Maria Stella Vari, Monica Traverso, Tommaso Bellini, Francesca Madia, Francesca Pinto, Pasquale Striano, Carlo Minetti and Federico Zara. De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy. Seizure: European Journal of Epilepsy, In press.
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be
associated with acquired central nervous system lesions (symptomatic cases) or be genetic in
Family studies have shown that relatives of patients with temporal lobe epilepsy are at higher
risk of suffering from seizures and EEG abnormalities compared to relatives of controls.
Therefore, various susceptibility genes and environmental factors are believed to be involved
in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder.
Rare point mutations in LGI1, DEPDC5 and RELN have been reported in families with a monogenic type of TLE and only a few anaedoctical copy number variations (CNVs) have been described in TLE.
We report a partial duplication of the long arm of chromosome 12 detected by whole-genome
array comparative genomic hybridization in a 5-years old girl with temporal lobe epilepsy…
This girl was the second child of Caucasian healthy non-consanguineous parents. Familial
history was unremarkable. The girl was born at 37 weeks + 5 days gestation by a cesarean
section. Perinatal and neonatal periods were uneventfully. At birth, she weighted 3460 g (75-
90th centile), length was 51 cm (90th centile), and occipitofrontal circumference (OFC) was
34,5 cm (75-90th centile). The girl’s development milestones were mildly delayed: she
acquired head control at 4 months, sitting position at 10 months, and she started walking at
17 months. She pronounced her first words at age of 2 years and 5 months. At 30 months, the
patient experienced a simple tonic-clonic seizure during fever.
At 3 years and 3 months of life, she was admitted to our department due to a second febrile
seizure, characterized by loss of contact, oromasticatory automatisms, and left head
deviation, lasting about 5 minutes with post-ictal somnolence. In the following months, the
girls suffered from weekly dyscognitive seizures with impaired contact and oromasticatory or
gestural automatisms, lasting up to a few minutes…
Inter-ictal EEG revealed high voltage paroxysmal anomalies in the posterior region of the
right temporal area, more evident during sleep recordation (Fig 1B). 1.5 Tesla Brain MRI was
unremarkable. Treatment with carbamazepine (30 mg/Kg/day) resulted in complete seizure
control and disappearance of EEG abnormalities. At 24-month-follow-up the patient is still
Genetic analysis by 44K kit array-CGH (Agilent Technologies, Inc) revealed a 12 Mb de
novo duplication on chromosome 12q22-q23.3 (arr [hg19]12q22q23.3(94.135.069-
This is the first reported case of de novo 12q22-q23.3 duplication associated with temporal
We identified a patient with an overlapping de novo duplication which was already described
in the DECIPHER v8.9 database (ID 258582) (FIG 2B). Both Decipher’s patient and our case
share dysmorphic features, focal epilepsy, and intellectual disability; in addition, patient
258582 also featured obesity, myopia, and strabismus.
In our case, the 12Mb duplication at 12q22-q23.3 encompasses 67 genes, many of which
have an established function in brain development and functioning.
In 2004 a locus for TLE was mapped in this region by linkage analysis performed on a large
family segregating idiopathic temporal lobe epilepsy and febrile seizures in 21 members. The
reported phenotype was characterised by temporal lobe epilepsy with average age of onset at
eight years, recurrence of febrile seizures in about half of the individuals, no hippocampal
sclerosis, and a usually good prognosis. Additional evidence for an epilepsy at this locus
was provided by a second, large Caucasian family study showing febrile and afebrile focal
Comparative analysis of the locus identified by Claes et al. and duplicated regions in our case
and in patient 258582 shows an overlapping genomic segment of about 6.1 Mb. This region
includes 27 genes and, among these, DEPDC4 represents an appealing candidate for a
causative role. Indeed, DEPDC4 gene belongs to the IML1 family of proteins involved in Gprotein
signaling pathways, regulating cells growth and development which also include
DEPDC5. Mutations in this gene have been identified in autosomal dominant focal epilepsy
with variable foci and in few families with familial TLE.