Introduction: The zinc finger BTB domain-containing protein ZBTB18 binds to FOXG1 to form a transcriptional repressive complex involved in neuronal differentiation. Disruption of the components of this complex results in chromosome 1q43–q44 deletion syndrome/intellectual developmental disorder 22 or in FOXG1 syndrome. Case Presentation: This study reports on five patients with cognitive and behavioral impairment, seizures, microcephaly, and/or congenital brain abnormalities. Whole-exome sequencing identified deleterious ZBTB18 variants in three patients and deleterious FOXG1 variants in the remaining patients. We have detected a missense variant within the BTB domain of ZBTB18 in two affected monozygotic twins. In addition, we observed agenesis of the septum pellucidum in a missense FOXG1 carrier with a severe FOXG1 syndrome. Conclusion: Although the ZBTB18 zinc finger domains harbor the majority of known deleterious variants, we report a novel de novo rare missense variant within the BTB domain. The agenesis of the septum pellucidum observed in a missense FOXG1 carrier could be considered as a novel clinical feature associated with FOXG1 syndrome. The severe FOXG1 syndrome in this patient contrasts with the milder phenotype expected for a missense. Genetic or environmental factors may explain this phenotypic variability in FOXG1 syndrome.

Xiang C, Frietze KK, Bi Y, Li Y, Dal Pozzo V, Pal S, et al. RP58 represses transcriptional programs linked to nonneuronal cell identity and glioblastoma subtypes in developing neurons. Mol Cell Biol. 2021;41(7):e0052620.
Heng JI-T, Viti L, Pugh K, Marshall OJ, Agostino M. Understanding the impact of ZBTB18 missense variation on transcription factor function in neurodevelopment and disease. J Neurochem. 2022;161(3):219–35.
Cargnin F, Kwon J, Katzman S, Chen B, Lee J, Lee SK. FOXG1 orchestrates neocortical organization and corticocortical connections. Neuron. 2018;100(5):1083–96.e5.
van der Schoot V, de Munnik S, Venselaar H, Elting M, Mancini GMS, Ravenswaaij-Arts CMA, et al. Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene. Mol Genet Genomic Med. 2018;6(3):393–400.
Wang T, Hoekzema K, Vecchio D, Wu H, Sulovari A, Coe BP, et al. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nat Commun. 2020;11(1):4932.
Akol I, Gather F, Vogel T. Paving therapeutic avenues for FOXG1 syndrome: untangling genotypes and phenotypes from a molecular perspective. Int J Mol Sci. 2022;23(2):954.
Hou P-S, hAilín DÓ, Vogel T, Hanashima C. Transcription and beyond: delineating FOXG1 function in cortical development and disorders. Front Cell Neurosci. 2020;14:35.
Mitter D, Pringsheim M, Kaulisch M, Plümacher KS, Schröder S, Warthemann R, et al. FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants. Genet Med. 2018;20(1):98–108.
Vegas N, Cavallin M, Maillard C, Boddaert N, Toulouse J, Schaefer E, et al. Delineating FOXG1 syndrome: from congenital microcephaly to hyperkinetic encephalopathy. Neurol Genet. 2018;4(6):e281.
Brea-Fernández AJ, Álvarez-Barona M, Amigo J, Tubío-Fungueiriño M, Caamaño P, Fernández-Prieto M, et al. Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability. Eur J Hum Genet. 2022;30(8):938–45.
Chaharbakhshi E, Jemc JC. Broad-complex, tramtrack, and bric-à-brac (BTB) proteins: critical regulators of development. Genesis. 2016;54(10):505–18.
Stogios PJ, Downs GS, Jauhal JJS, Nandra SK, Privé GG. Sequence and structural analysis of BTB domain proteins. Genome Biol. 2005;6(10):R82.
Wong L-C, Huang C-H, Chou W-Y, Hsu C-J, Tsai W-C, Lee WT. The clinical and sleep manifestations in children with FOXG1 syndrome. Autism Res. 2023;16(5):953–66.
You do not currently have access to this content.