Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays

Genomic microarray analysis is rapidly replacing conventional chromosome analysis by molecular karyotyping due to the significant increase in the power to detect causative CNVs. Here, we extensively validated the HumanHap550 and Human610-Quadv1_B Illumina platforms for potential diagnostic applicati...

Descripción completa

Detalles Bibliográficos
Autor: Rivera Brugués, Núria
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/81745
Acceso en línea:http://hdl.handle.net/10803/81745
Access Level:acceso abierto
Palabra clave:Genòmica
Genomics
Genómica
Ciències Experimentals i Matemàtiques
575
id ES_58ac2a5cf6de6bec34dec2f2a0a3f6a8
oai_identifier_str oai:www.tdx.cat:10803/81745
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
title Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
spellingShingle Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
Rivera Brugués, Núria
Genòmica
Genomics
Genómica
Ciències Experimentals i Matemàtiques
575
title_short Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
title_full Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
title_fullStr Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
title_full_unstemmed Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
title_sort Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays
dc.creator.none.fl_str_mv Rivera Brugués, Núria
author Rivera Brugués, Núria
author_facet Rivera Brugués, Núria
author_role author
dc.contributor.none.fl_str_mv Meitinger, Thomas
Vilageliu i Arqués, Lluïsa
Universitat de Barcelona. Departament de Genètica
dc.subject.none.fl_str_mv Genòmica
Genomics
Genómica
Ciències Experimentals i Matemàtiques
575
topic Genòmica
Genomics
Genómica
Ciències Experimentals i Matemàtiques
575
description Genomic microarray analysis is rapidly replacing conventional chromosome analysis by molecular karyotyping due to the significant increase in the power to detect causative CNVs. Here, we extensively validated the HumanHap550 and Human610-Quadv1_B Illumina platforms for potential diagnostic application by using patients with undiagnosed intellectual disability (ID). The first and foremost goal of our application study was to use these arrays for reliable genome wide detection of rare CNVs in patients of three different cohorts: 1) patients with unexplained intellectual disability 2) patients with unknown diffuse congenital hyperinsulinism (CHI) and 3) a family with a distinctive diagnosis of Holt-Oram syndrome (HOS). We showed that SNP-based arrays allow the detection of intragenic deletions and duplications. The identification of a disease-CNV affecting only a single gene allowed us to consider that particular gene as a candidate for intellectual disability. This was the case for three unrelated patients with moderate intellectual disability, global developmental delay, and severe speech and language disorders in which a de novo deletion encompassing solely the FOXP1 gene was detected. To prove further the causality of the FOXP1 deletion following-up investigations were based on a screening of the entire coding region of FOXP1 for nucleotide changes in a panel of 883 probands with intellectual disability. Eight non-synonymous coding changes, three synonymous and nine non-coding variants were identified. In addition to the de novo cases of ID, also patients suffering from an autosomal recessive form of ID were found in our cohort. We detected three partial heterozygous deletions of the COH1 gene at locus 8q22 which is mutated in Cohen syndrome. After sequencing the entire coding region and the exon/intron boundaries of COH1 we identified a stop mutation, a frameshift and two missense mutations in the remaining allele, respectively. Therefore, three compound heterozygous mutations were identified in the COH1 gene, thus providing a distinctive Cohen Syndrome diagnose to three unrelated patients of our ID cohort. We studied the genetic basis of a rare human autosomal disorder such as diffuse Congenital Hyperinsulinsm (CHI) in a cohort of 40 patients with inconspicuous mutation screening of ABCC8 and KCNJ11 genes. Chromosomal abnormalities detected by SNP oligonucleotide arrays accounted for 20% of the studied cases. The most interesting rearrangement was a 970kb deletion at the chromosomal band 1p31.1 which was found to encompass the PTGER3 and ZRANB2 genes and the last exon of the NEGR1 gene. We hypothesized that the haploinsufficiency of PTGER3 gene induces a 50% reduction of the stimulation by PGE2, thus diminishing the inhibition of glucose-stimulated insulin secretion (GSIS) and resulting in elevated insulin secretion. The screening for point mutations in the candidate gene PTGER3 did not reveal any pathogenic variant neither in the second allele of the patient in which a de novo deletion was detected nor in a cohort of 39 unrelated patients with unexplained CHI. Instead we identified a novel polymorphic variant which was also detected in 18 individuals of our control cohort. CNV analysis in a family with both atypical Holt-Oram syndrome and additional mammary glands was performed allowing the detection of a contiguous heterozygous duplication at the chromosomal band 12q24.21. The maximal duplication size could be estimated as aproximately 345,6kb including the whole coding region of the TBX5 and TBX3 genes. Gene dosage assessment at specific genetic loci demonstrated the cosegregation of the duplication and the Holt-Oram syndrome/supernumerary mammary glands phenotype in this pedigree, this being a strong indicator of its pathogenecity. Up to date, this is the first report of a heterozygous duplication encompassing both TBX5 and TBX3 genes, and consequently the first report of a combined phenotype of Holt-Oram syndrome and supernumerary mammary glands.
publishDate 2012
dc.date.none.fl_str_mv 2012
2012
2012
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/81745
url http://hdl.handle.net/10803/81745
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 242 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408559808118784
spelling Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarraysRivera Brugués, NúriaGenòmicaGenomicsGenómicaCiències Experimentals i Matemàtiques575Genomic microarray analysis is rapidly replacing conventional chromosome analysis by molecular karyotyping due to the significant increase in the power to detect causative CNVs. Here, we extensively validated the HumanHap550 and Human610-Quadv1_B Illumina platforms for potential diagnostic application by using patients with undiagnosed intellectual disability (ID). The first and foremost goal of our application study was to use these arrays for reliable genome wide detection of rare CNVs in patients of three different cohorts: 1) patients with unexplained intellectual disability 2) patients with unknown diffuse congenital hyperinsulinism (CHI) and 3) a family with a distinctive diagnosis of Holt-Oram syndrome (HOS). We showed that SNP-based arrays allow the detection of intragenic deletions and duplications. The identification of a disease-CNV affecting only a single gene allowed us to consider that particular gene as a candidate for intellectual disability. This was the case for three unrelated patients with moderate intellectual disability, global developmental delay, and severe speech and language disorders in which a de novo deletion encompassing solely the FOXP1 gene was detected. To prove further the causality of the FOXP1 deletion following-up investigations were based on a screening of the entire coding region of FOXP1 for nucleotide changes in a panel of 883 probands with intellectual disability. Eight non-synonymous coding changes, three synonymous and nine non-coding variants were identified. In addition to the de novo cases of ID, also patients suffering from an autosomal recessive form of ID were found in our cohort. We detected three partial heterozygous deletions of the COH1 gene at locus 8q22 which is mutated in Cohen syndrome. After sequencing the entire coding region and the exon/intron boundaries of COH1 we identified a stop mutation, a frameshift and two missense mutations in the remaining allele, respectively. Therefore, three compound heterozygous mutations were identified in the COH1 gene, thus providing a distinctive Cohen Syndrome diagnose to three unrelated patients of our ID cohort. We studied the genetic basis of a rare human autosomal disorder such as diffuse Congenital Hyperinsulinsm (CHI) in a cohort of 40 patients with inconspicuous mutation screening of ABCC8 and KCNJ11 genes. Chromosomal abnormalities detected by SNP oligonucleotide arrays accounted for 20% of the studied cases. The most interesting rearrangement was a 970kb deletion at the chromosomal band 1p31.1 which was found to encompass the PTGER3 and ZRANB2 genes and the last exon of the NEGR1 gene. We hypothesized that the haploinsufficiency of PTGER3 gene induces a 50% reduction of the stimulation by PGE2, thus diminishing the inhibition of glucose-stimulated insulin secretion (GSIS) and resulting in elevated insulin secretion. The screening for point mutations in the candidate gene PTGER3 did not reveal any pathogenic variant neither in the second allele of the patient in which a de novo deletion was detected nor in a cohort of 39 unrelated patients with unexplained CHI. Instead we identified a novel polymorphic variant which was also detected in 18 individuals of our control cohort. CNV analysis in a family with both atypical Holt-Oram syndrome and additional mammary glands was performed allowing the detection of a contiguous heterozygous duplication at the chromosomal band 12q24.21. The maximal duplication size could be estimated as aproximately 345,6kb including the whole coding region of the TBX5 and TBX3 genes. Gene dosage assessment at specific genetic loci demonstrated the cosegregation of the duplication and the Holt-Oram syndrome/supernumerary mammary glands phenotype in this pedigree, this being a strong indicator of its pathogenecity. Up to date, this is the first report of a heterozygous duplication encompassing both TBX5 and TBX3 genes, and consequently the first report of a combined phenotype of Holt-Oram syndrome and supernumerary mammary glands.Universitat de BarcelonaMeitinger, ThomasVilageliu i Arqués, LluïsaUniversitat de Barcelona. Departament de Genètica201220122012info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion242 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/81745TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/817452026-06-14T12:46:07Z
score 15,300719

Similares en LA Referencia