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De novo ZBTB7A variant in a patient with macrocephaly, intellectual disability, and sleep apnea: implications for the phenotypic development in 19p13.3 microdeletions


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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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.


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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Correspondence to Tsutomu Ogata.

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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).

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