Broadening the Phenotypic and Molecular Spectrum of FINCA Syndrome: Biallelic NHLRC2 Variants in 15 Novel Individuals

Authors

Henrike L Sczakiel
Max Zhao
Brigitte Wollert-Wulf
Magdalena Danyel
Nadja Ehmke
Corinna Stoltenburg
Nadirah Damseh
Motee Al-Ashhab
Tugce B Balci
Matthew Osmond
Andrea Andrade
Jens Schallner
Joseph Porrmann
Kimberly McDonald
Mingjuan Liao
Henry Oppermann
Konrad Platzer
Nadine Dierksen
Majid Mojarrad
Atieh Eslahi
Behnaz Bakaeean
Daniel G Calame
James R Lupski
Zahra Firoozfar
Seyed Mohammad Seyedhassani
Seyed Ahmad Mohammadi
Najwa Anwaar
Fatima Rahman
Dominik Seelow
Martin Janz
Denise Horn
Reza Maroofian
Felix Boschann

Publication Date

8-1-2023

Journal

European Journal of Human Genetics

DOI

10.1038/s41431-023-01382-0

PMID

37188825

PMCID

PMC10400545

PubMedCentral® Posted Date

5-15-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Disease Progression, Fibrosis, HEK293 Cells, Intellectual Disability, Movement Disorders, Phenotype, Seizures, Syndrome, Genetics research, Clinical genetics

Abstract

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.

Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.

We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.

Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement.