The contribution of 7q33 copy number variations for intellectual disability
- 382 Downloads
Copy number variations (CNVs) at the 7q33 cytoband are very rarely described in the literature, and almost all of the cases comprise large deletions affecting more than just the q33 segment. We report seven patients (two families with two siblings and their affected mother and one unrelated patient) with neurodevelopmental delay associated with CNVs in 7q33 alone. All the patients presented mild to moderate intellectual disability (ID), dysmorphic features, and a behavioral phenotype characterized by aggressiveness and disinhibition. One family presents a small duplication in cis affecting CALD1 and AGBL3 genes, while the other four patients carry two larger deletions encompassing EXOC4, CALD1, AGBL3, and CNOT4. This work helps to refine the phenotype and narrow the minimal critical region involved in 7q33 CNVs. Comparison with similar cases and functional studies should help us clarify the relevance of the deleted genes for ID and behavioral alterations.
Keywords7q33 CNVs CALD1 AGBL3 EXOC4 CNOT4 Duplication
We would like to thank all the patients and their families for their participation in the genetic studies and for allowing this publication. We would also like to acknowledge the DECIPHER Consortium, Database of Genomic Variants, and OMIM since this study makes use of data generated by these platforms.
FL, FT, SS, and PR performed the molecular studies and analyzed the molecular data. AMF, SAL, AJ, and JS collected clinical data. FL, FT, and PM drafted the paper. PM obtained funding for this study. The study was performed under the direction of PM.
This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the projects PIC/IC/83026/2007, PIC/IC/83013/2007, and POCI-01-0145-FEDER-007038. This work has also been funded by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). FL was supported by Foundation for Science and Technology (FCT) through the fellowship SFRH/BD/90167/2012.
Compliance with ethical standards
The authors declare that they have no conflict of interest.
- 1.Xu Z, Geng Q, Luo F, Xu F, Li P, Xie J (2014) Multiplex ligation-dependent probe amplification and array comparative genomic hybridization analyses for prenatal diagnosis of cytogenomic abnormalities. Mol Cytogenet 7(1):84. https://doi.org/10.1186/s13039-014-0084-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 2.Malmgren H, Malm G, Sahlén S, Karlsson M, Blennow E (2005) Molecular cytogenetic characterization of an insertional translocation, ins(6;7)(p25;q33q34): deletion/duplication of 7q33-34 and clinical correlations. Am J Med Genet A 139(1):25–31. https://doi.org/10.1002/ajmg.a.30983 CrossRefPubMedGoogle Scholar
- 4.Mitchell S, Siegel DH, Shieh JTC, Stevenson DA, Grimmer JF, Lewis T, Metry D, Frieden I, Blei F, Kayserili H, Drolet BA, Bayrak-Toydemir P (2012) Candidate locus analysis for PHACE syndrome. Am J Med Genet A 158A(6):1363–1367. https://doi.org/10.1002/ajmg.a.35341 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Rossi E, Verri AP, Patricelli MG, Destefani V, Ricca I, Vetro A, Ciccone R, Giorda R, Toniolo D, Maraschio P, Zuffardi O (2008) A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea. Eur J Med Genet 51(6):631–638. https://doi.org/10.1016/j.ejmg.2008.06.010 CrossRefPubMedGoogle Scholar
- 6.Petrin AL, Giacheti CM, Maximino LP, Abramides DVM, Zanchetta S, Rossi NF, Richieri-Costa A, Murray JC (2010) Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case. Am J Med Genet A 152A(12):3164–3172. https://doi.org/10.1002/ajmg.a.33749 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Dilzell K, Darcy D, Sum J, Wallerstein R (2015) Deletion of 7q33-q35 in a patient with intellectual disability and dysmorphic features: further characterization of 7q interstitial deletion syndrome. Case Rep Genet 2015:131852–131855. https://doi.org/10.1155/2015/131852 PubMedPubMedCentralGoogle Scholar
- 14.Krijgsman O, Israeli D, van Essen HF, Eijk PP, Berens MLM, Mellink CHM, Nieuwint AW, Weiss MM, Steenbergen RDM, Meijer GA, Ylstra B (2013) Detection limits of DNA copy number alterations in heterogeneous cell populations. Cell Oncol Dordr 36(1):27–36. https://doi.org/10.1007/s13402-012-0108-2 CrossRefPubMedGoogle Scholar
- 16.Jovanovic L, Delahunt B, McIver B et al (2003) Optimising restriction enzyme cleavage of DNA derived from archival histopathological samples: an improved HUMARA assay. Pathology (Phila) 35:70–74Google Scholar
- 17.Hoebeeck J, van der Luijt R, Poppe B, de Smet E, Yigit N, Claes K, Zewald R, de Jong GJ, de Paepe A, Speleman F, Vandesompele J (2005) Rapid detection of VHL exon deletions using real-time quantitative PCR. Lab Investig J Tech Methods Pathol 85(1):24–33. https://doi.org/10.1038/labinvest.3700209 CrossRefGoogle Scholar
- 18.Wechsler D (1991) Wechsler intelligence scale for children—third editionGoogle Scholar
- 19.Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Vooren SV, Moreau Y, Pettett RM, Carter NP (2009) DECIPHER: database of chromosomal imbalance and phenotype in humans using Ensembl resources. Am J Hum Genet 84(4):524–533. https://doi.org/10.1016/j.ajhg.2009.03.010 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Rippey C, Walsh T, Gulsuner S, Brodsky M, Nord AS, Gasperini M, Pierce S, Spurrell C, Coe BP, Krumm N, Lee MK, Sebat J, McClellan JM, King MC (2013) Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. Am J Hum Genet 93(4):697–710. https://doi.org/10.1016/j.ajhg.2013.09.004 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Córdova-Fletes C, Domínguez MG, Delint-Ramirez I, Martínez-Rodríguez HG, Rivas-Estilla AM, Barros-Núñez P, Ortiz-López R, Neira VA (2015) A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations. Neurogenetics 16(4):287–298. https://doi.org/10.1007/s10048-015-0452-2 CrossRefPubMedGoogle Scholar
- 24.Tort O, Tanco S, Rocha C, Bieche I, Seixas C, Bosc C, Andrieux A, Moutin MJ, Aviles FX, Lorenzo J, Janke C (2014) The cytosolic carboxypeptidases CCP2 and CCP3 catalyze posttranslational removal of acidic amino acids. Mol Biol Cell 25(19):3017–3027. https://doi.org/10.1091/mbc.E14-06-1072 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.GTEx Portal. http://www.gtexportal.org/home/. Accessed 25 Feb 2017
- 44.Brookes E, Laurent B, Õunap K, Carroll R, Moeschler JB, Field M, Schwartz CE, Gecz J, Shi Y (2015) Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity. Hum Mol Genet 24(10):2861–2872. https://doi.org/10.1093/hmg/ddv046 CrossRefPubMedPubMedCentralGoogle Scholar
- 45.IMPC | International Mouse Phenotyping Consortium. http://www.mousephenotype.org/. Accessed 21 Sep 2017
- 46.Cnot4 MGI Mouse Gene Detail - MGI:1859026 - CCR4-NOT transcription complex, subunit 4. http://www.informatics.jax.org/marker/MGI:1859026. Accessed 14 Apr 2017