THE IMPORTANCE OF THE RE-ANALYSIS OF THE EXOMIC SEQUENCING: DETECTION OF A NOVO VARIANT IN THE SECOND INSTANCE IN KCNA2 GENE.

PEREZ MATURO JOSEFINA; VEGA PATRICIA; MARTINEZ NERINA; KAUFFMAN MARCELO ANDRÉS

Villa Carlos Paz, Cordoba

Encuentro; Kollege Alexander von Humbolt Current Advances on Neurodegeneraon: From Molecular Biology to Translaonal Medicine; 2017

Whole exome sequencing is a diagnosc tool of great ulity in the study of clinical and genecally heterogeneous disorders. Its overall diagnosc performance is approximately 30%. A non-diagnosc result may be due to pathogenic variants not priorized in the inial analysis, either for issues related to annotaon of variants, interpretaon of phenotype, incorporaon of variants into databases, lack of associaon between genes and phenotypes. The aim of this study is to highlight the importance of the reanalysis of a whole exome sequencing study without inial diagnosis. Case report: A 2-year-old paent with neurological development delay since the 8 months, who at 15 months presented seizures with loss of contact and palpebral clonings, lasng seconds, with rapid recovery, constung an epilepsy, absence of early onset, evoluonary ataxia. There is no relevant family history. Cerebral MRI, metabolic laboratories, glucose/ glucose rao without anomalies, normal female karyotype. A whole exome was requested, which did not find conclusive conclusions in the first instance. Two years aerthe study, the scienfic literature described clinical cases with a very similar phenotype to our paent,aributed to the KCNA2 gene, which resulted in an immediate reanalysis. A nonheterozygous synonymous variant was detected in exon 3 of theKCNA2 gene: c.890 G> A (p.R297Q), previously reported as a pathogen in the series of cases published in the same year, which was found to be new. The found variant generates funcon gain in the potassium voltage-gated cannel Kv1.2, involved in neuronal excitability. This example illustrates how a non-diagnosc result in the exomic sequencing does not discard that the eology of the disease is outside the data already produced. The idenficaon of the causal variant of the disorder allows the genec counseling of the family and in our case study also has therapeuc implicaons, since the treatment was inially iniated with acetazolamide and then with fampridine, Kv1 potassium channel blocker. In paents with high suspicion of a monogenic disorder, periodic reanalysis of the data produced in the first sequencing analysis is essenal to arrive at an eological diagnosis.