Genetic Diagnosis of Neuroacanthocytosis Disorders Using Exome Sequencing
Identifieur interne : 001112 ( Main/Exploration ); précédent : 001111; suivant : 001113Genetic Diagnosis of Neuroacanthocytosis Disorders Using Exome Sequencing
Auteurs : Ruth H. Walker [États-Unis] ; Vincent P. Schulz [États-Unis] ; Irina R. Tikhonova [États-Unis] ; Milind C. Mahajan [États-Unis] ; Shrikant Mane [États-Unis] ; Maritza Arroyo Muniz [Porto Rico] ; Patrick G. Gallagher [États-Unis]Source :
- Movement disorders [ 0885-3185 ] ; 2012.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
Neuroacanthocytoses are neurodegenerative disorders marked by phenotypic and genetic heterogeneity. There are several associated genetic loci, and many defects, including gene deletions and insertions, and missense, nonsense, and splicing mutations, have been found spread over hundreds of kilobases of genomic DNA. In some cases, specific diagnosis is unclear, particularly in the early stages of disease or when there is an atypical presentation. Determination of the precise genetic defect allows assignment of the diagnosis and permits carrier detection and genetic counseling. The objective of this report was to utilize exome sequencing for genetic diagnosis in the neuroacanthocytosis syndromes. Genomic DNA from 2 patients with clinical features of chorea-acanthocytosis was subjected to targeted exon capture. Captured DNA was subjected to ultrahigh throughput next-generation sequencing. Sequencing data were assembled, filtered against known human variant genetic databases, and results were analyzed. Both patients were compound heterozygotes for mutations in the VPS13A gene, the gene associated with chorea-acanthocytosis. Patient 1 had a 4-bp deletion that removes the 5' donor splice site of exon 58 and a nucleotide substitution that disrupts the 5' donor splice site of exon 70. Patient 2 had a dinucleotide deletion in exon 16 and a dinucleotide insertion in exon 33. No mutations were identified in the XK, PANK2, or JPH3 gene loci. Exome sequencing is a valuable diagnostic tool in the neuroacanthocytosis syndromes. These studies may provide a better understanding of the function of the associated proteins and provide insight into the pathogenesis of these disorders.
Affiliations:
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Walker</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Neurology, James J. Peters Veterans Affairs Medical Center</s1><s2>Bronx, New York</s2><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Neurology, Mount Sinai School of Medicine, New York</s1><s2>New York</s2><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Schulz, Vincent P" sort="Schulz, Vincent P" uniqKey="Schulz V" first="Vincent P." last="Schulz">Vincent P. Schulz</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Pediatrics, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Tikhonova, Irina R" sort="Tikhonova, Irina R" uniqKey="Tikhonova I" first="Irina R." last="Tikhonova">Irina R. Tikhonova</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Genetics, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Yale Center for Genome Analysis, Yale University</s1><s2>Orange, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Mahajan, Milind C" sort="Mahajan, Milind C" uniqKey="Mahajan M" first="Milind C." last="Mahajan">Milind C. Mahajan</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Genetics, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Yale Center for Genome Analysis, Yale University</s1><s2>Orange, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Mane, Shrikant" sort="Mane, Shrikant" uniqKey="Mane S" first="Shrikant" last="Mane">Shrikant Mane</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Genetics, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Yale Center for Genome Analysis, Yale University</s1><s2>Orange, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Arroyo Muniz, Maritza" sort="Arroyo Muniz, Maritza" uniqKey="Arroyo Muniz M" first="Maritza" last="Arroyo Muniz">Maritza Arroyo Muniz</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Neurology Section, Medicine Department, Medical Science Campus, University of Puerto Rico</s1><s2>San Juan</s2><s3>PRI</s3><sZ>6 aut.</sZ></inist:fA14><country>Porto Rico</country><wicri:noRegion>San Juan</wicri:noRegion></affiliation></author><author><name sortKey="Gallagher, Patrick G" sort="Gallagher, Patrick G" uniqKey="Gallagher P" first="Patrick G." last="Gallagher">Patrick G. Gallagher</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Pediatrics, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Genetics, Yale University School of Medicine</s1><s2>New Haven, Connecticut</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Connecticut</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acanthocytosis</term><term>Chorea</term><term>Diagnosis</term><term>Genetic disease</term><term>Nervous system diseases</term><term>Nucleotide sequence</term><term>Sequencing</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Maladie héréditaire</term><term>Syndrome choréique</term><term>Acanthocytose</term><term>Pathologie du système nerveux</term><term>Diagnostic</term><term>Séquence nucléotide</term><term>Séquençage</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Neuroacanthocytoses are neurodegenerative disorders marked by phenotypic and genetic heterogeneity. There are several associated genetic loci, and many defects, including gene deletions and insertions, and missense, nonsense, and splicing mutations, have been found spread over hundreds of kilobases of genomic DNA. In some cases, specific diagnosis is unclear, particularly in the early stages of disease or when there is an atypical presentation. Determination of the precise genetic defect allows assignment of the diagnosis and permits carrier detection and genetic counseling. The objective of this report was to utilize exome sequencing for genetic diagnosis in the neuroacanthocytosis syndromes. Genomic DNA from 2 patients with clinical features of chorea-acanthocytosis was subjected to targeted exon capture. Captured DNA was subjected to ultrahigh throughput next-generation sequencing. Sequencing data were assembled, filtered against known human variant genetic databases, and results were analyzed. Both patients were compound heterozygotes for mutations in the VPS13A gene, the gene associated with chorea-acanthocytosis. Patient 1 had a 4-bp deletion that removes the 5' donor splice site of exon 58 and a nucleotide substitution that disrupts the 5' donor splice site of exon 70. Patient 2 had a dinucleotide deletion in exon 16 and a dinucleotide insertion in exon 33. No mutations were identified in the XK, PANK2, or JPH3 gene loci. Exome sequencing is a valuable diagnostic tool in the neuroacanthocytosis syndromes. These studies may provide a better understanding of the function of the associated proteins and provide insight into the pathogenesis of these disorders.</div></front></TEI><affiliations><list><country><li>Porto Rico</li><li>États-Unis</li></country><region><li>Connecticut</li><li>État de New York</li></region></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Walker, Ruth H" sort="Walker, Ruth H" uniqKey="Walker R" first="Ruth H." last="Walker">Ruth H. Walker</name></region><name sortKey="Gallagher, Patrick G" sort="Gallagher, Patrick G" uniqKey="Gallagher P" first="Patrick G." last="Gallagher">Patrick G. Gallagher</name><name sortKey="Gallagher, Patrick G" sort="Gallagher, Patrick G" uniqKey="Gallagher P" first="Patrick G." last="Gallagher">Patrick G. Gallagher</name><name sortKey="Mahajan, Milind C" sort="Mahajan, Milind C" uniqKey="Mahajan M" first="Milind C." last="Mahajan">Milind C. Mahajan</name><name sortKey="Mahajan, Milind C" sort="Mahajan, Milind C" uniqKey="Mahajan M" first="Milind C." last="Mahajan">Milind C. Mahajan</name><name sortKey="Mane, Shrikant" sort="Mane, Shrikant" uniqKey="Mane S" first="Shrikant" last="Mane">Shrikant Mane</name><name sortKey="Mane, Shrikant" sort="Mane, Shrikant" uniqKey="Mane S" first="Shrikant" last="Mane">Shrikant Mane</name><name sortKey="Schulz, Vincent P" sort="Schulz, Vincent P" uniqKey="Schulz V" first="Vincent P." last="Schulz">Vincent P. Schulz</name><name sortKey="Tikhonova, Irina R" sort="Tikhonova, Irina R" uniqKey="Tikhonova I" first="Irina R." last="Tikhonova">Irina R. Tikhonova</name><name sortKey="Tikhonova, Irina R" sort="Tikhonova, Irina R" uniqKey="Tikhonova I" first="Irina R." last="Tikhonova">Irina R. Tikhonova</name><name sortKey="Walker, Ruth H" sort="Walker, Ruth H" uniqKey="Walker R" first="Ruth H." last="Walker">Ruth H. Walker</name></country><country name="Porto Rico"><noRegion><name sortKey="Arroyo Muniz, Maritza" sort="Arroyo Muniz, Maritza" uniqKey="Arroyo Muniz M" first="Maritza" last="Arroyo Muniz">Maritza Arroyo Muniz</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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