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

DDD Study

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalEuropean Journal of Human Genetics
DOIs
Publication statusE-pub ahead of print - Oct 5 2018

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Congenital Heart Defects
Intellectual Disability
Exome
Eyebrows
Haploinsufficiency
Chromosome Deletion
Gene Deletion
Cleft Palate
Genotype
Phenotype

Cite this

@article{643a6b3557314ff5b6017ba876ca14ae,
title = "Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability",
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.",
author = "{DDD Study} and Rosalind Verheije and Kupchik, {Gabriel S} and Bertrand Isidor and Kroes, {Hester Y} and Lynch, {Sally Ann} and Lara Hawkes and Maja Hempel and Gelb, {Bruce D} and Jamal Ghoumid and Guylaine D'Amours and Kate Chandler and Christ{\`e}le Dubourg and Sara Loddo and Zeynep T{\"u}mer and Charles Shaw-Smith and Mathilde Nizon and Michael Shevell and {Van Hoof}, Evelien and Kwame Anyane-Yeboa and Gaetana Cerbone and Jill Clayton-Smith and Benjamin Cogn{\'e} and Pierre Corre and Anniek Corveleyn and {De Borre}, Marie and Hjortsh{\o}j, {Tina Duelund} and M{\'e}lanie Fradin and Marc Gewillig and Elizabeth Goldmuntz and Greet Hens and Emmanuelle Lemyre and Hubert Journel and Usha Kini and Fanny Kort{\"u}m and {Le Caignec}, Cedric and Antonio Novelli and Sylvie Odent and Florence Petit and Anya Revah-Politi and Nicholas Stong and Strom, {Tim M} and {van Binsbergen}, Ellen and Koenraad Devriendt and Jeroen Breckpot",
year = "2018",
month = "10",
day = "5",
doi = "10.1038/s41431-018-0281-5",
language = "English",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability

AU - DDD Study

AU - Verheije, Rosalind

AU - Kupchik, Gabriel S

AU - Isidor, Bertrand

AU - Kroes, Hester Y

AU - Lynch, Sally Ann

AU - Hawkes, Lara

AU - Hempel, Maja

AU - Gelb, Bruce D

AU - Ghoumid, Jamal

AU - D'Amours, Guylaine

AU - Chandler, Kate

AU - Dubourg, Christèle

AU - Loddo, Sara

AU - Tümer, Zeynep

AU - Shaw-Smith, Charles

AU - Nizon, Mathilde

AU - Shevell, Michael

AU - Van Hoof, Evelien

AU - Anyane-Yeboa, Kwame

AU - Cerbone, Gaetana

AU - Clayton-Smith, Jill

AU - Cogné, Benjamin

AU - Corre, Pierre

AU - Corveleyn, Anniek

AU - De Borre, Marie

AU - Hjortshøj, Tina Duelund

AU - Fradin, Mélanie

AU - Gewillig, Marc

AU - Goldmuntz, Elizabeth

AU - Hens, Greet

AU - Lemyre, Emmanuelle

AU - Journel, Hubert

AU - Kini, Usha

AU - Kortüm, Fanny

AU - Le Caignec, Cedric

AU - Novelli, Antonio

AU - Odent, Sylvie

AU - Petit, Florence

AU - Revah-Politi, Anya

AU - Stong, Nicholas

AU - Strom, Tim M

AU - van Binsbergen, Ellen

AU - Devriendt, Koenraad

AU - Breckpot, Jeroen

PY - 2018/10/5

Y1 - 2018/10/5

N2 - 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.

AB - 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.

U2 - 10.1038/s41431-018-0281-5

DO - 10.1038/s41431-018-0281-5

M3 - Article

C2 - 30291340

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

ER -