scholarly journals A de novo 2.78-Mb duplication on chromosome 21q22.11 implicates candidate genes in the partial trisomy 21 phenotype

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
James D Weisfeld-Adams ◽  
Amanda K Tkachuk ◽  
Kenneth N Maclean ◽  
Naomi L Meeks ◽  
Stuart A Scott
Keyword(s):  
Candidate Genes ◽  
Clinical Features ◽  
Critical Region ◽  
Trisomy 21 ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Partial Trisomy ◽  
Chromosome 21 ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic

Abstract Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) and in the majority of cases is the result of complete trisomy 21. The hypothesis that the characteristic DS clinical features are due to a single DS critical region (DSCR) at distal chromosome 21q has been refuted by recently reported segmental trisomy 21 cases characterised by microarray-based comparative genomic hybridisation (aCGH). These rare cases have implicated multiple regions on chromosome 21 in the aetiology of distinct features of DS; however, the map of chromosome 21 copy-number aberrations and their associated phenotypes remains incompletely defined. We report a child with ID who was deemed very high risk for DS on antenatal screening (1 in 13) and has partial, but distinct, dysmorphologic features of DS without congenital heart disease (CHD). Oligonucleotide aCGH testing of the proband detected a previously unreported de novo 2.78-Mb duplication on chromosome 21q22.11 that includes 16 genes; however, this aberration does not harbour any of the historical DSCR genes (APP, DSCR1, DYRK1A and DSCAM). This informative case implicates previously under-recognised candidate genes (SOD1, SYNJ1 and ITSN1) in the pathogenesis of specific DS clinical features and supports a critical region for CHD located more distal on chromosome 21q. In addition, this unique case illustrates how the increasing resolution of microarray and high-throughput sequencing technologies can continue to reveal new biology and enhance understanding of widely studied genetic diseases that were originally described over 50 years ago.

scholarly journals Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR‐DSCR) on human chromosome 21

2019 ◽  
Vol 7 (8) ◽  
Author(s):  
Maria Chiara Pelleri ◽  
Elena Cicchini ◽  
Michael B. Petersen ◽  
Lisbeth Tranebjærg ◽  
Teresa Mattina ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Human Chromosome ◽  
Critical Region ◽  
Trisomy 21 ◽  
Partial Trisomy ◽  
Chromosome 21 ◽  
Human Chromosome 21

scholarly journals Erratum: A de novo 2.78-Mb duplication on chromosome 21q22.11 implicates candidate genes in the partial trisomy 21 phenotype

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
James D Weisfeld-Adams ◽  
Amanda K Tkachuk ◽  
Kenneth N Maclean ◽  
Naomi L Meeks ◽  
Stuart A Scott
Keyword(s):  
Candidate Genes ◽  
Trisomy 21 ◽  
De Novo ◽  
Partial Trisomy

RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3735-3741 ◽  
Author(s):  
Catherine Roche-Lestienne ◽  
Lauréline Deluche ◽  
Sélim Corm ◽  
Isabelle Tigaud ◽  
Sami Joha ◽  
...  
Keyword(s):  
Dna Binding ◽  
High Frequency ◽  
Trisomy 21 ◽  
De Novo ◽  
Blast Crisis ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Chromosome 21 ◽  
Imatinib Resistance ◽  
Molecular Abnormalities

Abstract Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.

De novo monosomy 9p24.3-pter and trisomy 17q24.3-qter characterised by microarray comparative genomic hybridisation in a fetus with an increased nuchal translucency

2006 ◽  
Vol 26 (3) ◽  
pp. 206-213 ◽  
Author(s):  
Sophie Brisset ◽  
Serdar Kasakyan ◽  
Aurore Coulomb L'Herminé ◽  
Valérie Mairovitz ◽  
Evelyne Gautier ◽  
...  
Keyword(s):  
De Novo ◽  
Nuchal Translucency ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Increased Nuchal Translucency

scholarly journals Systematic analysis of copy number variation associated with congenital diaphragmatic hernia

2018 ◽  
Vol 115 (20) ◽  
pp. 5247-5252 ◽  
Author(s):  
Qihui Zhu ◽  
Frances A. High ◽  
Chengsheng Zhang ◽  
Eliza Cerveira ◽  
Meaghan K. Russell ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Candidate Genes ◽  
Birth Defects ◽  
Diaphragmatic Hernia ◽  
Copy Number ◽  
Large Scale ◽  
De Novo ◽  
Comparative Genomic ◽  
High Morbidity ◽  
Systematic Analysis

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B. We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects.

Constitutional de novo deletion CNV encompassing REST predisposes to diffuse hyperplastic perilobar nephroblastomatosis (HPLN)

2020 ◽  
pp. jmedgenet-2020-107087
Author(s):  
Zerin Hyder ◽  
Adele Fairclough ◽  
Mike Groom ◽  
Joan Getty ◽  
Elizabeth Alexander ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Cancer Predisposition ◽  
Tumour Suppressor ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Predisposition Genes ◽  
Work Up

BackgroundNephroblastomatosis is a recognised precursor for the development of Wilms tumour (WT), the most common childhood renal tumour. While the majority of WT is sporadic in origin, germline intragenic mutations of predisposition genes such as WT1, REST and TRIM28 have been described in apparently isolated (non-familial) WT.Despite constitutional CNVs being a well-studied cause of developmental disorders, their role in cancer predisposition is less well defined, so that the interpretation of cancer risks associated with specific CNVs can be complex.ObjectiveTo highlight the role of a constitutional deletion CNV (delCNV) encompassing the REST tumour suppressor gene in diffuse hyperplastic perilobar nephroblastomatosis (HPLN).Methods/resultsArray comparative genomic hybridisation in an infant presenting with apparently sporadic diffuse HPLN revealed a de novo germline CNV, arr[GRCh37] 4q12(57,385,330–57,947,405)x1. The REST tumour suppressor gene is located at GRCh37 chr4:57,774,042–57,802,010.ConclusionThis delCNV encompassing REST is associated with nephroblastomatosis. Deletion studies should be included in the molecular work-up of inherited predisposition to WT/nephroblastomatosis. Detection of delCNVs involving known cancer predisposition genes can yield insights into the relationship between underlying genomic architecture and associated tumour risk.

scholarly journals Organization Features of the Mitochondrial Genome of Sunflower (Helianthus annuus L.) with ANN2-Type Male-Sterile Cytoplasm

Plants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 439 ◽  
Author(s):  
Maksim S. Makarenko ◽  
Alexander V. Usatov ◽  
Tatiana V. Tatarinova ◽  
Kirill V. Azarin ◽  
Maria D. Logacheva ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Male Sterility ◽  
Helianthus Annuus ◽  
Candidate Genes ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Simultaneous Action ◽  
Male Sterile ◽  
Helianthus Annuus L ◽  
Sunflower Line

This study provides insights into the flexibility of the mitochondrial genome in sunflower (Helianthus annuus L.) as well as into the causes of ANN2-type cytoplasmic male sterility (CMS). De novo assembly of the mitochondrial genome of male-sterile HA89(ANN2) sunflower line was performed using high-throughput sequencing technologies. Analysis of CMS ANN2 mitochondrial DNA sequence revealed the following reorganization events: twelve rearrangements, seven insertions, and nine deletions. Comparisons of coding sequences from the male-sterile line with the male-fertile line identified a deletion of orf777 and seven new transcriptionally active open reading frames (ORFs): orf324, orf327, orf345, orf558, orf891, orf933, orf1197. Three of these ORFs represent chimeric genes involving atp6 (orf1197), cox2 (orf558), and nad6 (orf891). In addition, orf558, orf891, orf1197, as well as orf933, encode proteins containing membrane domain(s), making them the most likely candidate genes for CMS development in ANN2. Although the investigated CMS phenotype may be caused by simultaneous action of several candidate genes, we assume that orf1197 plays a major role in developing male sterility in ANN2. Comparative analysis of mitogenome organization in sunflower lines representing different CMS sources also allowed identification of reorganization hot spots in the mitochondrial genome of sunflower.

scholarly journals A New Case of 13q12.2q13.1 Microdeletion Syndrome Contributes to Phenotype Delineation

2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Giorgia Mandrile ◽  
Eleonora Di Gregorio ◽  
Alessandro Calcia ◽  
Alessandro Brussino ◽  
Enrico Grosso ◽  
...  
Keyword(s):  
Clinical Features ◽  
Critical Region ◽  
Array Cgh ◽  
De Novo ◽  
Genetic Disorder ◽  
Phenotypic Expression ◽  
Microdeletion Syndrome ◽  
Complex Rearrangement

A recently described genetic disorder has been associated with 13q12.3 microdeletion spanning three genes, namely,KATNAL1, LINC00426, andHMGB1. Here, we report a new case with similar clinical features that we have followed from birth to 5 years old. The child carried a complex rearrangement with a double translocation: 46,XX,t(7;13)(p15;q14),t(11;15)(q23;q22). Array-CGH identified ade novomicrodeletion at 13q12.2q13.1 spanning 3–3.4 Mb and overlapping 13q12.3 critical region. Clinical features resembling those reported in the literature confirm the existence of a distinct 13q12.3 microdeletion syndrome and provide further evidence that is useful to characterize its phenotypic expression during the 5 years of development.

scholarly journals Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

2014 ◽  
Vol 171 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Ana P M Canton ◽  
Sílvia S Costa ◽  
Tatiane C Rodrigues ◽  
Debora R Bertola ◽  
Alexsandra C Malaquias ◽  
...  
Keyword(s):  
Short Stature ◽  
Candidate Genes ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Comparative Genomic ◽  
Growth Disorders ◽  
Genomic Regions

BackgroundThe etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders.ObjectiveTo analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause.Patients and methodsA total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature.ResultsIn 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation.ConclusionPathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

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