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2.
Mol Genet Metab ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30473481

RESUMO

Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect.

3.
Mol Cytogenet ; 11: 43, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123325

RESUMO

Background: Partial monosomy 21 is a rare finding with variable sizes and deletion breakpoints, presenting with a broad spectrum of phenotypes. Case presentation: We report a 10-month-old boy with short stature, minor anomalies and mild motor delay. The patient had a monosomy 21 and duplication of the 21q22.11q22.3 region on the remaining derivative chromosome 21 which represents a partial 21q uniparental disomy of paternal origin, upd(21q22.11q22.3)pat. The abnormalities were characterized by karyotyping, FISH, chromosomal microarray, and genotyping. Conclusions: This is the first case showing a monosomy 21 compensated by upd(21q22.11q22.3) as a mechanism of genomic rescue. Because there is no strong evidence showing imprinting on chromosome 21, the uniparental disomy itself is not associated with abnormal phenotype but has reduced phenotype severity of monosomy 21. We reviewed the previously published cases with isolated 21q deletions and identified a common deletion of 5.7 Mb associated with low birth weight, length and head circumference in the 21q21.2 region.

4.
Pediatr Neurol ; 79: 61-64, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29413639

RESUMO

BACKGROUND: Patients with autism spectrum disorder and developmental delay or encephalopathy rarely demonstrate no or negligible hair and nail growth, suggesting a biotin-responsive clinical disorder. METHODS: A ten-year-old girl presented with features of autism spectrum disorder, isolated headaches, and episodes of headaches and limb shaking. Her medical history revealed that her hair and nails did not grow. Administration of biotin restored her nail and hair growth and improved intellectual ability and school performance. Her episodes of headaches, single limb shaking, and loss of consciousness responded to administration of acetazolamide, and her school performance and social skills further improved. RESULTS: A de novo c.1091 C > T, p.T364M pathogenic variant was found in the ATP1A2 gene by whole-exome sequencing, but a genetic etiology in the biotin-responsive metabolic pathways was not identified. CONCLUSIONS: The combination of biotin and acetazolamide treatment was successful in restoring normal mental function and school performance. Poor or no clinical nail and hair growth in any child with a developmental delay-autism spectrum disorder presentation should be considered as evidence for a biotin-responsive genetic disorder even when exome testing is negative.

5.
Mol Genet Metab ; 123(3): 309-316, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29269105

RESUMO

Serine biosynthesis defects are autosomal recessive metabolic disorders resulting from the deficiency of any of the three enzymes involved in de novo serine biosynthesis, specifically phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). In this study, we performed metabolomic profiling on 4 children with serine biosynthesis defects; 3 with PGDH deficiency and 1 with PSAT deficiency. The evaluations were performed at baseline and with serine and glycine supplementation. Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin. All children had low serine and glycine as expected. Low glycerophosphocholine compounds were found in 4 children, low glycerophosphoethanolamine compounds in 3 children, and low sphingomyelin species in 2 children. Metabolic profiling with serine and glycine supplementation showed normalization of most of the low phospholipid compounds in the 4 children. Phospholipids are the major component of plasma and intracellular membranes, and phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles. Phosphatidylcholine is of particular importance for the nervous system, where it is essential for neuronal differentiation. The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine. The vital role that phosphatidylcholine has during neuronal differentiation and the pronounced neurological manifestations in serine biosynthesis defects suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations in individuals with serine biosynthesis defects.

6.
J Med Genet ; 55(8): 561-566, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28866611

RESUMO

BACKGROUND: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism. OBJECTIVES: To explore whether variants in CHD1 are associated with a human phenotype. METHODS: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. RESULTS: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1. CONCLUSIONS: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.

7.
Am J Hum Genet ; 101(5): 664-685, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100083

RESUMO

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Mutação/genética , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Deficiência Intelectual/genética , Masculino , Recidiva , Convulsões/genética
8.
J Child Neurol ; 32(6): 543-549, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28135894

RESUMO

Serine biosynthesis defects can present in a broad phenotypic spectrum ranging from Neu-Laxova syndrome, a lethal disease with multiple congenital anomalies at the severe end, to an infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype, to a childhood disease with intellectual disability at the mild end. In this report we present 6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency who presented with psychomotor delay, growth failure, microcephaly, and spasticity. The phenotype was variable with absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3. The initiation of serine treatment had pronounced effect on seizures and spasticity in the sisters in family 3, but minimal developmental effects on the children in families 1 and 2. With such phenotypic variability, the diagnosis of PGDH deficiency can be challenging.


Assuntos
Anormalidades Múltiplas , Encefalopatias , Erros Inatos do Metabolismo dos Carboidratos/complicações , Retardo do Crescimento Fetal , Ictiose , Deformidades Congênitas dos Membros , Microcefalia/complicações , Mutação/genética , Fosfoglicerato Desidrogenase/deficiência , Fosfoglicerato Desidrogenase/genética , Transtornos Psicomotores/complicações , Convulsões/complicações , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Adolescente , Encefalopatias/diagnóstico por imagem , Encefalopatias/etiologia , Encefalopatias/genética , Encefalopatias/terapia , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico por imagem , Erros Inatos do Metabolismo dos Carboidratos/genética , Pré-Escolar , Saúde da Família , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/terapia , Humanos , Ictiose/diagnóstico por imagem , Ictiose/etiologia , Ictiose/genética , Ictiose/terapia , Lactente , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/etiologia , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/terapia , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/etiologia , Microcefalia/genética , Microcefalia/terapia , Fenótipo , Transtornos Psicomotores/diagnóstico por imagem , Transtornos Psicomotores/genética , Convulsões/diagnóstico por imagem , Convulsões/genética , Serina/biossíntese , Adulto Jovem
9.
Hum Genet ; 136(2): 253-261, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27904971

RESUMO

The human sodium-dependent multivitamin transporter (hSMVT) is a product of the SLC5A6 gene and mediates biotin, pantothenic acid, and lipoate uptake in a variety of cellular systems. We report here the identification of mutations R94X, a premature termination, and R123L, a dysfunctional amino acid change, both in exon 3 of the SLC5A6 gene in a child using whole genome-scanning. At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures. After identification of the SLC5A6 mutations, he responded clinically to supplemental administration of excess biotin, pantothenic acid, and lipoate with improvement in clinical findings. Functionality of the two mutants was examined by 3H-biotin uptake assay following expression of the mutants in human-derived intestinal HuTu-80 and brain U87 cells. The results showed severe impairment in biotin uptake in cells expressing the mutants compared to those expressing wild-type hSMVT. Live cell confocal imaging of cells expressing the mutants showed the R94X mutant to be poorly tolerated and localized in the cytoplasm, while the R123L mutant was predominantly retained in the endoplasmic reticulum. This is the first reporting of mutations in the SLC5A6 gene in man, and suggests that this gene is important for brain development and a wide variety of clinical functions.


Assuntos
Doenças Ósseas/genética , Encefalopatias/genética , Enteropatias/genética , Mutação , Simportadores/genética , Biotina/administração & dosagem , Biotina/farmacocinética , Doenças Ósseas/diagnóstico , Doenças Ósseas/tratamento farmacológico , Encefalopatias/diagnóstico , Encefalopatias/tratamento farmacológico , Linhagem Celular Tumoral , Éxons , Genoma Humano , Humanos , Lactente , Enteropatias/diagnóstico , Enteropatias/tratamento farmacológico , Masculino , Ácido Pantotênico/administração & dosagem , Ácido Pantotênico/farmacocinética , Ácido Tióctico/administração & dosagem , Ácido Tióctico/farmacocinética
10.
Mol Genet Genomic Med ; 3(1): 40-58, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25629078

RESUMO

WNT10A is a signaling molecule involved in tooth development, and WNT10A defects are associated with tooth agenesis. We characterized Wnt10a null mice generated by the knockout mouse project (KOMP) and six families with WNT10A mutations, including a novel p.Arg104Cys defect, in the absence of EDA,EDAR, or EDARADD variations. Wnt10a null mice exhibited supernumerary mandibular fourth molars, and smaller molars with abnormal cusp patterning and root taurodontism. Wnt10a (-/-) incisors showed distinctive apical-lingual wedge-shaped defects. These findings spurred us to closely examine the dental phenotypes of our WNT10A families. WNT10A heterozygotes exhibited molar root taurodontism and mild tooth agenesis (with incomplete penetrance) in their permanent dentitions. Individuals with two defective WNT10A alleles showed severe tooth agenesis and had fewer cusps on their molars. The misshapened molar crowns and roots were consistent with the Wnt10a null phenotype and were not previously associated with WNT10A defects. The missing teeth contrasted with the presence of supplemental teeth in the Wnt10a null mice and demonstrated mammalian species differences in the roles of Wnt signaling in early tooth development. We conclude that molar crown and root dysmorphologies are caused by WNT10A defects and that the severity of the tooth agenesis correlates with the number of defective WNT10A alleles.

11.
PLoS One ; 5(3): e9476, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-20221430

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract. METHODOLOGY/PRINCIPAL FINDINGS: To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations. CONCLUSIONS/SIGNIFICANCE: These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Deleção de Genes , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Expansão das Repetições de Trinucleotídeos
12.
Hum Mutat ; 30(5): E618-28, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19309688

RESUMO

The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hünermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.


Assuntos
Hipoplasia Dérmica Focal/genética , Hipoplasia Dérmica Focal/patologia , Proteínas de Membrana/genética , Mutação/genética , Aciltransferases , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/química , Dados de Sequência Molecular , Isoformas de Proteínas/química , Isoformas de Proteínas/genética
13.
Genet Med ; 9(1): 23-33, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17224687

RESUMO

PURPOSE: Long QT Syndrome, Marfan Syndrome, hypertrophic and dilated cardiomyopathy are caused by mutations in large, multi-exon genes that are principally expressed in cardiovascular tissues. Genetic testing for these disorders is labor-intensive and expensive. We sought to develop a more rapid, comprehensive, and cost-effective approach. METHODS: Paired whole blood samples were collected into tubes with or without an RNA-preserving solution, and harvested for whole blood RNA or leukocyte DNA, respectively. Large overlapping cDNA fragments from KCNQ1 and KCNH2 (Long QT Syndrome), MYBPC3 (hypertrophic and dilated cardiomyopathy), or FBN1 (Marfan Syndrome) were amplified from RNA and directly sequenced. Variants were confirmed in leukocyte DNA. RESULTS: All 4 transcripts were amplified and sequenced from whole blood mRNA. Six known and 2 novel mutations were first identified from RNA of 10 probands, and later confirmed in genomic DNA, at considerable savings in time and cost. In one patient with MFS, RNA sequencing directly identified a splicing mutation. Results from RNA and DNA were concordant for single nucleotide polymorphisms at the same loci. CONCLUSION: Taking advantage of new whole blood RNA stabilization methods, we have designed a cost-effective, comprehensive method for mutation detection that should significantly facilitate clinical genetic testing in four lethal cardiovascular disorders.


Assuntos
Doenças Cardiovasculares/diagnóstico , Proteínas de Transporte/genética , Canais de Potássio Éter-A-Go-Go/genética , Canal de Potássio KCNQ1/genética , Proteínas dos Microfilamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Criança , Canal de Potássio ERG1 , Éxons/genética , Feminino , Fibrilina-1 , Fibrilinas , Testes Genéticos , Genótipo , Humanos , Lactente , Recém-Nascido , Síndrome do QT Longo/sangue , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Masculino , Síndrome de Marfan/sangue , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Pessoa de Meia-Idade , Mutação/genética , Estudos Prospectivos , RNA/genética , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Am J Med Genet A ; 127A(2): 149-51, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15108202

RESUMO

We present a case of 46,XX sex reversal in the absence of SRY but with partial duplication of chromosome 22q. The subject had multiple congenital anomalies but nearly complete masculinization of the external genitalia. Our case along with a previous case supports the existence of a gene on chromosome 22q that can trigger testis determination in the absence of SRY. We proposed that overexpression of the SOX10 gene at 22q13 might be the cause of sex reversal. We investigated 13 additional subjects with SRY-negative 46,XX sex reversal for microduplication of chromosome arm 22q in the region of SOX10 gene, but could not find evidence for it.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Proteínas de Ligação a DNA/metabolismo , Transtornos do Desenvolvimento Sexual , Proteínas de Grupo de Alta Mobilidade/metabolismo , Processos de Determinação Sexual , Aneuploidia , Análise Citogenética , Proteínas de Ligação a DNA/genética , Feminino , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Masculino , Repetições de Microssatélites/genética , Fatores de Transcrição SOXE , Fatores de Transcrição
15.
Nat Genet ; 35(3): 264-9, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14556008

RESUMO

Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island. Comparative mapping suggested that the locus on 19p13.3 associated with Cayman ataxia might be homologous to the locus on mouse chromosome 10 associated with the recessive ataxic mouse mutant jittery. Screening genes in the region of overlap identified mutations in a novel predicted gene in three mouse jittery alleles, including the first mouse mutation caused by an Alu-related (B1 element) insertion. We found two mutations exclusively in all individuals with Cayman ataxia. The gene ATCAY or Atcay encodes a neuron-restricted protein called caytaxin. Caytaxin contains a CRAL-TRIO motif common to proteins that bind small lipophilic molecules. Mutations in another protein containing a CRAL-TRIO domain, alpha-tocopherol transfer protein (TTPA), cause a vitamin E-responsive ataxia. Three-dimensional protein structural modeling predicts that the caytaxin ligand is more polar than vitamin E. Identification of the caytaxin ligand may help develop a therapy for Cayman ataxia.


Assuntos
Ataxia/genética , Distonia/genética , Mutação , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Cromossomos Humanos Par 19 , Modelos Animais de Doenças , Humanos , Camundongos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
16.
Hum Mol Genet ; 5(4): 525-31, Apr. 1996.
Artigo em Inglês | MedCarib | ID: med-2962

RESUMO

A non-progressive recessive cerebellar ataxia was identified in a highly inbred Cayman island population. Cayman cerebellar ataxia is characterized by marked psychomtor retardation, and prominent cerebellar dysfunction manifested by nystagmus, intention tremor, dysarthric speech, and an ataxic gait. In this study, we identify to chromosome 19p 13.3 using pooled DNA samples of affected individuals from an isolated population as PCR template for a genome wide screen with short tandem repeat markers. Our data demonstrate that the DNA pooling approach to identify disease gene loci is feasible using individuals from isolated populations in which kindred relationship are highly complex and exact relationships between all affected individuals are not known. Genetic fine mapping demonstrates that the genetic disease interval is approximately 9 cM, but contained within a small physical region. The existence of multiple individuals that are recombinant with flanking markers indicates that the disease interval can be further narrowed with additional markers. (AU)


Assuntos
Humanos , Ataxia Cerebelar/genética , Ataxia Cerebelar/epidemiologia , DNA/genética , Região do Caribe/epidemiologia , Mapeamento Cromossômico , Doenças Genéticas Inatas
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