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Neurologia Pediatrica e Malattie Muscolari, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Istituto ‘G. Gaslini’, Università di Genova, Italy
Terminal deletions of long arm of chromosome 13 are rare and poorly characterized by cytogenetic studies, making for difficult genotype-phenotype correlations. We report two siblings presenting generalized epilepsy, intellectual disability, and genitourinary tract defects. Array CGH detected a 1.3 Mb deletion at 13q34; it contains two protein-coding genes, SOX1 and ARHGEF7, whose haploinsufficiency can contribute to the epileptic phenotype.
Terminal deletions of long arm of chromosome 13 are rare and poorly characterized by cytogenetic studies, making for difficult genotype-phenotype correlations. We describe two siblings with generalized epilepsy, intellectual disability, and genitourinary tract defects who carried a 1.3 Mb deletion at 13q34 detected by array-CGH. Analysis of the genes included within the deleted region suggests that two protein-coding genes, SOX1 and ARHGEF7, can contribute to this neurological phenotype.
2. Case descriptions
The proband is a 7-year-old boy born at term after an uncomplicated pregnancy and presenting hypospadias at birth. He showed delayed developmental milestones, i.e. head control at 5 months, rolling at 9 months, and sitting at 10 months. The boy started walking at 2 years of age. Since he was 3 years old, he has had two simple febrile convulsive seizures and myoclonic jerks of the upper limbs, sometimes associated with tonic-clonic seizures. His EEG showed high-voltage spike and polyspike waves more evident over the anterior and central regions (Fig. 1a). Treatment with valproate (15 mg/kg/day) enabled complete control and the disappearance of EEG abnormalities at the 24-month-follow-up. His 18-month-old brother experienced two afebrile tonic-clonic seizures at the age of 12 months. His EEG showed high-voltage spike wave activity that was more evident over the centro-temporal regions.
Fig. 1a) EEG discharge at 3 years of age: high-voltage spike and polyspike waves activity more evident over the anterior and central regions; b) Facial appearance of the proband at age 7 years of age, showing prominent nose, long nasal bridge, wide and rectangular forehead, small chin, down-slanting palpebral fissures, and ptosis..
On examination, the two siblings showed facial dysmorphisms, i.e. prominent nose, long nasal bridge, wide and rectangular forehead, small chin, down-slanting palpebral fissures, and ptosis (Fig. 1b). Both subjects had short stature (II-1: <2 SD; II-2: <1,8 SD), low growth parameters (II-1: <2 SD; II-2: <1,7 SD), and microcephaly (II-1: <2 SD; II-2: <1,9 SD). Endocrinological investigations, such as thyroid function, IGF-1, and GH, were unremarkable as was the brain MRI. Psychodiagnostic evaluation revealed attention deficit disorder and mild intellectual disability (performance motor scores 75) in the proband and immaturity of communicative development as well as labile attention in his younger brother. The family history was unremarkable, however, the mother of the patients had short stature (150 cm) and borderline IQ. She did not report seizures or any other neurological symptoms.
3. Results
Array-CGH (60 K, probe spatial resolution: 30Kb; Agilent, Santa Clara, California, US) showed a 1.3 Mb deletion at 13q34, spanning from 111511614 to 112873904 (GRCh37/hg19), in both siblings and their mother. Array-CGH analysis in the father was unremarkable. The deleted region contains 2 protein-coding genes (ARHGEF7 and SOX1) and 14 non-proteing coding sequences (LINC00346, ANKRD10, LINC00431, LINC000368, ARHGEF7-AS2, ARHGEF7-AS1, LOC101060553, TEX29, LINC002337, LINC00354, LINC00403, LOC100506016, LINC01070 and LINC010). Putative interaction networks between genes harboured in the 13q34 deleted region were built by GeneMania (http://genemania.org/). Physical, co-expression, and pathway gene-gene interactions were evaluated. SOX1 is co-localized, is part of the same pathway and physically interacts with CTNNB1, as well as with other members of the SOX gene family, such as SOX2 and SOX3. ARHGEF7 shows physical interactions mainly with ARHGEF6, SHANK1 and SHANK2, and PAK1, PAK2 and PAK3; it is co-expressed with GIT2 and PAK3; and it is part of the same pathway with the PAK gene family, ARHGEF6, GT1 and EGFR (Fig. 2).
Fig. 2a) CGH-array analysis showing the 1.3 Mb deletion at 13q34; b) SOX1 gene that is present in the two families reported by Reinstein et al.; c) ARHGEF7 gene interactions; d) SOX1 gene interactions..
]. Our patients harbour the smallest deletion described so far and share similar features with other patients, such as growth retardation, mild intellectual disability, microcephaly, facial dysmorphisms, however, they do not present cardiac defects that could be caused by more distal genes. Both patients suffered from seizures supporting that it is linked to a gene harboured in the deleted region. However, this gene has an incomplete penetrance, since the mother is not affected. Accordingly, epilepsy is described only in one individual from family II, a 28-year-old woman with mild intellectual disability although no details about the epilepsy type were provided [
To get further insights on the effects of gene haploinsufficiency in 13q34 deletions, we reviewed the literature data and checked the public databases available that report chromosomal rearrangements similar to that identified in our patients. According to USCS (https://genome-euro.ucsc.edu), the deleted region contains 16 RefSEq genes: 14 are non-protein coding RNA, either uncharacterized or with no known function, whereas two are protein-coding genes, SOX1 and ARHGEF7; they may play a role in the epileptic phenotype. To assess the role of SOX1 and ARHGEF7, we investigated their functional connections, which show that both genes interact with other genes clearly implicated in epilepsy circuitry. SOX1 interacts both with CTNNB1 (Cadherin-Associated Protein, Beta 1, Catenin beta 1) and with GRIN2D (Glutamate Receptor, Ionotropic, N-Methyl-Aspartate, subunit 2D). CTNNB1 is known to increase the expression of genes involved in the modulation of neuronal excitability, among them being neurotransmitters for glutamate [
]. GRIN2D codes for a subunit of the N-methyl-d-aspartate (NMDA) receptors, a class of ionotropic glutamate receptors involved in the efficiency of synaptic; a de novo heterozygous missense mutation in GRIN2D was identified in 2 unrelated girls with early infantile epileptic encephalopathy-46 (EIEE46; 617162) (Fig. 2) [
ARHGEF7 interacts with genes either directly related to epileptic phenotypes or with a clear role in neuronal activity, such as TSC1and ITPA (Inosine Triphosphate Pyrophosphohydrolase), whose mutations were detected in unrelated patients with early infantile epileptic encephalopathy-35 (EIEE35;616647) [
]. The second group comprises genes widely expressed in the neuronal cells and that are required for the development and function of neuronal synapses such as SHANK1 and SHANK2 (SH3 and Multiple Ankyrin Repeat Domains 1 and 2) and PAK1, PAK2 and PAK3 genes. (Fig. 2)
5. Conclusion
The new genomic technologies, including chromosome microarrays and next-generation sequencing, are improving our understanding of the genetic architecture of epilepsies. Recent findings in some genetic epilepsy syndromes provide insights into the mechanisms of epileptogenesis, revealing the role of a number of genes with different functions.
Our data indicate that epilepsy may be part of the phenotype of 13q34 deletion syndrome and that SOX1 and ARHGEF7 are good candidate genes whose haploinsufficiency can contribute to the epileptic phenotype of this condition.
Conflict of interest
None.
Acknowledgements
We thank Wendy Doherty, native English speaker and English Lecturer at University of Pisa for her assistance in screen and correct our manuscript for English language.
Appendix A. Supplementary data
The following is Supplementary data to this article:
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