De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy

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

the origin.

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

seizure-free.

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-

106.102.007)x3)…

This is the first reported case of de novo 12q22-q23.3 duplication associated with temporal

lobe epilepsy.

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

seizures.

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.