FINCA syndrome beyond pulmonary affection: biallelic NHLRC2 variants in eight families with intellectual disability and epilepsy

Abstract

FINCA syndrome is an autosomal recessive inherited multisystemic disorder characterized by pulmonary fibrosis, neurodegeneration and cerebral angiomatosis. So far, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected at least on one allele. Common manifestations comprised pulmonary fibrosis, respiratory distress, developmental delay, muscular hypotonia, dystonia, seizures and brain atrophy, followed mostly by early demise due to progression of disease. Here, we present ten individuals from eight families with an overlapping but static phenotype with much longer survival, associated with seven novel NHLRC2 variants identified by exome analysis. All of the here described patients presented with severe global developmental delay. While seizures and EEG abnormalities were observed as frequent manifestations, eight individuals did not show any signs of pulmonary involvement or distinct MRI abnormalities. Notably, we also present the first seven cases in which the recurrent p.(Asp148Tyr) variant was not detected, neither in homozygous nor in compound heterozygous state. Interestingly, none of these cases presented with the classic FINCA phenotype. However, bioinformatic modeling and analyses could not establish a distinct genotype phenotype correlation. Taken together, our findings broaden the known phenotypic and molecular spectrum and propose that NHLRC2 related disease should also be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy without pulmonary findings.