1 - Unidade de Genética Médica, Área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central (CHULC), Lisboa, Portugal
2 -Centro de Genética Preditiva e Preventiva (CGPP), Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Portugal
- ERN-ITHACA EuroNDD Workshop: interdisciplinary perspectives for rare genetic Neurodevelopmental Disorders, 20-21 abril 2023, Amesterdão - Países Baixos
- (Reunião Internacional)
Case description: A healthy non-consanguineous couple had two infant deaths. The first baby boy deceased at 4-month-old with early-onset epileptic encephalopathy with burst-suppression pattern on EEG, resistant to treatment. He also had progressive hypotonia, microcephaly and arthrogryposis. WES revealed a novel heterozygous in GRIN2B(NM_000834.3):1852G>A, p.(Val618Ile), of unknown significance, inherited from the mother and grandmother, both healthy. Four years later, a second baby boy was born with the same epilepsy pattern and died at 24 days-old. A second WES in trio did not show any further variants.
Discussion: GRIN2B pathogenic variants are known to cause Epileptic Encephalopathy, Early Infantile, 27 (EEEI27; MIM#616139). EEEI27 patients usually present with early-onset encephalopathy irresponsive to treatment. Other findings include microcephaly; dystonic, dyskinetic, or choreiform movement disorder; cortical visual impairment; malformation of cortical development; hypsarrhytmia seen on EEG; and/or malformations of cortical development. Regarding the reported variant, it was not present in gnomAD population database (PM2), nor the literature. It is a missense variant in a gene with low rate of benign missense mutations and for which missense mutation is a common mechanism of a disease (PP2). It is located in a mutational hot spot and critical and well-established functional domain, corresponding to the ion channel-forming reentrant loop implicated in magnesium blockade (PM1). Finally, it locates to the same codon as of known other pathogenic variant with a different amino acid change (PM5). However, this variant was present in the healthy mother. Given the current information and the fact that all reported cases of GRIN2B-encephalopathy were de novo, the variant was classified as of unknown significance.
Conclusion: We describe an inherited heterozygous variant in the GRIN2B gene in two brothers with early-onset epileptic encephalopathy. To our knowledge, there is no report of incomplete penetrance related to GRIN2B gene variants. We need further studies or evidence to solve this family case. A molecular diagnosis would be important for the couple. Without a molecular diagnosis, a precise recurrence risk and reproductive options such as invasive prenatal diagnosis or pre-implantation diagnosis are not possible.
Palavras Chave: Epileptic Encephalopathy, GRIN2B gene