Background: Patients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co-occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development. Methods: Patients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein. Results: We give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found. Conclusion: Homology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.

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Keywords C2H2zinc finger (ZNF) domain, Corpus callosum anomalies, Homology modeling, Intellectual disability, ZBTB18
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Journal Molecular Genetics and Genomic Medicine
van der Schoot, V. (Vyne), de Munnik, S, Venselaar, H, Elting, M, Mancini, G.M.S, Ravenswaaij-Arts, C.M.A. (Conny M. A.), … Stevens, S.J.C. (Servi J. C.). (2018). Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene. Molecular Genetics and Genomic Medicine. doi:10.1002/mgg3.387