chudley A.E. Fujiwara T.M. Morgan K. Wirrell E. McLeod D.R. Autosomal recessive cerebellar hypoplasia in the Hutterite population.Dev. Med. Child Neurol. 2005; 47: 691-695Crossref PubMed Scopus (28) Google Scholar, 8Lagier-Tourenne C. Tazir M. López L.C. Quinzii C.M. Assoum M. Drouot N. Busso C. Makri S. Ali-Pacha L. Benhassine T. et al.ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.Am. J. Hum. Genet. 2008; 82: 661-672Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, 9Türkmen S. Hoffmann K. Demirhan O. Aruoba D. Humphrey N. Mundlos S. Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene.Eur. J. Hum. Genet. 2008; 16: 1070-1074Crossref PubMed Scopus (42) Google Scholar, 10Türkmen S. Guo G. Garshasbi M. Hoffmann K. Alshalah A.J. Mischung C. Kuss A. Humphrey N. Mundlos S. Robinson P.N. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait.PLoS Genet. 2009; 5: e1000487Crossref PubMed Scopus (100) Google Scholar Although a number of genes have already been implicated in ARCAs, many rare forms and their molecular basis remain to be discovered. Here, we describe a form of congenital cerebellar ataxia identified in patients of Roma ethnicity in Bulgaria. The disorder was first encountered during our studies of congenital cataracts facial dysmorphism neuropathy11Angelicheva D. Turnev I. Dye D. Chandler D. Thomas P.K. Kalaydjieva L. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: A novel developmental disorder in Gypsies maps to 18qter.Eur. J. Hum. Genet. 1999; 7: 560-566Crossref PubMed Scopus (57) Google Scholar, 12Varon R. Gooding R. Steglich C. Marns L. Tang H. Angelicheva D. Yong K.K. Ambrugger P. Reinhold A. Morar B. et al.Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome.Nat. Genet. 2003; 35: 185-189Crossref PubMed Scopus (125) Google Scholar (CCFDN [MIM 604168]) in patients M II-1 and M II-2, who belonged to an extended CCFDN-affected kindred. A similar phenotype was observed recently in two children (V III-1 and V III-2) from another Roma family, suggesting a common founder mutation.13Kalaydjieva L. Morar B. Chaix R. Tang H. A newly discovered founder population: The Roma/Gypsies.Bioessays. 2005; 27: 1084-1094Crossref PubMed Scopus (78) Google Scholar A search of old hospital records and field-trip notes identified three additional families for a total of ten living patients and 14 unaffected relatives participating in the study (Figure 1). All individuals belonged to the same Roma group, the Bowlmakers, a young population subisolate characterized by small founding size, historically stagnant demographic regime, and low genetic diversity.14Kalaydjieva L. Calafell F. Jobling M.A. Angelicheva D. de Knijff P. Rosser Z.H. Hurles M.E. Underhill P. Tournev I. Marushiakova E. Popov V. Patterns of inter- and intra-group genetic diversity in the Vlax Roma as revealed by Y chromosome and mitochondrial DNA lineages.Eur. J. Hum. Genet. 2001; 9: 97-104Crossref PubMed Scopus (59) Google Scholar, 15Gresham D. Morar B. Underhill P.A. Passarino G. Lin A.A. Wise C. Angelicheva D. Calafell F. Oefner P.J. Shen P. et al.Origins and divergence of the Roma (gypsies).Am. J. Hum. Genet. 2001; 69: 1314-1331Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar Parents were clinically healthy; those deceased or unavailable were described as symptom free, supporting autosomal-recessive inheritance. Written informed consent was provided by all participating subjects or guardians of minors. The study complied with the guidelines of the institutions involved. Eight patients were admitted to university hospitals for detailed investigations, and two were examined during home visits. The clinical findings are summarized in Table 1.Table 1Clinical Observations in the Ten Living Ataxia PatientsPatientLi 1V III-2V III-1B IV-2P II-2B IV-3P II-1P II-3M II-2M II-1Age (years) at examination691126273237424757SexfemalefemalemalefemalemalefemalemalemalemalemalePregnancy and deliveryno datanormalintranatal asphyxianormallung atelectasisnormalnormalnormalpretermpretermAge (years) at walking445childhoodnever1nevernever3no dataAge (years) at simple sentences423no dataneverno dataneverneverneverneverHeight (cm)120126137147138143151150154152Weight (kg)22404242.52342.5506047.145.1Cerebellar Ataxia (SARA Scores)Gait (0–8)4555847867Stance (0–6)2444626656Sitting (0–4)0110403312Speech disturbance (0–6)2222no speech2no speechno speechno speechno speechFinger chase (R + L)/2 (0–4)1121not testedaProfound intellectual deficit precluded these assessments in patient P II-2.11121Nose-finger test (R + L)/2 (0–4)1121not testedaProfound intellectual deficit precluded these assessments in patient P II-2.11210Fast alternating hand movements (R + L)/2 (0–4)1221not testedaProfound intellectual deficit precluded these assessments in patient P II-2.12221Heel-shin slide (R + L)/2 (0–4)1222not testedaProfound intellectual deficit precluded these assessments in patient P II-2.12322Total SARA score (0–40)bThe second figure is the maximal possible total SARA score, which can be lower than the theoretical maximum of 40 if some assessments were not possible (e.g., a dysarthria score is missing in patients who never learned to speak).13/4018/4020/4016/4018/1812/4022/3425/3419/3419/34Oculomotor SignsGaze-evoked horizontal nystagmusnononoyesnoyesyesnononoHypometric saccadesnoyesnonoyesnoyesnonoyesAbduction deficityesnonoyesyesnonoyesnonoEsotropianoyesyesnoyesnonononoyesPtosisnononoyesnonononoyesyesAdditionalIntellectual deficitmildmildmildmoderateprofoundmoderatemoderatesevereseveresevereHyperreflexiayesyesyesyesnoyesyesyesyesyesSpasticitynononononononoyesnonoPolyneuropathynonononomildnonono datano datano dataSeizuresnoat 2 yearsat 5 monthsnoone abnormal EEGnononononoThe scoring of the eight SARA16Schmitz-Hübsch T. du Montcel S.T. Baliko L. Berciano J. Boesch S. Depondt C. Giunti P. Globas C. Infante J. Kang J.S. et al.Scale for the assessment and rating of ataxia: Development of a new clinical scale.Neurology. 2006; 66: 1717-1720Crossref PubMed Scopus (1162) Google Scholar items is shown in the first column; 0 indicates a lack of impairment, and higher scores indicate increasing severity. The following abbreviations are used: R, right; L, left; SARA, Scale for the Assessment and Rating of Ataxia; and EEG, electroencephalography.a Profound intellectual deficit precluded these assessments in patient P II-2.b The second figure is the maximal possible total SARA score, which can be lower than the theoretical maximum of 40 if some assessments were not possible (e.g., a dysarthria score is missing in patients who never learned to speak). Open table in a new tab The scoring of the eight SARA16Schmitz-Hübsch T. du Montcel S.T. Baliko L. Berciano J. Boesch S. Depondt C. Giunti P. Globas C. Infante J. Kang J.S. et al.Scale for the assessment and rating of ataxia: Development of a new clinical scale.Neurology. 2006; 66: 1717-1720Crossref PubMed Scopus (1162) Google Scholar items is shown in the first column; 0 indicates a lack of impairment, and higher scores indicate increasing severity. The following abbreviations are used: R, right; L, left; SARA, Scale for the Assessment and Rating of Ataxia; and EEG, electroencephalography. Collected from previous hospital records and parental interviews, data on early manifestations and evolution of the disorder pointed to impaired psychomotor development. Three patients never walked, and five never learned to talk, whereas developmental milestones were markedly delayed in the remaining subjects (Table 1). Upon current examination, height and weight were within normal limits in the three affected children but were markedly low in the adult patients. Ataxia manifestations were evaluated with the Scale for the Assessment and Rating of Ataxia (SARA).16Schmitz-Hübsch T. du Montcel S.T. Baliko L. Berciano J. Boesch S. Depondt C. Giunti P. Globas C. Infante J. Kang J.S. et al.Scale for the assessment and rating of ataxia: Development of a new clinical scale.Neurology. 2006; 66: 1717-1720Crossref PubMed Scopus (1162) Google Scholar Moderate to severe gait and stance ataxia were invariably present, had a mean score of 11.9 (SARA items 1–3; maximum score of 18), and tended to have higher values in older patients (Table 1). Mild dysarthria was present in all who were able to speak. Dysmetria, tremors, and dysdiadochokinesia were also mild and had a mean score of 5.2 for limb kinetic function (SARA items 5–8; maximum score of 16). Pyramidal signs were relatively mild and localized mostly to the lower limbs. Abnormalities revealed by ophthalmological examination included gaze-induced horizontal nystagmus, hypometric saccades, mild abduction deficits, strabismus, and ptosis (Table 1). Cognitive function was assessed through interviews with the affected subjects and care providers with the use of the Diagnostic and Statistical Manual of Mental Disorders17American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders.Fourth Edition. American Psychiatric Association, Washington, DC2000Google Scholar criteria targeting adaptive functioning. Intellectual deficit, ranging in severity from mild to profound, was present in all patients. Brain-imaging data were collected on seven subjects, and spine imaging was performed on two subjects; magnetic resonance imaging (MRI [1.5T imagers, Signa Excite HDxt, GE Healthcare Milwaukee, USA]) was used for all of these patients, and additional computed tomography (CT) scans were used for two of the patients (Tables 2 and 3 and Figure 2). Generalized cerebellar atrophy was invariably present and was mostly classified as moderate to severe. A constitutional small inferior vermis was observed in three individuals, and a small brain was observed in five of the seven subjects. The middle cerebellar peduncle and brainstem were mostly normal. Isolated findings included atrophy of the right hippocampal body and bilateral-posterior-putamen signal change and atrophy associated with prominent perivascular spaces. The spine was normal.Table 2Neuroimaging Findings in the Ataxia PatientsPatientLi 1V III-2aLongitudinal imaging data of V III-2 and V III-1 are shown in Table 3.V III-1aLongitudinal imaging data of V III-2 and V III-1 are shown in Table 3.B IV-2P II-2B IV-3P II-3Age (years) at imaging661124273237ModalityMRIMRICTMRIMRIMRIMRIProtocolT1 FLAIR sagittal, T1 SPGR coronal, T2 FSE coronal, T2 FSE axialPD and T2 axialvolumetric axial with orthogonal MPRT1 sagittal, T2 propeller axial, T2 FLAIR coronal, DWI (b = 1,000)T1 MEMP axial, T2 FSE coronal, DWI (b = 1,000), T2 GRE axial, T1 3D BRAVO with MPRs, T2 FSE axial, T2 FSEIR coronal, T2 FLAIR coronalvolumetric T1 MPRs—coronal and sagittalT1 MEMP axial, T2 FSE coronal, DWI (b = 1,000), T2 GRE axial, T1 3D BRAVO with MPRs, T2 FSE axial, T2 FSEIR coronal, T2 FLAIR coronalGlobal atrophynononononononoGlobal small brain (score)no (0)no (0)yes (1)mild (1)yes (1)yes (1)mild (1)Ventricular systemfourth enlargedfourth enlargedmild to moderate generalized increase; no hydrocephalyfourth enlargednofourth enlargednoSelective cerebral atrophynononononononoSelective cerebellar atrophy (score)moderate generalized (2)moderate to marked generalized (3)moderate generalized (2)mild hemispheric (1)marked generalized (3)moderate to severe generalized (3)moderate generalized (2)Cerebellar hypoplasia (score)no (0)no (0)inferior vermian (1)no (0)inferior vermian (1)inferior vermian (1)no (0)Posterior cranial fossa size (score)normal (0)normal (0)small (1)normal (0)small (1)normal (0)normal (0)Retrocerebellar cystnoyesyesnoyesyesyesMiddle cerebellar peduncle size (score)normal (0)normal (0)mild decrease (1)normal (0)normal (0)normal (0)normal (0)Brainstem size and signalnormalnormalnormalnormalnormalnormalnormalHippocampal sizenormalnormalnormalnormalnormalnormalright posterior body atrophicCerebral white matternormalnormalnormalnormalnormalnormalnormalBasal ganglia and thalaminormalnormalnormalnormalposterior putaminal signal and atrophynormalnormalTotal imaging scorebScores for individual signs are 0 or 1 (absent or present, respectively). However, for cerebellar atrophy, 0, 1, 2, and 3 correspond to nil, mild, moderate, and marked, respectively.2362653Total SARA scorecTotal SARA scores are as shown in Table 1.13/4018/4020/4016/4018/1812/4022/34The following abbreviations are used: FLAIR, fluid attenuation inversion recovery; SPGR, spoiled gradient echo; FSE, fast spin echo; PD, proton density; MPR, multiplanar reformat; DWI, diffusion-weighted imaging; MEMP, multiecho multiplanar; GRE, gradient echo; BRAVO, brain volume; and FSEIR, fast spin-echo inversion recovery.a Longitudinal imaging data of V III-2 and V III-1 are shown in Table 3.b Scores for individual signs are 0 or 1 (absent or present, respectively). However, for cerebellar atrophy, 0, 1, 2, and 3 correspond to nil, mild, moderate, and marked, respectively.c Total SARA scores are as shown in Table 1. Open table in a new tab Table 3Reassessment of CT and MRI Scans Performed at Different Ages in the Affected Siblings of Family VPatientV III-2V III-1Age (years) at imaging11 year, 8 months3699558811Body regionheadheadheadheadheadT-spineheadheadheadL-spineheadModalityCTMRICTMRICTMRICTMRICTMRICTnonvolumetric axial (8 mm slices)T1 midline sagittal, PD, and T2 axialnonvolumetric axial (5 mm slices)PD and T2 axialnonvolumetric axial (3 mm slices)T2 frFSE sagittal, T1 FLAIR sagittal, T2 STIR sagittal, 2D MERGE axialnonvolumetric axial (5 mm slices)PD and T2 axialnonvolumetric axial (3 mm slices)T1 FSE sagittal, T2 IR-STIR sagittal, 2D MERGE axial, T1 FSE axial, T2 FSE coronalvolumetric axial with orthogonal MPRVentricular systemnonofourth enlargedfourth enlargedfourth enlarged−mild generalized increasemild to moderate generalized increase (no hydrocephalus)mild to moderate generalized increase (no hydrocephalus)−mild to moderate generalized increase (no hydrocephalus)Selective cerebellar atrophynonomoderate generalizedmoderate to marked generalizedmoderate generalized−mild to moderate generalizedmoderate generalizedmoderate generalized−moderate generalizedCerebellar hypoplasianonononono−inferior vermianinferior vermianinferior vermian−inferior vermianPosterior cranial fossa sizenormalnormalnormalnormalnormal−smallsmallsmall−smallRetrocerebellar cystnonoyesyesyes−yesyesyes−yesMiddle cerebellar pedunclenormalnormalnormalnormalnormal−mild decreasemild decreasemild decrease−mild decreaseComparisonnew—cellebellar atrophyslight increase in ventricular size and cerebellar atrophySpinenormalsmall lower spinal cord syrinxThe following abbreviations are used: CT, computed tomography; MRI, magnetic resonance image; PD, proton density; frFSE, fast-recovery fast spin echo; FLAIR, fluid attenuation inversion recovery; STIR, short-tau inversion recovery; MERGE, multiple-echo recombined gradient echo; FSE, fast spin echo; IR-STIR, inversion-recovery short-tau inversion recovery; and MPR, multiplanar reformat. Open table in a new tab The following abbreviations are used: FLAIR, fluid attenuation inversion recovery; SPGR, spoiled gradient echo; FSE, fast spin echo; PD, proton density; MPR, multiplanar reformat; DWI, diffusion-weighted imaging; MEMP, multiecho multiplanar; GRE, gradient echo; BRAVO, brain volume; and FSEIR, fast spin-echo inversion recovery. The following abbreviations are used: CT, computed tomography; MRI, magnetic resonance image; PD, proton density; frFSE, fast-recovery fast spin echo; FLAIR, fluid attenuation inversion recovery; STIR, short-tau inversion recovery; MERGE, multiple-echo recombined gradient echo; FSE, fast spin echo; IR-STIR, inversion-recovery short-tau inversion recovery; and MPR, multiplanar reformat. Reassessment of CT and MRI scans performed at different ages in two patients (Table 3 and Figure 2) suggested a progressive nature of the structural brain changes: in V III-2, the findings were unremarkable at 1 year and 1 year and 8 months of age and became abnormal at the age of 3 (volume loss in the cerebellum), whereas in V III-1, the cerebellar atrophy became more prominent at 11 years of age compared to 8 years of age. Nerve-conduction studies and needle electromyography (Dantec–Keypoint portable electromyograph [Natus, Copenhagen, Denmark]) were mostly normal. Routine blood counts and biochemistry and blood and urine metabolites were within reference limits. We sequenced the exomes of 11 individuals—six patients and five parents from families V, M, and B (Figure 1). Exome capture (Illumina TruSeq) and sequencing (Illumina HiSeq 2000) were performed by Axeq Technologies (Seoul, South Korea). The 101 bp paired-end reads were aligned to UCSC hg19 with Novoalign version 2.0.7. Reads mapping to multiple locations and presumed PCR duplicates were discarded with the Picard utility MarkDuplicates. Variants were detected with the mpileup and bcftools view commands from SAMtools 0.1.1818Li H. Ruan J. Durbin R. Mapping short DNA sequencing reads and calling variants using mapping quality scores.Genome Res. 2008; 18: 1851-1858Crossref PubMed Scopus (2015) Google Scholar, 19Li H. Improving SNP discovery by base alignment quality.Bioinformatics. 2011; 27: 1157-1158Crossref PubMed Scopus (190) Google Scholar with parameters -C50 and -q13. Variant filtering was performed with the vcfutils.pl varFilter script from the same program. Variants were annotated with the UCSC KnownGene annotation and ANNOVAR.20Wang K. Li M. Hakonarson H. ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res. 2010; 38: e164Crossref PubMed Scopus (7872) Google Scholar The functional effects of coding nonsynonymous variants were assessed with SIFT21Kumar P. Henikoff S. Ng P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.Nat. Protoc. 2009; 4: 1073-1081Crossref PubMed Scopus (5006) Google Scholar and HumVar-trained PolyPhen2 version 2.1.0.22Adzhubei I.A. Schmidt S. Peshkin L. Ramensky V.E. Gerasimova A. Bork P. Kondrashov A.S. Sunyaev S.R. A method and server for predicting damaging missense mutations.Nat. Methods. 2010; 7: 248-249Crossref PubMed Scopus (9290) Google Scholar We used SAMtools to infer from the exome sequence data genotypes at the location of HapMap Phase II SNPs.23Smith K.R. Bromhead C.J. Hildebrand M.S. Shearer A.E. Lockhart P.J. Najmabadi H. Leventer R.J. McGillivray G. Amor D.J. Smith R.J. Bahlo M. Reducing the exome search space for mendelian diseases using genetic linkage analysis of exome genotypes.Genome Biol. 2011; 12: R85Crossref PubMed Scopus (65) Google Scholar From 40,464 SNPs with inferred genotypes, we selected a subset of 6,855 that were in approximate linkage equilibrium, spaced at least 0.15 cM apart, and chosen for maximizing heterozygosity (average of 0.40) according to HapMap CEU (Utah residents with ancestry from northern and western Europe from the CEPH collection) genotypes. We used this subset to estimate relatedness between affected families and inbreeding within each family. The proportion of alleles shared identically by descent between every pair of the 11 individuals was assessed with PLINK.24Purcell S. Neale B. Todd-Brown K. Thomas L. Ferreira M.A. Bender D. Maller J. Sklar P. de Bakker P.I. Daly M.J. Sham P.C. PLINK: A tool set for whole-genome association and population-based linkage analyses.Am. J. Hum. Genet. 2007; 81: 559-575Abstract Full Text Full Text PDF PubMed Scopus (19634) Google Scholar The findings (Table S1, available online) validated the known relationships within each of the three families. No sharing was detected between individuals from different families, indicating that although the affected families belonged to the same Roma group, they were not closely related. Inbreeding coefficients (F) were estimated with FEstim;25Leutenegger A.L. Prum B. Génin E. Verny C. Lemainque A. Clerget-Darpoux F. Thompson E.A. Estimation of the inbreeding coefficient through use of genomic data.Am. J. Hum. Genet. 2003; 73: 516-523Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar we used CEU allele frequencies and starting values of 0.05 for the parameters F and A. All six patients were estimated to be inbred; F ranged from 0.023 to 0.113 (Table S2). Inbreeding was also detected in four of the five unaffected parents; the exception, mother V II-2, was known to have a non-Roma mother. Inbreeding and relatedness detection appeared to be robust to potential misspecification of allele frequencies as a result of the usage of CEU frequencies; known relationships were estimated accurately by both PLINK and FEstim. Parametric multipoint linkage analysis was performed on the same subset of 6,855 SNPs with MERLIN26Abecasis G.R. Cherny S.S. Cookson W.O. Cardon L.R. Merlin—rapid analysis of dense genetic maps using sparse gene flow trees.Nat. Genet. 2002; 30: 97-101Crossref PubMed Scopus (2780) Google Scholar under a fully penetrant autosomal-recessive model with a 0% phenocopy rate, a disease allele frequency of 0.00001, and CEU SNP allele frequencies. We added hypothetical consanguinity loops to the pedigrees to approximate the estimated inbreeding coefficients (Figure S1). Genome-wide linkage analysis identified in chromosomal region 6q24 a unique peak with a maximum heterogeneity LOD score of 6.009 (Figure S2). This was the only genomic region in which all three families showed linkage. The contribution of each family to the overall result is shown in Figure S3. Examination of inferred 6q24 haplotypes with the use of HaploPainter27Thiele H. Nürnberg P. HaploPainter: A tool for drawing pedigrees with complex haplotypes.Bioinformatics. 2005; 21: 1730-1732Crossref PubMed Scopus (231) Google Scholar showed a stretch of 11 SNPs (147.86– 151.16 cM) homozygous in all patients (Figure S4). Inspection of all polymorphic SNPs in the region showed homozygosity extending over 59 SNPs spanning 3.3 cM (3.8 Mb). The flanking (nonhomozygous) SNPs rs2073214 at 147.86 cM and rs2272998 at 152.38 cM defined an interval containing 32 genes (including nine pseudogenes), of which 12 have associated OMIM entries. Of the total 565,618 sequence variants detected in at least one of the 11 exomes, 352,599 survived filtering. Of these, 294 (including 88 rare or novel [not found in any database] variants) were located within the linkage interval. Five were coding (one synonymous, two nonsynonymous, a nonframeshift deletion, and a stop-gain change), and one was within 2 bp of a predicted splice site. All six were within the shared homozygous haplotype. Only two of the six followed the expected segregation pattern, which is that all patients and parents are homozygous and heterozygous, respectively, for the mutant allele (illustrated for family V in Figure S5). The two homozygous variants segregating with the disease are located in GRM1, the gene encoding metabotropic glutamate receptor 1 (mGluR1) and are c.2652_2654del and c.2660+2T>G (RefSeq accession number NM_000838.3). Database and literature searches identified multiple mutant animal models showing severe motor incoordination (Table S3), making GRM1 a highly plausible candidate in human ataxia. One mutation (c.2652_2654del [p.Asn885del]) (hg19, chr6: 146,720,827–146,720,829; RefSeq NM_000838.3) is a 3 bp deletion close to the 3′ end of exon 8. Seven base pairs downstream, the second mutation (c.2660+2T>G; hg19, chr6: 146,720,837) affects the second nucleotide of the canonical splice donor site of intron 8. The presence of the mutations was verified by Sanger sequencing (Figure S5); analysis of the 11 original samples, additional members of families V, M, and B, and two newly recruited families showed that genotypes for the two mutations predicted disease perfectly under the autosomal-recessive inheritance model (Figure 1). Neither c.2652_2654del no" @default.
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• W2057509417 title "Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1" @default.
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