Autosomal-Dominant Microtia Linked to Five Tandem Copies of a Copy-Number- Variable Region at Chromosome 4p16 Irina Balikova, Kevin Martens, Cindy Melotte,

Slides:

Advertisements

Similar presentations

Margaret L. Gulley, Thomas C. Shea, Yuri Fedoriw

Advertisements

Additional file 2: Supplementary Figures

Recurrent Reciprocal Genomic Rearrangements of 17q12 Are Associated with Renal Disease, Diabetes, and Epilepsy Heather C. Mefford, Séverine Clauin, Andrew.

Mosaic Uniparental Disomies and Aneuploidies as Large Structural Variants of the Human Genome Benjamín Rodríguez-Santiago, Núria Malats, Nathaniel Rothman,

Lisa Edelmann, Raj K. Pandita, Bernice E. Morrow

Kendy K. Wong, Ronald J. deLeeuw, Nirpjit S. Dosanjh, Lindsey R

Identification of Multiple Complex Rearrangements Associated with Deletions in the 6q23-27 Region in Sézary Syndrome Katarzyna Iżykowska, Mariola Zawada,

Margaret L. Gulley, Thomas C. Shea, Yuri Fedoriw

Microarray-Based Comparative Genomic Hybridization Using Sex-Matched Reference DNA Provides Greater Sensitivity for Detection of Sex Chromosome Imbalances.

Copy-Number Mutations on Chromosome 17q24. 2-q24

Recurrent CNVs Disrupt Three Candidate Genes in Schizophrenia Patients

Resolving the Breakpoints of the 17q21

Volume 74, Issue 11, Pages (December 2008)

Jianbin Wang, H. Christina Fan, Barry Behr, Stephen R. Quake Cell

Application of Single-Molecule Amplification and Resequencing Technology for Broad Surveillance of Plasma Mutations in Patients with Advanced Lung Adenocarcinoma

Mutations in the Transcription Factor Gene SOX18 Underlie Recessive and Dominant Forms of Hypotrichosis-Lymphedema-Telangiectasia Alexandre Irrthum,

Application of Single-Molecule Amplification and Resequencing Technology for Broad Surveillance of Plasma Mutations in Patients with Advanced Lung Adenocarcinoma

Diagnostic Genome Profiling in Mental Retardation

Copy Number Variation Sequencing for Comprehensive Diagnosis of Chromosome Disease Syndromes Desheng Liang, Ying Peng, Weigang Lv, Linbei Deng, Yanghui.

A Comprehensive Strategy for Accurate Mutation Detection of the Highly Homologous PMS2 Jianli Li, Hongzheng Dai, Yanming Feng, Jia Tang, Stella Chen,

DNA Diagnostics by Surface-Bound Melt-Curve Reactions

Mutations in TPRN Cause a Progressive Form of Autosomal-Recessive Nonsyndromic Hearing Loss Yun Li, Esther Pohl, Redouane Boulouiz, Margit Schraders,

Reciprocal Crossovers and a Positional Preference for Strand Exchange in Recombination Events Resulting in Deletion or Duplication of Chromosome 17p11.2

Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles Carl E.G. Bruder, Arkadiusz Piotrowski,

High-Resolution Mapping of Genotype-Phenotype Relationships in Cri du Chat Syndrome Using Array Comparative Genomic Hybridization Xiaoxiao Zhang, Antoine.

Recombination between Palindromes P5 and P1 on the Human Y Chromosome Causes Massive Deletions and Spermatogenic Failure Sjoerd Repping, Helen Skaletsky,

Genomic Rearrangements Resulting in PLP1 Deletion Occur by Nonhomologous End Joining and Cause Different Dysmyelinating Phenotypes in Males and Females

The Fine-Scale and Complex Architecture of Human Copy-Number Variation

A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

Molecular Cytogenetic Evidence for a Common Breakpoint in the Largest Inverted Duplications of Chromosome 15 A.E. Wandstrat, J. Leana-Cox, L. Jenkins,

A Multicolor FISH Assay Does Not Detect DUP25 in Control Individuals or in Reported Positive Control Cells Yanina Weiland, Jürgen Kraus, Michael R. Speicher

Volume 12, Issue 6, Pages (December 2010)

AZFc Deletions and Spermatogenic Failure: A Population-Based Survey of 20,000 Y Chromosomes Steven G. Rozen, Janet D. Marszalek, Kathryn Irenze, Helen.

Peter Ianakiev, Michael W

Recurrent 10q22-q23 Deletions: A Genomic Disorder on 10q Associated with Cognitive and Behavioral Abnormalities Jorune Balciuniene, Ningping Feng, Kelly.

Comprehensive Mutation Analysis of the CYP21A2 Gene

Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males Hilde Van Esch, Marijke.

Syed Hussain Askree, Lawrence N

Mutations in the ZNF41 Gene Are Associated with Cognitive Deficits: Identification of a New Candidate for X-Linked Mental Retardation Sarah A. Shoichet,

Bassem A. Bejjani, Lisa G. Shaffer

Recurrent Reciprocal Genomic Rearrangements of 17q12 Are Associated with Renal Disease, Diabetes, and Epilepsy Heather C. Mefford, Séverine Clauin, Andrew.

X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3 Hongwen.

Copy-Number Variations Measured by Single-Nucleotide–Polymorphism Oligonucleotide Arrays in Patients with Mental Retardation Janine Wagenstaller, Stephanie.

DPY19L2 Deletion as a Major Cause of Globozoospermia

Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria Barbara Kloeckener-Gruissem,

Disruption of Contactin 4 (CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome Thomas Fernandez, Thomas Morgan, Nicole Davis,

High-Resolution Molecular Characterization of 15q11-q13 Rearrangements by Array Comparative Genomic Hybridization (Array CGH) with Detection of Gene Dosage

Adaptive Evolution of UGT2B17 Copy-Number Variation

Germline Epigenetic Silencing of the Tumor Suppressor Gene PTPRJ in Early-Onset Familial Colorectal Cancer Ramprasath Venkatachalam Gastroenterology

Molecular and Fluorescence In Situ Hybridization Characterization of the Breakpoints in 46 Large Supernumerary Marker 15 Chromosomes Reveals an Unexpected.

A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders Jennifer A. Lee, Claudia M.B. Carvalho, James.

A Physical Map, Including a BAC/PAC Clone Contig, of the Williams-Beuren Syndrome– Deletion Region at 7q11.23 Risa Peoples, Yvonne Franke, Yu-Ker Wang,

High-Throughput Analysis of Subtelomeric Chromosome Rearrangements by Use of Array-Based Comparative Genomic Hybridization Joris A. Veltman, Eric F.P.M.

Reciprocal Crossovers and a Positional Preference for Strand Exchange in Recombination Events Resulting in Deletion or Duplication of Chromosome 17p11.2

Complete Haplotype Sequence of the Human Immunoglobulin Heavy-Chain Variable, Diversity, and Joining Genes and Characterization of Allelic and Copy-Number.

Mechanisms for Nonrecurrent Genomic Rearrangements Associated with CMT1A or HNPP: Rare CNVs as a Cause for Missing Heritability Feng Zhang, Pavel Seeman,

A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

Disruption of ERBB2IP Is not Associated with Dystrophic Epidermolysis Bullosa in Both Father and Son Carrying a Balanced 5;13 Translocation Margarita.

Dosage-Dependent Severity of the Phenotype in Patients with Mental Retardation Due to a Recurrent Copy-Number Gain at Xq28 Mediated by an Unusual Recombination

Genetic Characterization of a Human Skin Carcinoma Progression Model: from Primary Tumor to Metastasis Susanne Popp, Stefan Waltering, Petra Boukamp

A Definitive Haplotype Map as Determined by Genotyping Duplicated Haploid Genomes Finds a Predominant Haplotype Preference at Copy-Number Variation Events

Volume 41, Issue 2, Pages (January 2011)

Exon Array CGH: Detection of Copy-Number Changes at the Resolution of Individual Exons in the Human Genome Pawandeep Dhami, Alison J. Coffey, Stephen.

C. E. Browne, N. R. Dennis, E. Maher, F. L. Long, J. C. Nicholson, J

Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L

Exon Skipping in IVD RNA Processing in Isovaleric Acidemia Caused by Point Mutations in the Coding Region of the IVD Gene Jerry Vockley, Peter K. Rogan,

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints Scott Newman, Karen E. Hermetz,

High-Resolution Identification of Chromosomal Abnormalities Using Oligonucleotide Arrays Containing 116,204 SNPs Howard R. Slater, Dione K. Bailey, Hua.

Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males Hilde Van Esch, Marijke.

Sequence Homology between 4qter and 10qter Loci Facilitates the Instability of Subtelomeric KpnI Repeat Units Implicated in Facioscapulohumeral Muscular.

Presentation transcript:

Autosomal-Dominant Microtia Linked to Five Tandem Copies of a Copy-Number- Variable Region at Chromosome 4p16 Irina Balikova, Kevin Martens, Cindy Melotte, Mustapha Amyere, Steven Van Vooren, Yves Moreau, David Vetrie, Heike Fiegler, Nigel P. Carter, Thomas Liehr, Miikka Vikkula, Gert Matthijs, Jean-Pierre Fryns, Ingele Casteels, Koen Devriendt, Joris Robert Vermeesch The American Journal of Human Genetics Volume 82, Issue 1, Pages 181-187 (January 2008) DOI: 10.1016/j.ajhg.2007.08.001 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotype of the Patients (A) Right microtia, (B) imperforated nasolacrimal duct, (C) left-eye coloboma of the iris, and (D) chorioretinal coloboma. The American Journal of Human Genetics 2008 82, 181-187DOI: (10.1016/j.ajhg.2007.08.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Linkage of the Phenotype with 4p15-4p16.1 Primer sequences for linkage analysis were as published (GDB Human Genome Database). The region between the red lines is linked with the phenotype. Patients with eye coloboma are indicated by a filled upper-left square, patients with absent canaliculi are indicated by a filled lower-left square, and patients with microtia are indicated by filled upper- and lower-right squares. In those family members karyotyped, it is indicated whether only normal chromosomes 4 were identified (N) or an abnormal chromosome 4 was detected (4p+). No material was available from the II:9 family member. The American Journal of Human Genetics 2008 82, 181-187DOI: (10.1016/j.ajhg.2007.08.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 The LOD Score for Chromosome 4 Calculated from the 250K SNP Array Analysis of the Affected and Unaffected Family Members On the x axis is shown the position on chromosome 4 in megabases (Mb); on the y axis is shown the corresponding LOD score. (A) The LOD score for the entire chromosome 4. (B) Detailed view on the region from 1–25 Mb showing the maximum LOD score of 3.1–3.79 for the region from 8.2 to 21.0 Mb. The American Journal of Human Genetics 2008 82, 181-187DOI: (10.1016/j.ajhg.2007.08.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Identification of the Aberration on Chromosome 4 (A) Partial karyotype of the patient showing the G-banded normal and aberrant chromosome 4. On the right, an ideogram of a normal chromosome 4 is presented. (B) MFISH analysis showing that only genetic material from chromosome 4 is present in the 4p+. (C) Multicolor-banding FISH shows that the chromosome 4p cytogenetic anomaly is caused by the 4p15-16 region, and the pink band is larger on the altered chromosome than on normal one. (D) Tiling-path array of chromosome 4pter demonstrates the amplification. The red line indicates the 4 × the standard deviation (SD) threshold. (E) Copy-number analysis for Genechip (CNAG) view of copy-number analysis of chromosome 4 by 250K SNP array (Genome Laboratory, Tokyo University). Red spots represent log2 ratios of the signal intensities between the sample and the references for each SNP. The blue line shows the averaged log2 ratios and the green bar the heterozygous SNPs. The American Journal of Human Genetics 2008 82, 181-187DOI: (10.1016/j.ajhg.2007.08.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 5 Delineation of the Breakpoints of the Amplicon (A) FISH confirmation of the array CGH data and delineation of the CNV. FISH using (Aa) RP11-689P11 (not amplified), (Ab) RP11-637J21 and (Ae) RP11-751L19 (amplified at 4p16), and (Ac) RP11-264E23 and (Ad) RP11-180A12 (amplified at 4p and multiple loci scattered across the genome) is shown. (B) Ensembl view (Ensembl release 45, June 2007) for chr 4p16 (from 8.67 Mb to 9.57 Mb) showing the Ensembl genes, nc RNA genes, the tiling-path clones, and Redon CNV regions. (C) Q-PCR result showing the copy numbers of the family members and of the controls for the different primer pairs, estimated with the dCt method and p53 as a reference gene (primers 5′-CCCAAGCAATGGATGATTTGA-3′ and 5′-GAGCTTCATCTGGACCTGGGT-3′). The relative location of the primers to the amplified region is shown with colored bars. Dark blue is for the primer located at 8.6672 Mb, gray is for the one at 8.7802 Mb, purple is for the one at 9.4241 Mb, and light blue is for the one at 9.4242 Mb. The numbers indicating the family members are the same as in Figure 2. The colors in the graphic correspond to the different amplicons. The duplication control is a patient with t(4,8) with breakpoint at the ORGC region. The American Journal of Human Genetics 2008 82, 181-187DOI: (10.1016/j.ajhg.2007.08.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 6 Analysis of the Orientation of the Fragments (A) Schematic view of the different possible alleles: wild-type (“WT”), tandem (“T”), and inverted (“INV”). The black and gray horizontal arrows indicate the reverse and the forward primer from the distal and proximal side of the amplified region, respectively. PCR with different combination of primers was performed: forward distal and reverse proximal, only the forward proximal and only the reverse distal primers. The vertical black and gray arrows show relative position of the restriction sites for BglII and StuI, respectively. (B) PCR product generated from the first combination of primers, present in the patients and not present in the control. “L” indicates ladder. (C) Sequence fragment showing the breakpoint. “Ref b” indicates reference sequence from the beginning of the amplified region, “P” (patient) indicates sequence derived from the breakpoint spanning PCR, and “Ref e” indicates reference sequence from the end of the region. The 3 nucleotide sequence homology is indicated in the box. (D) Southern-blot analysis. Genomic DNA was digested with BglII and StuI enzymes, and the fragments were detected with a PCR-generated probe (primers 5′-CTAACATACCTGCTCTCATC-3′ and 5′-CTCTGGGAGTTCAGATCATT-3′). The horizontal arrows indicate the three possible alleles: wild-type (“WT”), tandem (“T”), and inverted (“INV”). For both enzymes, a presence of the wild-type and the tandem allele in the patients and absence of an inverted allele is shown. The unaffected family members and the controls have only the wild-type allele. The American Journal of Human Genetics 2008 82, 181-187DOI: (10.1016/j.ajhg.2007.08.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions