Chromosomal imbalance letter4.45 Mb microduplication in chromosome band 14q12 including FOXG1 in a girl with refractory epilepsy and intellectual impairment
Introduction
Mutations in FOXG1 (MIM 164874) have recently been found to cause the congenital variant of Rett syndrome, which is phenotypically similar to classical Rett syndrome (MIM 312750) but with the additional findings of hypotonia and delayed development from the first months of life [1]. Haploinsufficiency for FOXG1 has also been reported in three patients who have 14q12 microdeletions that comprise 2.9–3.6 Mb and include the FOXG1 locus [2], [3], [4]. The 14q12 microdeletion patients have a similar phenotype to the FOXG1 mutated patients, but with additional minor dysmorphisms, including prominent metopic suture, large ears, epicanthic folds, depressed nasal bridge and bulbous nasal tip. One 14q12 microdeletion patient had not yet developed seizures or EEG abnormalities at 10 months of age [3].
Here we describe the corresponding 14q12 microduplication in a nine year old girl who presented with severe epilepsy, intellectual disability and minor dysmorphisms.
Section snippets
Case report
The patient, a nine year old female, is the only child of unrelated Chinese and Serbian parents. She was born by vaginal delivery at 41 weeks gestation following a normal pregnancy. Birth weight was 3835 g and no resuscitation was required. There were early feeding difficulties but no other neonatal complications.
Seizures commenced at 3 months of age, comprising periods of brief elevation of the arms. At 6 months of age she was diagnosed with infantile spasms and her EEG showed hypsarrhythmia.
Methods of detection and result
The chromosomal analysis was performed using G-banding of cultured lymphocytes. The patient had a 46,XX karyotype determined by analyzing 15 metaphase cells at a band resolution level of 550.
Microarray analysis was carried out using the Affymetrix SNP 6.0 microarray in accordance with the manufacturer's protocol (Affymetrix, California, USA). SNP 6.0 data analysis was performed using the Affymetrix Genotyping Console 3.0.2 software. Copy number data were generated by comparing intensities for
Discussion
We present the first report of a microduplication at 14q12 in a patient with refractory generalised epilepsy, severe intellectual impairment, and minor dysmorphisms. This microduplication corresponds to the recently described 14q12 microdeletion syndrome [3], and is the first report of microduplication involving the FOXG1 gene, mutations in which have been found to cause the congenital variant of Rett syndrome [1].
There is considerable phenotypic overlap between our 14q12 microduplication
Acknowledgments
We thank the patient and her family for collaborating in our research. Funding has been provided by the Instituto de Salud Carlos III, Spain, and the National Health and Medical Research Council of Australia.
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Cited by (56)
FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants
2018, Genetics in MedicineAutism spectrum disorder and epilepsy: Disorders with a shared biology
2015, Epilepsy and BehaviorA haploinsufficiency of FOXG1 identified in a boy with congenital variant of Rett syndrome
2014, Brain and DevelopmentCitation Excerpt :In 2008, Ariani et al. reported the first two cases with point mutations of FOXG1 [4]. In 2009, Yeung et al. reported a case of microduplication in chromosome band 14q12 including FOXG1 [14]. A considerable phenotypic overlap exists between patients with 14q12 microdeletion, loss of function of mutation in FOXG1, 14q12 microduplication, and our patient (presented in the Table 1), suggesting a dosage-sensitive role for FOXG1 in brain development [14].
Epilepsy in patients with duplications of chromosome 14 harboring FOXG1
2014, Pediatric NeurologyCitation Excerpt :It also regulates neurogenesis in the postnatal hippocampus and continues to be expressed at high levels in other areas of postnatal neurogenesis. Therefore the potential role of FOXG1 duplication in determining severe epilepsy, developmental delay, and especially infantile spasms, as a result of increased gene dosage, is an emerging theory.2-7 On the other hand, the clinical picture determined by deletions and inactivating mutations of FOXG1 is represented by Rett-like syndrome (one of the congenital variants) with hypotonia, irritability, severe developmental delay, autism, microcephaly, and late-onset epilepsy.3,9,10