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

Article metrics

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Erdogan F, Ullmann R, Chen W, et al. Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome "tiling path" BAC array in a girl with heart defect, cleft palate, and developmental delay. Am J Med Genet A. 2007;143A:172–8.

  2. 2.

    Brunetti-Pierri N, Sahoo T, Frioux S, et al. 15q13q14 deletions: phenotypic characterization and molecular delineation by comparative genomic hybridization. Am J Med Genet A. 2008;146A:1933–41.

  3. 3.

    Chen CP, Lin SP, Tsai FJ, Chern SR, Lee CC, Wang W. A 5.6-Mb deletion in 15q14 in a boy with speech and language disorder, cleft palate, epilepsy, a ventricular septal defect, mental retardation and developmental delay. Eur J Med Genet. 2008;51:368–72.

  4. 4.

    Crowley MA, Conlin LK, Zackai EH, Deardorff MA, Thiel BD, Spinner NB. Further evidence for the possible role of MEIS2 in the development of cleft palate and cardiac septum. Am J Med Genet A. 2010;152A:1326–7.

  5. 5.

    Roberti MC, Surace C, Digilio MC, et al. Complex chromosome rearrangements related 15q14 microdeletion plays a relevant role in phenotype expression and delineates a novel recurrent syndrome. Orphanet J Rare Dis. 2011;6:17.

  6. 6.

    Johansson S, Berland S, Gradek GA, et al. Haploinsufficiency of MEIS2 is associated with orofacial clefting and learning disability. Am J Med Genet A. 2014;164A:1622–6.

  7. 7.

    Chen CP, Chen CY, Chern SR, et al. Prenatal diagnosis and molecular cytogenetic characterization of a de novo 4.858-Mb microdeletion in 15q14 associated with ACTC1 and MEIS2 haploinsufficiency and tetralogy of Fallot. Taiwan J Obstet Gynecol. 2016;55:270–4.

  8. 8.

    Shimojima K, Ondo Y, Okamoto N, Yamamoto T. A 15q14 microdeletion involving MEIS2 identified in a patient with autism spectrum disorder. Hum Genome Var. 2017;4:17029.

  9. 9.

    Gambin T, Yuan B, Bi W, et al. Identification of novel candidate disease genes from de novo exonic copy number variants. Genome Med. 2017;9:83.

  10. 10.

    Louw JJ, Corveleyn A, Jia Y, Hens G, Gewillig M, Devriendt K. MEIS2 involvement in cardiac development, cleft palate, and intellectual disability. Am J Med Genet A. 2015;167A:1142–6.

  11. 11.

    Fujita A, Isidor B, Piloquet H, et al. De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux. J Hum Genet. 2016;61:835–8.

  12. 12.

    Larsen KB, Lutterodt MC, Laursen H, et al. Spatiotemporal distribution of PAX6 and MEIS2 expression and total cell numbers in the ganglionic eminence in the early developing human forebrain. Dev Neurosci. 2010;32:149–62.

  13. 13.

    Zerucha T, Prince VE. Cloning and developmental expression of a zebrafish meis2 homeobox gene. Mech Dev. 2001;102:247–50.

  14. 14.

    Melvin VS, Feng W, Hernandez-Lagunas L, Artinger KB, Williams T. A morpholino-based screen to identify novel genes involved in craniofacial morphogenesis. Dev Dyn. 2013;242:817–31.

  15. 15.

    Glickman NS, Yelon D. Cardiac development in zebrafish: coordination of form and function. Semin Cell Dev Biol. 2002;13:507–13.

  16. 16.

    Paige SL, Thomas S, Stoick-Cooper CL, et al. A temporal chromatin signature in human embryonic stem cells identifies regulators of cardiac development. Cell. 2012;151:221–32.

  17. 17.

    Machon O, Masek J, Machonova O, Krauss S, Kozmik Z. Meis2 is essential for cranial and cardiac neural crest development. BMC Dev Biol. 2015;15:40.

  18. 18.

    Kupchik GS, Revah-Politi A, Stong N, Anyane-Yeboa K. Expanding genotype and phenotype of MEIS2-related neurocristopathy (P11.070B). Presented at the European Society of Human Genetics 28 May 2017, Copenhagen, Denmark.

  19. 19.

    Wright CF, Fitzgerald TW, Jones WD, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015;385:1305–14.

  20. 20.

    Homsy J, Zaidi S, Shen Y, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350:1262–6.

  21. 21.

    Firth HV, Richards SM, Bevan AP, et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources. Am J Hum Genet. 2009;84:524–33.

  22. 22.

    Ioannidis NM, Rothstein JH, Pejaver V, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877–85.

  23. 23.

    Belcaro C, Dipresa S, Morini G, Pecile V, Skabar A, Fabretto A. CTNND2 deletion and intellectual disability. Gene. 2015;565:146–9.

  24. 24.

    Kumar R, Corbett MA, van Bon BW, et al. THOC2 mutations implicate mRNA-export pathway in X-linked intellectual disability. Am J Hum Genet. 2015;97:302–10.

  25. 25.

    Rigaud S, Fondaneche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444:110–4.

  26. 26.

    Di Benedetto D, Musumeci SA, Avola E, et al. Definition of minimal duplicated region encompassing the XIAP and STAG2 genes in the Xq25 microduplication syndrome. Am J Med Genet A. 2014;164A:1923–30.

  27. 27.

    Krissinel E, Henrick K. Inference of macromolecular assemblies from crystalline state. J Mol Biol. 2007;372:774–97.

  28. 28.

    Posey JE, Harel T, Liu P, et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017;376:21–31.

  29. 29.

    Donnai D, Barrow M. Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder? Am J Med Genet. 1993;47:679–82.

  30. 30.

    Le Fevre AK, Taylor S, Malek NH, et al. FOXP1 mutations cause intellectual disability and a recognizable phenotype. Am J Med Genet A. 2013;161A:3166–75.

  31. 31.

    Hamdan FF, Daoud H, Rochefort D, et al. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet. 2010;87:671–8.

  32. 32.

    Chang SW, Mislankar M, Misra C, et al. Genetic abnormalities in FOXP1 are associated with congenital heart defects. Hum Mutat. 2013;34:1226–30.

  33. 33.

    Brems H, Chmara M, Sahbatou M, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39:1120–6.

  34. 34.

    Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

  35. 35.

    Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

Download references

Acknowledgements

We thank the patients and their parents for their cooperation. J.B. is funded by a clinical research fund of the University Hospitals Leuven (Klinisch onderzoeksfond KOF Leuven). This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://decipher.sanger.ac.uk/ and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study was supported by New York State Genetics Services Program C029418. This work was supported by grants U01HL131003, UM1HL098147, UM1HL098123, UM1HL128761, UM1HL128711, and UM1HL098162 in support of the Pediatric Cardiac Genomics Consortium from the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver Institute of Child Health and Development, or the National Institutes of Health.

Author information

Correspondence to Jeroen Breckpot.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary table 1

Supplementary table 2

Supplementary table 3

Supplementary Methods

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark