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Genet Med. 2019 Mar;21(3):663-675. doi: 10.1038/s41436-018-0085-6. Epub 2018 Aug 30.

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA.
2
Baylor Genetics, Houston, Texas, 77021, USA.
3
Texas Children's Hospital, Houston, Texas, 77030, USA.
4
Department of Pediatrics, Section of Child Neurology, Baylor College of Medicine, Houston, Texas, 77030, USA.
5
Seattle Children's Hospital, Seattle, Washington, 98105, USA.
6
Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, 98105, USA.
7
University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.
8
Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital, Gladstone Road, Exeter, EX1 2ED, UK.
9
Clinical Genetics Service, NHS Grampian, Aberdeen, AB25 2ZA, Scotland.
10
Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, 14642, USA.
11
Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, 43205, USA.
12
Division of Medical Genetics, Stanford University, Stanford, California, 94305, USA.
13
Rare Disease Institute, Children's National Health System, Washington, DC, 20010, USA.
14
Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, 15224, USA.
15
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
16
Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, 0424, Oslo, Norway.
17
Department of Medical Genetics, Telemark Hospital Trust, 3710, Skien, Norway.
18
New Leaf Center, Clinic for Special Children, Mt. Eaton, Ohio, 44659, USA.
19
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.
20
Dell Children's Medical Center of Central Texas, Austin, Texas, 78723, USA.
21
Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.
22
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
23
Center for Rare Diseases, University Hospital Cologne, Cologne, Germany.
24
Center for Human Genetics, Department of Human Genetics, KU Leuven, 3000, Leuven, Belgium.
25
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA.
26
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA. pengfei.liu@bcm.edu.
27
Baylor Genetics, Houston, Texas, 77021, USA. pengfei.liu@bcm.edu.

Abstract

PURPOSE:

Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

METHODS:

We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

RESULTS:

Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

CONCLUSION:

CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

KEYWORDS:

Atypical cohesinopathies; Clinical exome sequencing (CES); Cohesin pathway; STAG1; STAG2

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