Tallgren A, Kager L, O’Grady G, Tuominen H, Körkkö J, Kuismin O, Feucht M, Wilson C, Behunova J, England E, Kurki MI, Palotie A, Hallman M, Kaarteenaho R, Laccone F, Boztug K, Hinttala R and Uusimaa J (2023) Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease. Front. Neurosci. 17:1123327. doi: 10.3389/fnins.2023.1123327
Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease
|Author:||Tallgren, Antti1; Kager, Leo2,3,4; O’Grady, Gina5;|
1Research Unit of Clinical Medicine and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
2St. Anna Children’s Hospital, Vienna, Austria
3Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
4St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
5Paediatric Neuroservices, Starship Children’s Health, Te Whatu Ora Health New Zealand, Auckland, New Zealand
6Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland
7Center for Intellectual Disability Care, Oulu University Hospital, Oulu, Finland
8Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
9Department of Paediatrics, Center for Rare and Complex Epilepsies, Medical University of Vienna, Vienna, Austria
10National Metabolic Service, Auckland City Hospital, Auckland, New Zealand
11Department of Medical Genetics, Medical University of Vienna, Vienna, Austria
12Mendelian Genomics, Programme in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
13Programme in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
14Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
15Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
16Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
17Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
18Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
19Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
20Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland
21Research Unit of Internal Medicine, University of Oulu, Oulu, Finland
22Center of Internal Medicine and Respiratory Medicine and Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland
23CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
24Biocenter Oulu, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 4.8 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe20231002138019
|Publish Date:|| 2023-10-02
Purpose: FINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene. Our previous studies have shown that Nhlrc2-null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown.
Methods: The clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic NHLRC2 variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients.
Results: One patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic NHLRC2 gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain.
Conclusion: This report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations.
Frontiers in neuroscience
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3121 General medicine, internal medicine and other clinical medicine
This study was supported by the Academy of Finland Grants 266498, 273790, 303996, 317711, 311934, and 331436, the Sigrid Jusélius Foundation, the Foundation for Pediatric Research, Finland, the Emil Aaltonen Foundation, and the Alma and K. A. Snellman Foundation. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Centre for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141, and the Athlae Lyons Starship Research Trust and Starship Foundation.
|Academy of Finland Grant Number:||
266498 (Academy of Finland Funding decision)
273790 (Academy of Finland Funding decision)
303996 (Academy of Finland Funding decision)
317711 (Academy of Finland Funding decision)
331436 (Academy of Finland Funding decision)
© 2023 Tallgren, Kager, O’Grady, Tuominen, Körkkö, Kuismin, Feucht, Wilson, Behunova, England, Kurki, Palotie, Hallman, Kaarteenaho, Laccone, Boztug, Hinttala and Uusimaa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.