ArticleAmerican journal of human genetics2020
Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 2 of them syntheses that pooled it.
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41citing papers in PubMed, 2 pooled it
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Who cites it
41 citing papers in PubMed, 2 syntheses or guidelines pooled it, 73 citations in OpenAlex.
- Correlation between 22q11.2 deletion syndrome phenotype and deletion location: a meta-analysis.Archives of gynecology and obstetrics · 2025Pooled it
- Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits.Genome medicine · 2022Pooled it
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- Non-coding RNAs in congenital heart disease and placental development: Bridging molecular mechanisms to clinical biomarkers and therapies.Non-coding RNA research · 2026Review
- Neurodevelopment in congenital heart disease: a review of antenatal mechanisms and therapeutic potentials.Pediatric research · 2025Review
- Prenatal diagnostic value of medium-coverage WGS and clinical Exome sequencing in fetal congenital heart disease.Future science OA · 2025Article
- Mexican Patients With Suspected 22q11.2 Deletion Syndrome: Clinical Characterization and Molecular Findings by Fluorescence In Situ Hybridization and Multiplex Ligation-Dependent Probe Amplification.Molecular genetics & genomic medicine · 2025Article
- Maternal Genotype and Dietary Vitamin A Modify Aortic Arch Phenotypes in a Mouse Model of 22q11DS.International journal of molecular sciences · 2025Article
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- Solitary median maxillary central incisor syndrome caused by 22q11.2 microdeletion.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2025Article
- Prenatal cardiac findings and 22q11.2 deletion syndrome: Fetal detection and evaluation.Prenatal diagnosis · 2024Review
- A regulatory variant impacting TBX1 expression contributes to basicranial morphology in Homo sapiens.American journal of human genetics · 2024Article
- Untargeted metabolomic, and proteomic analysis identifies metabolic biomarkers and pathway alterations in individuals with 22q11.2 deletion syndrome.Metabolomics : Official journal of the Metabolomic Society · 2024Article
- In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease.International journal of molecular sciences · 2024Review
- Human Genetics of Truncus Arteriosus.Advances in experimental medicine and biology · 2024Review
- Variants in Candidate Genes for Phenotype Heterogeneity in Patients with the 22q11.2 Deletion Syndrome.Genetics research · 2024Article
- Clinically Relevant Genetic Considerations for Patients With Tetralogy of Fallot.CJC pediatric and congenital heart disease · 2023Review
- Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.NPJ genomic medicine · 2023Article
- Chromosome 22q11.2 Deletion Syndrome: A Comprehensive Review of Molecular Genetics in the Context of Multidisciplinary Clinical Approach.International journal of molecular sciences · 2023Review
- Article
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Authors and funding
52 authors at 20 institutions in 13 countries.
Yingjie ZhaoDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Alexander DiacouDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
H Richard JohnstonDepartment of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Fadi I MusfeeDepartment of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, Texas 77225, USA.
Donna M McDonald-McGinnDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Daniel McGinnDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
T Blaine CrowleyDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Gabriela M RepettoCenter for Genetics and Genomics, Facultad de Medicina Clinica Alemana-Universidad del Desarrollo, Santiago 7710162, Chile.
Ann SwillenCenter for Human Genetics, University of Leuven (KU Leuven), Leuven 3000, Belgium.
Jeroen BreckpotCenter for Human Genetics, University of Leuven (KU Leuven), Leuven 3000, Belgium.
Joris R VermeeschCenter for Human Genetics, University of Leuven (KU Leuven), Leuven 3000, Belgium.
Wendy R KatesDepartment of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY 13202, USA; Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY 13202, USA.
M Cristina DigilioDepartment of Medical Genetics, Bambino Gesù Hospital, Rome 00165, Italy.
Marta UnoltDepartment of Medical Genetics, Bambino Gesù Hospital, Rome 00165, Italy; Department of Pediatrics, Gynecology, and Obstetrics, La Sapienza University of Rome, Rome 00185, Italy.
Bruno MarinoDepartment of Pediatrics, Gynecology, and Obstetrics, La Sapienza University of Rome, Rome 00185, Italy.
Maria PontilloDepartment of Neuroscience, Bambino Gesù Hospital, Rome 00165, Italy.
Marco ArmandoDepartment of Neuroscience, Bambino Gesù Hospital, Rome 00165, Italy; Developmental Imaging and Psychopathology Lab, University of Geneva, Geneva 1211, Switzerland.
Fabio Di FabioDepartment of Pediatrics, Gynecology, and Obstetrics, La Sapienza University of Rome, Rome 00185, Italy.
Stefano VicariDepartment of Neuroscience, Bambino Gesù Hospital, Rome 00165, Italy; Department of Psychiatry, Catholic University, Rome 00153, Italy.
Marianne van den BreeMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales CF24 4HQ, UK.
Hayley MossMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales CF24 4HQ, UK.
Michael J OwenMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales CF24 4HQ, UK.
Kieran C MurphyDepartment of Psychiatry, Royal College of Surgeons in Ireland, Dublin 505095, Ireland.
Clodagh M MurphyDepartment of Forensic and Neurodevelopmental Sciences, King's College London, Institute of Psychiatry, Psychology, and Neuroscience, London SE5 8AF, UK; Behavioural and Developmental Psychiatry Clinical Academic Group, Behavioural Genetics Clinic, National Adult Autism and ADHD Service, South London and Maudsley Foundation National Health Service Trust, London SE5 8AZ, UK.
Declan MurphyDepartment of Forensic and Neurodevelopmental Sciences, King's College London, Institute of Psychiatry, Psychology, and Neuroscience, London SE5 8AF, UK; Behavioural and Developmental Psychiatry Clinical Academic Group, Behavioural Genetics Clinic, National Adult Autism and ADHD Service, South London and Maudsley Foundation National Health Service Trust, London SE5 8AZ, UK.
Kelly SchochDepartment of Pediatrics, Duke University, Durham, NC 27710, USA.
Vandana ShashiDepartment of Pediatrics, Duke University, Durham, NC 27710, USA.
Flora TassoneDepartment of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Davis, CA 95817, USA.
Tony J SimonDepartment of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Davis, CA 95817, USA.
Robert J ShprintzenThe Virtual Center for Velo-Cardio-Facial Syndrome, Syracuse, NY 13206, USA.
Linda CampbellSchool of Psychology, University of Newcastle, Newcastle 2258, Australia.
Nicole PhilipDepartment of Medical Genetics, Aix-Marseille University, Marseille 13284, France.
Damian Heine-SuñerGenomics of Health and Unit of Molecular Diagnosis and Clinical Genetics, Son Espases University Hospital, Balearic Islands Health Research Institute, Palma de Mallorca 07120, Spain.
Sixto García-MiñaúrInstitute of Medical and Molecular Genetics, University Hospital La Paz, Madrid 28046, Spain.
Luis FernándezInstitute of Medical and Molecular Genetics, University Hospital La Paz, Madrid 28046, Spain.
International 22q11.2 Brain and Behavior ConsortiumSee Table S1.
Carrie E BeardenDepartment of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Claudia VingerhoetsDepartment of Psychiatry and Psychology, Maastricht University, Maastricht, 6200 MD, the Netherlands.
Therese van AmelsvoortDepartment of Psychiatry and Psychology, Maastricht University, Maastricht, 6200 MD, the Netherlands.
Stephan EliezDevelopmental Imaging and Psychopathology Lab, University of Geneva, Geneva 1211, Switzerland.
Maude SchneiderDevelopmental Imaging and Psychopathology Lab, University of Geneva, Geneva 1211, Switzerland.
Jacob A S VorstmanProgram in Genetics and Genome Biology, Research Institute, Toronto, Ontario, Canada; Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht, 3584 CG, the Netherlands.
Doron GothelfThe Child Psychiatry Unit, Edmond and Lily Sapfra Children's Hospital, Sackler Faculty of Medicine, Tel Aviv University and Sheba Medical Center, Tel Aviv, 52621, Israel.
Elaine ZackaiDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
A J AgopianDepartment of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, Texas 77225, USA.
Raquel E GurDepartment of Psychiatry, Perelman School of Medicine of the University of Pennsylvania Philadelphia, PA 19104, USA; Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Anne S BassettDalglish Family 22q Clinic, Clinical Genetics Research Program, Toronto M5T 1L8, Ontario Canada; Toronto General Hospital, Centre for Addiction and Mental Health, Toronto M5T 1L8, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto M5T 1L8, Ontario, Canada.
Beverly S EmanuelDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Elizabeth GoldmuntzDivision of Cardiology, Children's Hospital of Philadelphia Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Laura E MitchellDepartment of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, Texas 77225, USA.
Tao WangDepartment of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Bernice E MorrowDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: bernice.morrow@einsteinmed.org.
Children's Hospital of Philadelphia · USAlbert Einstein College of Medicine · USUniversity of Geneva · CHUniversity of Texas Health Science Center at Dallas · USMaastricht University · NLBambino Gesù Children's Hospital · ITCardiff University · GBHospital Universitario La Paz · ESKU Leuven · BESapienza University of Rome · ITCentre for Addiction and Mental Health · CADuke University · USNational Health Service · GBTel Aviv University · ILUniversity of California, Davis · USUniversity of California, Los Angeles · USUniversity of Toronto · CAAix-Marseille Université · FREmory University · USHealth Research Institute of the Balearic Islands · ES
Funding
Project 2: Genetic Mechanisms of Non-syndromic Congenital Cardiac DefectsP01HD070454 · NICHD · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI MORROW, BERNICE E · 2011 to 2020
$14.0M2/5 International Consortium on Brain and Behavior in 22q11.2 Deletion SyndromeU01MH101720 · NIMH · EMORY UNIVERSITY · PI WARREN, STEPHEN T. · 2013 to 2016
$6.2MNeurodevelopment and Psychosis in the 22q11.2 Deletion SyndromeR01MH085953 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI BEARDEN, CARRIE E · 2010 to 2020
$6.2MSupport for the Rose F. Kennedy IDDRCU54HD090260 · NICHD · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI WALKLEY, STEVEN UPSHAW · 2016 to 2020
$6.0MGenetic Modifiers for 22q 11.2 Deletion SyndromeR01HL084410 · NHLBI · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI MORROW, BERNICE E · 2007 to 2010
$3.3MMolecular aspects of CRKL in heart development and human diseaseR01HL132577 · NHLBI · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI MORROW, BERNICE E, ZHOU, BIN · 2016 to 2019
$3.2MNeurodevelopment and Psychosis in the 22q11.2 Copy Number VariantsR37MH085953 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CARRIE E BEARDEN · 2023 to 2026
$2.9MMedical Research Council MR/L010305/1Medical Research Council MR/N026063/1NHLBI NIH HHS R01 HL084410NHLBI NIH HHS R01 HL132577NICHD NIH HHS P01 HD070454NICHD NIH HHS U54 HD090260NIMH NIH HHS R37 MH085953NIMH NIH HHS U01 MH101720
Abstract
The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10
Indexed as
Chromosome DeletionPolymorphism, Single NucleotideCase-Control StudiesChromosomes, Human, Pair 22Cohort StudiesFemaleGenome-Wide Association StudyHeart Defects, CongenitalHumansLinkage DisequilibriumMalePhenotypeProto-Oncogene MasSegmental Duplications, GenomicProto-Oncogene Maschromosome 22q11.2 deletion syndromecomplex traitcongenital heart diseaseconotruncal heart defectscopy number variationCRKLDiGeorge syndromegenetic associationgenetic modifierhaploinsufficiencyTBX1
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