Segal E, Pedro H, Valdez-Gonzalez K, Parisotto S, Gliksman
F, Thompson S, Sabri J, Fertig E. Diagnostic Yield of Epilepsy Panels in
Children With Medication-Refractory Epilepsy. Pediatr Neurol. 2016 Jul 1.
pii:S0887-8994(15)30249-6. doi:
10.1016/j.pediatrneurol.2016.06.019. [Epub ahead of print] PubMed PMID: 27726903.
Abstract
BACKGROUND:
When no chromosomal variations are identified, patients with
suspected genetic etiologies can be tested using next-generation sequencing
utilizing epilepsy panels. The primary objective of this study was to analyze
the diagnostic yield of next-generation sequencing epilepsy panels in
medication-resistant epilepsy subjects with non-clinically significant
comparative genomic hybridization microarray results.
METHODS:
We completed a single-center retrospective review of the
diagnostic yield of next-generation sequencing epilepsy panels in
medication-resistant epilepsy subjects aged 18 years or less who had
non-clinically significant comparative genomic hybridization microarray results
from January 2011 to December 2014. The primary end point was the yield of
clinically significant next-generation sequencing results.
RESULTS:
Forty-nine subjects (21 male) with medication-refractory
epilepsy with clinically in significant comparative genomic hybridization
microarray results were identified. Next-generation sequencing abnormalities
were seen in 28 subjects (57%): seven of these 28 subjects (25%) had clinically
significant findings. Mutations were found in the SCN1A gene in three subjects,
in the PCDH19 gene in two subjects, and in DLG3, MECP2, TSC2, and SLC9A6 genes
in one subject each. Only the MECP2 mutation was found to be pathogenic in this
last subject. The additional yield of next-generation sequencing with
uninformative chromosomal microarray was 14%. Positive findings were primarily
seen in those with Dravet syndrome, all with SCN1A mutations (42% of clinically
significant results). Given the small sample size, a larger prospective study
would help to determine the clinical yield of next-generation sequencing.
CONCLUSION:
Next-generation sequencing seizure panels could be a useful
tool in the diagnosis of nonacquired pediatric medication-refractory epilepsy
with uninformative comparative genomic hybridization microarray.
Parrini E, Marini C, Mei D, Galuppi A, Cellini E, Pucatti D, Chiti L, Rutigliano D, Bianchini C, Virdò S, De Vita D, Bigoni S, Barba C, Mari F, Montomoli M, Pisano T, Rosati A; Clinical Study Group., Guerrini R. Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Hum Mutat. 2016 Nov 19. doi: 10.1002/humu.23149. [Epub ahead of print]
ReplyDeleteAbstract
Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients seizures onset occurred before age 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5 and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype-genotype correlations. Molecular diagnosis might influence patient's management and translate into better and specific treatment recommendations in some conditions.