Journal Article

Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?

Maia, Nuno, Soares, Célia Azevedo, Nabais Sá, Maria João, Jorge, Paula, Prior, Catarina, Porto, Beatriz, Tkachenko, Nataliya, Oliveira, Cláudia, de Brouwer, Arjan P. M., Jacome, Ariana, Santos, Flávia, Santos, Rosário

2021

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Anemia / BRCA1 Protein - genetics / BRCA2 protein / BRCA2 Protein - genetics / Chromosomal Instability / Chromosomes / Complementation / Cytogenetics / Deoxyribonucleic acid / DNA / DNA Damage / DNA Repair / Epstein-Barr virus / FANCG gene / Fanconi anemia / Fanconi Anemia Complementation Group G Protein - genetics / Female / females / Fibroblasts / Genes / Genomes / Genomics / genotype-phenotype correlation / Genotypes / heterozygosity / Histone Deacetylases - genetics / Humans / Infant, Newborn / Laboratories / Mutation / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurodevelopmental Disorders - pathology / patients / Phenotype / Phenotypes / Repressor Proteins - genetics / tumor suppressor proteins