Abstract
Interstitial microdeletions at chromosome 19p13.3 are frequently associated with a constellation of clinical features including macrocephaly, characteristic face, intellectual disability, and sleep apnea. Previous studies in 25 patients with 19p13.3 microdeletions have revealed loss of MAP2K2 in 24 patients and that of PIAS4 and ZBTB7A in 23 patients, suggesting that these three adjacent genes are candidate genes for the phenotypic development in 19p13.3 microdeletions. We identified a de novo likely pathogenic heterozygous missense variant of ZBTB7A (NM_015898.3:c.1152C>G, p.(Cys384Trp)) in a Japanese boy with macrocephaly, intellectual disability, and sleep apnea. This variant affects the conserved cysteine residue forming the coordinate bond with Zn2+ ion at the first zinc finger domain, and is predicted to exert a dominant-negative effect because of the generation of homo- and hetero-dimers with the wild-type and variant ZBTB7A proteins. The results argue for a critical relevance of ZBTB7A to the development of most, but probably not all, of the 19p13.3 microdeletion phenotype.
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References
Al-Kateb H, Hahn A, Gastier-Foster JM, Jeng L, McCandless SE, Curtis CA. Molecular characterization of a novel, de novo, cryptic interstitial deletion on 19p13.3 in a child with a cutis aplasia and multiple congenital anomalies. Am J Med Genet A. 2010;152A:3148–53.
Siggberg L, Olsén P, Näntö-Salonen K, Knuutila S. 19p13.3 aberrations are associated with dysmorphic features and deviant psychomotor development. Cytogenet Genome Res. 2011;132:8–15.
de Smith AJ, van Haelst MM, Ellis RJ, Holder SE, Payne SJ, Hashim SK, et al. Chromosome 19p13.3 deletion in a patient with macrocephaly, obesity, mental retardation, and behavior problems. Am J Med Genet A. 2011;155:1192–5.
Risheg H, Pasion R, Sacharow S, Proud V, Immken L, Schwartz S, et al. Clinical comparison of overlapping deletions of 19p13.3. Am J Med Genet A. 2013;161A:1110–6.
Nowaczyk MJ, Thompson BA, Zeesman S, Moog U, Sanchez-Lara PA, Magoulas PL, et al. Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clin Genet. 2014;85:138–46.
Nevado J, Rosenfeld JA, Mena R, Palomares-Bralo M, Vallespín E, Ángeles Mori M, et al. PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome. Eur J Hum Genet. 2015;23:1615–26.
Shimojima K, Ondo Y, Matsufuji M, Sano N, Tsuru H, Oyoshi T, et al. Concurrent occurrence of an inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving MAP2K2 in a patient with developmental delay, distinctive facial features, and lambdoid synostosis. Eur J Med Genet. 2016;59:559–63.
Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, et al. The cardiofaciocutaneous syndrome. J Med Genet. 2006;43:833–42.
Xiong R, Nie L, Xiang LX, Shao JZ. Characterization of a PIAS4 homologue from zebrafish: insights into its conserved negative regulatory mechanism in the TRIF, MAVS, and IFN signaling pathways during vertebrate evolution. J Immunol. 2012;188:2653–68.
Roth W, Sustmann C, Kieslinger M, Gilmozzi A, Irmer D, Kremmer E, et al. PIASy-deficient mice display modest defects in IFNand Wnt signaling. J Immunol. 2004;173:6189–99.
Masuda T, Wang X, Maeda M, Canver MC, Sher F, Funnell AP, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science. 2016;351:285–9.
Delivoria-Papadopoulou M, Roncević NPopadić, Oski AN. Postnatal changes in oxygen transport of term, premature, and sick infants: The role of red cell 2,3-diphosphoglycerate and adult hemoglobin. Pediatr Res. 1971;5:235–45.
Liu XS, Liu Z, Gerarduzzi C, Choi DE, Ganapathy S, Pandolfi PP, et al. Somatic human ZBTB7A zinc finger mutations promote cancer progression. Oncogene. 2016;35:3071–8.
Ogata T, Tanaka T, Kagami M. Target height and target range for Japanese children: revisited. Clin Pediatr Endocrinol. 2007;16:85–7.
Nakashima M, Tohyama J, Nakagawa E, Watanabe Y, Siew CG, Kwong CS, et al. Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures. J Hum Genet. 2019;64:313–22.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Maeda T. Regulation of hematopoietic development by ZBTB transcription factors. Int J Hematol. 2016;104:310–23.
Hartmann L, Dutta S, Opatz S, Vosberg S, Reiter K, Leubolt G, et al. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation. Nat Commun. 2016;7:11733.
Liu XS, Genet MD, Haines JE, Mehanna EK, Wu S, Chen HI, et al. ZBTB7A suppresses melanoma metastasis by transcriptionally repressing MCAM. Mol Cancer Res. 2015;13:1206–17.
Acknowledgements
We thank Drs Nobuhiko Okamoto and Kenji Kurosawa for their comments on the phenotypic assessment of this boy. We also thank Ms Aya Kitamoto, and Mr Naoki Adachi for their technical support.
Funding
This study was funded by Japan Agency for Medical Research and Development (AMED) (19ek0109278 to MF, JP19ek0109297 to HS, and JP18ek0109301 to TO).
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Ohishi, A., Masunaga, Y., Iijima, S. et al. De novo ZBTB7A variant in a patient with macrocephaly, intellectual disability, and sleep apnea: implications for the phenotypic development in 19p13.3 microdeletions. J Hum Genet 65, 181–186 (2020). https://doi.org/10.1038/s10038-019-0690-5
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DOI: https://doi.org/10.1038/s10038-019-0690-5
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