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Deletions of the 19q13.11 region involving SCN1B are risk factors for febrile seizures

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
The deletion of the 19q13.11 region, while infrequent, is a clinically identifiable condition. Most of the reported cases have losses ranging from 1 to 11 Mb in size and are characterized by intrauterine and postnatal growth retardation, microcephaly, developmental delay/intellectual disabilities, language delay, feeding difficulties, slender habitus, cutis aplasia over the posterior occiput, and genital malformation. Less common features include cardiac conduction disturbance or generalized epilepsy, dystonia and renal anomalies. Accurate phenotypic characterization related to 19q13.11 deletions is complex due to the variability in size and the uncertain effects of the deleted genes on the observed phenotypic features. We report a 10‐year‐old female patient with the loss in the 19q13.11 region who’s only presenting phenotype is febrile seizures.

Case Presentation
Patient was born at term via vaginal delivery with no complications. Birth weight was 7 pounds, 10 ounces. Mother was healthy during pregnancy. Early motor and language milestones occurred at expected times. Patient walked at 12 months of age. There were no concerns with learning, speech, or behavior. Patient developed complex febrile seizures at around 1 year of age. Brain MRI showed bilateral mesial temporal sclerosis. The family history is notable for patient’s younger sister with a similar history of febrile seizures and an older sister who was treated for absence seizures in childhood which are now resolved. Patient was noted to have rapid weight gain since birth, however endocrine assessment including full lab profile were normal.

 

Diagnostic Workup
Patient had an epilepsy panel sequencing which identified SCN1B deletion. Follow up microarray analysis confirmed the deletion to be 311 kb [arr[GRCh38] 19q13.11q13.12(34847353_35158247)x1]. The loss included ten protein-coding genes (ZNF30, ZNF792, GRAMD1A, SCN1B, HPN, FXYD3, LGI4, FXYD1, FXYD7), four long non-coding RNAs (LINC02965, LINC03049, LINC00904, LINC01838) and two additional pseudogenes. Parental testing showed that the deletion was inherited from the patient’s healthy father with normal EKG and no history of seizures or cardiac issues.

 

Treatment and Management
Patient is using benzodiazepines prescribed as adjuvant medication for seizure control.

 

Outcome and Follow-Up
Seizures are adequately controlled; however, the patient has been experiencing a significant weight gain with an undetermined etiology.

 

Discussion
The 19q13.11 loss observed in our patient is the smallest reported to date. It includes a portion of the 324 kb critical and minimal region which is proposed to play a significant role in the phenotype. The critical region encompasses four zinc finger protein-coding genes (ZNF302, ZNF181, ZNF599, and ZNF30) of the Kruppel-associated box (KRAB)-containing ZNF protein family. Of these genes, our patient only has a loss of ZNF30. The study by Terada Abe et al. analyzed fifteen patients with deletions of 19q13.11. Of those whose losses involved SCN1B, 54% presented with congenital heart defects and 31% had epilepsy. Pathogenic variants involving SCN1B which codes for β1 subunit of the voltage-gated sodium channel are associated with both autosomal dominant and autosomal recessive forms of epilepsy. Monoallelic variants have been reported in a few individuals with generalized epilepsy with febrile seizures or absence epilepsy and display significantly reduced penetrance. We have observed that our patient’s father had the same deletion but exhibited no symptoms, which confirms that loss of one copy of SCN1B may only be a risk factor for febrile seizures.

 

Conclusion
We identified a novel 19q13.11 deletion proposing a minimal overlapping region which includes SCN1B as the cause of febrile seizures. Monoallelic variants that result in the loss of SCN1B function may contribute to a milder form of Genetic Epilepsy with Febrile Seizures Plus, which exhibit incomplete penetrance and have currently an undefined underlying mechanism of the disease.

 

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