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Am J Hum Genet. 2020 Jan 2;106(1):26-40. doi: 10.1016/j.ajhg.2019.11.010. Epub 2019 Dec 20.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

Author information

1
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
2
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
3
Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, Texas 77225, USA.
4
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
5
Center for Genetics and Genomics, Facultad de Medicina Clinica Alemana-Universidad del Desarrollo, Santiago 7710162, Chile.
6
Center for Human Genetics, University of Leuven (KU Leuven), Leuven 3000, Belgium.
7
Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY 13202, USA; Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY 13202, USA.
8
Department of Medical Genetics, Bambino Gesù Hospital, Rome 00165, Italy.
9
Department of Medical Genetics, Bambino Gesù Hospital, Rome 00165, Italy; Department of Pediatrics, Gynecology, and Obstetrics, La Sapienza University of Rome, Rome 00185, Italy.
10
Department of Pediatrics, Gynecology, and Obstetrics, La Sapienza University of Rome, Rome 00185, Italy.
11
Department of Neuroscience, Bambino Gesù Hospital, Rome 00165, Italy.
12
Department of Neuroscience, Bambino Gesù Hospital, Rome 00165, Italy; Developmental Imaging and Psychopathology Lab, University of Geneva, Geneva 1211, Switzerland.
13
Department of Neuroscience, Bambino Gesù Hospital, Rome 00165, Italy; Department of Psychiatry, Catholic University, Rome 00153, Italy.
14
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales CF24 4HQ, UK.
15
Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 505095, Ireland.
16
Department 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.
17
Department of Pediatrics, Duke University, Durham, NC 27710, USA.
18
Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Davis, CA 95817, USA.
19
The Virtual Center for Velo-Cardio-Facial Syndrome, Syracuse, NY 13206, USA.
20
School of Psychology, University of Newcastle, Newcastle 2258, Australia.
21
Department of Medical Genetics, Aix-Marseille University, Marseille 13284, France.
22
Genomics of Health and Unit of Molecular Diagnosis and Clinical Genetics, Son Espases University Hospital, Balearic Islands Health Research Institute, Palma de Mallorca 07120, Spain.
23
Institute of Medical and Molecular Genetics, University Hospital La Paz, Madrid 28046, Spain.
24
See Table S1.
25
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095, USA.
26
Department of Psychiatry and Psychology, Maastricht University, Maastricht, 6200 MD, the Netherlands.
27
Developmental Imaging and Psychopathology Lab, University of Geneva, Geneva 1211, Switzerland.
28
Program 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.
29
The 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.
30
Department of Psychiatry, Perelman School of Medicine of the University of Pennsylvania Philadelphia, PA 19104, USA; Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
31
Dalglish 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.
32
Division 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.
33
Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
34
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: bernice.morrow@einsteinmed.org.

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 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

KEYWORDS:

CRKL; DiGeorge syndrome; TBX1; chromosome 22q11.2 deletion syndrome; complex trait; congenital heart disease; conotruncal heart defects; copy number variation; genetic association; genetic modifier; haploinsufficiency

PMID:
31870554
DOI:
10.1016/j.ajhg.2019.11.010

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