Diagnosis of FOXG1 syndrome caused by recurrent balanced chromosomal rearrangements: case study and literature review
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CASE REPORT
Diagnosis of FOXG1 syndrome caused by recurrent balanced chromosomal rearrangements: case study and literature review Connor P. Craig1,2, Emily Calamaro3, Chin‑To Fong3, Anwar M. Iqbal1, Alexander R. Paciorkowski3,4,5,6 and Bin Zhang1,3*
Abstract Background: The FOXG1 gene plays a vital role in mammalian brain differentiation and development. Intra- and intergenic mutations resulting in loss of function or altered expression of the FOXG1 gene cause FOXG1 syndrome. The hallmarks of this syndrome are severe developmental delay with absent verbal language, post-natal growth restric‑ tion, post-natal microcephaly, and a recognizable movement disorder characterized by chorea and dystonia. Case presentation: Here we describe a case of a 7-year-old male patient found to have a de novo balanced translo‑ cation between chromosome 3 at band 3q14.1 and chromosome 14 at band 14q12 via G-banding chromosome and Fluorescence In Situ Hybridization (FISH) analyses. This rearrangement disrupts the proximity of FOXG1 to a previously described smallest region of deletion overlap (SRO), likely resulting in haploinsufficiency. Conclusions: This case adds to the growing body of literature implicating chromosomal structural variants in the manifestation of this disorder and highlights the vital role of cis-acting regulatory elements in the normal expression of this gene. Finally, we propose a protocol for reflex FISH analysis to improve diagnostic efficiency for patients with suspected FOXG1 syndrome. Keywords: FOXG1, Haploinsufficiency, Postnatal microcephaly, FISH, Enhancer, Chromosomal rearrangement, Diagnosis Introduction The Forkhead Box G1 (FOXG1) gene [OMIM: 164874], located on chromosome 14q12, encodes the protein forkhead box protein G1 (FOXG1). It belongs to a class of winged-helix transcriptional regulators and contains a highly conserved fork head DNA-binding domain. This protein plays an important role in mammalian *Correspondence: [email protected] 1 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 608, Rochester, NY 14642, USA Full list of author information is available at the end of the article
brain development, with high levels of expression in the developing fetal telencephalon [1–4]. Specifically, it is expressed in the rostral forebrain prior to differentiation into the telencephalon and diencephalon, indicating its role in early differentiation between these structures [5]. It exerts its effects via DNA binding-dependent and -independent mechanisms to encourage neocortical progenitor proliferation and prevent precocious differentiation [6]. In addition to regulating neocortical progenitor cell populations, it also plays an important role in controlling post-mitotic pyramidal cortical neuron migration and post-migration dorsal–ventral patterning to establish
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