Variants in MEIS2 were first reported in relation to syndromic intellectual disability by Johannson et al. in 2014 (PMID: 24678003). The authors identified a 58 kb intragenic, tandem duplication of exon 9 and the flanking intronic region that was predicted to result in a frameshift and protein truncation in a mother and three children with syndromic intellectual disability. Since that time, additional publications have described individuals with variants in the MEIS2 gene. Clinical features in affected individuals with MEIS2 variants include palatal defects, intellectual disability, autism spectrum disorder, dysmorphic features, gastroesophageal reflux, and various types of structural congenital heart disease, including atrial septal defect, ventricular septal defect, coarctation of aorta, and tetralogy of Fallot.
MEIS2 is a member of the Three Amino-acid Loop Extension (TALE) family and encodes a homeodomain-containing transcription factor. At least 27 probands with MEIS2 variants have been reported in the literature. At least three intragenic copy number variants have been reported in three probands (PMIDs: 20425846, 24678003, 28934986), 13 unique nonsense, canonical splice-site, and frameshift variants have been reported in 15 probands (PMIDs: 27225850, 27479907, 30291340, 30735726, 31452935, 32345733, 33004838, 33722742), six unique missense variants have been reported in seven probands (PMIDs: 29322350, 30055086, 30291340, 33427397), and one in-frame deletion in two probands (PMIDs: 25712757, 33091211). Missense variants cluster in the homeodomain alpha helices (PMID: 30055086). The mechanism of pathogenicity is loss of function. Variants are de novo in a majority of probands though inheritance from an unaffected parent with low-level mosaicism and mildly affected parent have been reported (PMIDs: 24678003, 33091211, 33722742). This gene-disease association is also supported by experimental evidence, including mouse (PMIDs: 26545946, 32169905) and zebrafish models (PMIDs: 22981225, 23559552).
In summary, there is definitive evidence to support the relationship between MEIS2 and autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on April 22, 2022 (SOP Version 8). As of June 2024, this record underwent administrative updates to include additional information about the cardiac presentation oif this condition which was provided by the Congenital Heart Disease GCEP. No new evidence was added or scored.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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