Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability
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Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability. / Verheije, Rosalind; Kupchik, Gabriel S; Isidor, Bertrand; Kroes, Hester Y; Lynch, Sally Ann; Hawkes, Lara; Hempel, Maja; Gelb, Bruce D; Ghoumid, Jamal; D'Amours, Guylaine; Chandler, Kate; Dubourg, Christèle; Loddo, Sara; Tümer, Zeynep; Shaw-Smith, Charles; Nizon, Mathilde; Shevell, Michael; Van Hoof, Evelien; Anyane-Yeboa, Kwame; Cerbone, Gaetana; Clayton-Smith, Jill; Cogné, Benjamin; Corre, Pierre; Corveleyn, Anniek; De Borre, Marie; Hjortshøj, Tina Duelund; Fradin, Mélanie; Gewillig, Marc; Goldmuntz, Elizabeth; Hens, Greet; Lemyre, Emmanuelle; Journel, Hubert; Kini, Usha; Kortüm, Fanny; Le Caignec, Cedric; Novelli, Antonio; Odent, Sylvie; Petit, Florence; Revah-Politi, Anya; Stong, Nicholas; Strom, Tim M; van Binsbergen, Ellen; Devriendt, Koenraad; Breckpot, Jeroen; DDD Study.
in: EUR J HUM GENET, Jahrgang 27, Nr. 2, 02.2019, S. 278-290.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability
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
AU - DDD Study
PY - 2019/2
Y1 - 2019/2
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.
KW - Journal Article
U2 - 10.1038/s41431-018-0281-5
DO - 10.1038/s41431-018-0281-5
M3 - SCORING: Journal article
C2 - 30291340
VL - 27
SP - 278
EP - 290
JO - EUR J HUM GENET
JF - EUR J HUM GENET
SN - 1018-4813
IS - 2
ER -