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

Rosalind Verheije, Gabriel S. Kupchik, Bertrand Isidor, Hester Y. Kroes, Sally Ann Lynch, Lara Hawkes, Maja Hempel, Bruce D. Gelb, Jamal Ghoumid, Guylaine D’amours, Kate Chandler, Christèle Dubourg, Sara Loddo, Zeynep Tümer, Charles Shaw-smith, Mathilde Nizon, Michael Shevell, Evelien Van Hoof, Kwame Anyane-yeboa, Gaetana CerboneJill Clayton-smith, Benjamin Cogné, Pierre Corre, Anniek Corveleyn, Marie De Borre, Tina Duelund Hjortshøj, Mélanie Fradin, Marc Gewillig, Elizabeth Goldmuntz, Greet Hens, Emmanuelle Lemyre, Hubert Journel, Usha Kini, Fanny Kortüm, Cedric Le Caignec, Antonio Novelli, Sylvie Odent, Florence Petit, Anya Revah-politi, Nicholas Stong, Tim M. Strom, Ellen Van Binsbergen, Koenraad Devriendt, Jeroen Breckpot

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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
Pages (from-to)278-290
Number of pages13
JournalEuropean Journal of Human Genetics
Volume27
Issue number2
Early online date5 Oct 2018
DOIs
Publication statusPublished - 1 Feb 2019

Keywords

  • Adolescent
  • Child
  • Child, Preschool
  • Cleft Palate/genetics
  • Female
  • Heart Defects, Congenital/genetics
  • Heterozygote
  • Homeodomain Proteins/genetics
  • Humans
  • Intellectual Disability/genetics
  • Loss of Function Mutation
  • Male
  • Phenotype
  • Syndrome
  • Transcription Factors/genetics
  • Young Adult

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