A female with clinical features of FOXG1 syndrome and 1.5-Mb size 14q12 microdeletion located more proximal to FOXG1 K. Õunap 1,2, O. Žilina 1,3, A. Kolk 2,4, T. Reimand 1,2,5 1 Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; 2 Department of Pediatrics, University of Tartu, Tartu, Estonia; 3 Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; 4 Children’s Clinic, Tartu University Hospital, Tartu, Estonia; 5 Department of Human Biology and Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia A female with clinical features of FOXG1 syndrome and 1.5-Mb size 14q12 microdeletion located more proximal to FOXG1 K. Õunap 1,2, O. Žilina 1,3, A. Kolk 2,4, T. Reimand 1,2,5 1 Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; 2 Department of Pediatrics, University of Tartu, Tartu, Estonia; 3 Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; 4 Children’s Clinic, Tartu University Hospital, Tartu, Estonia; 5 Department of Human Biology and Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia Introduction A severe Rett-like neurodevelopmental disorder is associated with de novo FOXG1 point mutations or submicroscopic 14q12 deletion which involve FOXG1 gene (1,2). It is now known as FOXG1 syndrome which clinically causes postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum (2,3). More than 30 cases of FOXG1 syndrome have been published. (1-6). Case report She was born at term with normal birth weight 3636g, length 51 cm and head circumference 33.5 cm (-1.5 SD). Since the birth developmental delay and spasticity was noticed. Family history was unremarkable. At the age of 8m she had microcephaly - her head circumference was 39 cm (- 3.5 SD), growth was normal. She had no eye contact and head control, spasticity, brisk tendon reflexes, hypersalivation, and constant irritability. Facial phenotype was mildly dysmorphic – deep set and almond shape eyes, relatively large tongue. Brain MRI showed hypogenesis of the corpus callosum, hypomyelinisation, arachnoid cyst in the left temporal region and subtle pachygyria (Fig. 1b, c). EEG was normal. Occasional vitamin B12 deficiency was diagnosed 103 pmol/L; N: ) and treated with i/m injections. IGF-1 was also low (<25 µg/L; N: ). At 11 months she has only weak head control, height 72.5 cm (0 SD), low weight 7.3 kg (-2 SD), microcephaly 40,8 cm (-3.5 SD), flat occiput, same dysmorphic facial phenotype (Fig.1a, d), increased muscle tonus and brisk tendon reflexes. At 13 months she was hospitalized due to epileptic status. Focal symptomatic epilepsy was diagnosed and treated with valproic acid. EEG showed slow background activity and ictal episodes. Brain MRI showed hypogenesis of the corpus callosum, improved myelinisation, but still signs of hypomyelinisation, arachnoid cyst in the left temporal region (Fig. 1e, f). Figure 2. CMA showing the 1.5-Mb size microdeletion in 14q12 (marked with a pink bar) found in our patient (GenomeStudio v software, Illumina Inc.). Discussion The forkhead box G1 (FOXG1) gene encodes a winged-helix transcriptional repressor important for early development of ventral telencephalon dorso- ventral patterning by integrating several signaling centers. Additionally, FOXG1 controls production of specific neuronal subtypes and regulates the balance between neuronal progenitor cell proliferation and differentiation in the telencephalon (see Review 7). Clinical features of FOXG1 syndrome are mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro- esophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria (1). Almost all these features are presented in our patient and therefore we can diagnose FOXG1 syndrome, although FOXG1 gene is not deleted in our case (Fig. 3, 4). Similarly, clinical features of FOXG1 syndrome were found in a patient with a chromosome translocation breakpoint located between FOXG1 and PRKD1 (2) and patients with 14q12 deletions that do not harbor the FOXG1 gene and are located more distally (2,4-6) (Fig.4). It strongly suggests the presence of long- range regulatory elements for FOXG1 expression in this region. For our knowledge, our case is the first one having 14q12 deletion that do not harbor the FOXG1 gene also, but are located more proximal from the FOXG1 gene. Molecular analysis Chromosomal microarray (CMA; HumanCytoSNP-12 v2-1-chip, resolution ~62 kb) identified 1.5-Mb microdeletion in the region 14q12. (Fig. 2). This area contains no diseases causing genes, but more distally FOXG1 gene is located (Fig. 3). References 1.Papa et al., 2008, Am J Med Genet 146A: Kortum et al., 2011, J Med Genet 48: Brunetti-Pierri et al., 2011, Eur J Med Genet 19: Santen et al., 2012, J Med Genet 49: Allou et al., 2012, Eur J Med Genet 20: Ellaway et al., 2013, Eur J Med Genet 21: Florian et al., 2011, Mol Syndromol 2: Conflict of interest The authors have no conflict of interest. This work is supported by GARLA 0355P from Estonian Science Foundation. Cases of a submicroscopic 14q12 deletion, involving regulatory elements of FOXG1, with the coding region of FOXG1 being unaffected, are described very seldom. A cis-acting regulatory sequence, acting as a silencer, is deleted more than 0.6 Mb distally from FOXG1 in these cases (2,4-6). We report a new case with clinical features of FOXG1 syndrome and 14q12 microdeletion, which is located contrariwise more proximal from FOXG1 gene. Figure 1. Facial view (a) and profile of the patient (d) at 11m of age; brain MRI at the age of 8m (b, c) and at the age of 13m (e, f), note the hypoplasia of the corpus callosum (frontal side), mild ventriculomegaly, delayed myelinisation. Figure 4. Adapted from Allou et al., 2012 adding our case. Our patient has 14q12 deletion that do not harbor the FOXG1 gene and 14q12 deletion is located more proximal from the FOXG1 gene. Figure 3. Deleted area in our patient by hg19 is 14:27,584,943-29,170,974 (genome.ucsc.edu). More distally is located FOXG1 gene (OMIM ; positions 14:29,236, ,239,482). This deletion was confirmed by qPCR analysis. The parents are not carrying this deletion. The ISCN karyotype: arr[hg19] 14q12(27,584,943-29,170,974)x1.