Format

Send to

Choose Destination
Eur J Hum Genet. 2019 Feb;27(2):278-290. doi: 10.1038/s41431-018-0281-5. Epub 2018 Oct 5.

Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability.

Author information

1
Center for Human Genetics, Catholic University Leuven, Leuven, Belgium.
2
Division of Medical Genetics, Infants and Children's Hospital of Brooklyn, Maimonides Medical Center, Brooklyn, NY, USA.
3
CHU Nantes, Service de génétique médicale, Nantes, France.
4
INSERM UMR 1238, Sarcomes osseux et remodelage des tissus calcifiés, Université Bretagne Loire, Nantes, France.
5
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
6
Departments of Clinical Genetics, Children's University Hospital Temple Street, Dublin, Ireland.
7
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
8
Spires Cleft Service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
9
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
10
The Mindich Child Health and Development Institute and the Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
11
Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.
12
Service de génétique médicale, CHU Sainte-Justine, Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada.
13
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
14
Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes, France.
15
Laboratory of Medical Genetics, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.
16
Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark.
17
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK.
18
Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
19
Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
20
Division of Medical Genetics, "S.G. Moscati" Hospital, Avellino, Italy.
21
Service de Stomatologie, CHU Nantes, Nantes, France.
22
Service de Génétique Médicale, Centre de Reference Anomalies du Développement, CHU Rennes, Rennes, France.
23
Pediatric and Congenital Cardiology, UZ Leuven, Leuven, Belgium.
24
Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
25
Department of Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium.
26
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
27
Institute for Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
28
Institute for Human Genetics, Technische Universitat Munchen, Munich, Germany.
29
Center for Human Genetics, Catholic University Leuven, Leuven, Belgium. Jeroen.Breckpot@uzleuven.be.

Abstract

Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype-phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.

PMID:
30291340
PMCID:
PMC6336847
DOI:
10.1038/s41431-018-0281-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center