Autor(es): Maia, N ; Nabais Sá, Maria João ; Oliveira, Cláudia ; Santos, Flávia ; Soares, Celia A ; Prior, Catarina ; Tkachenko, Nataliya ; Santos, Rosário ; de Brouwer, Arjan P. M. ; Jacome, Ariana ; Porto, Beatriz ; Jorge, Paula
Data: 2021
Identificador Persistente: http://hdl.handle.net/10400.16/2840
Origem: Repositório Científico da Unidade Local de Saúde de Santo António (ULSSA)
Assunto(s): DNA repair pathways; chromosome instability; neurodevelopmental disorder
We describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia/BRCA (FA/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient's chromosome instability represents the first report where heterozygous variant(s) in the FA/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype-phenotype correlations and motivating the biochemical study of the underlying mechanisms.
