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Global Presence and Penetrance of CSF1R-Related Disorder
Jaroslaw Dulski1, Matthew Baker1, Samantha A Banks1
1From the Department of Neurology (J.D., Z.K.W.), Mayo Clinic, Jacksonville, FL; Division of Neurological and Psychiatric Nursing (J.D.), Faculty of Health Sciences, Medical University of Gdansk; Neurology Department (J.D.), St Adalbert Hospital, Copernicus PL Ltd., Gdansk, Poland; Department of Neuroscience (M. Baker), Mayo Clinic, Jacksonville, FL; Department of Neurology (S.A.B., O.H.K.), Mayo Clinic, Rochester, MN; Department of Neurology (M. Bayat); Centre for Rare Diseases (M. Bayat), Aarhus University Hospital, Aarhus, Denmark; Experimental Neurobiology Unit (R.B.), Department of Biomedical Sciences, University of Antwerp; Department of Neurology, Antwerp University Hospital, Belgium; Center for Research in Genetics and Genomics (CIGEN) (G.O.C.), Autonomous University of Coahuila, México; Universidade Federal do Paraná (C.C.D.), Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Curitiba, Brazil; Department of Pediatrics (K.S.F.), Section of Neurology and Developmental Neuroscience, Baylor College of Medicine (BCM), Houston, TX; Department of Paediatrics (J.N.J.), St. Johns Medical College, Bangalore, Karnataka, India; Office of the Dean (B.K.), University of Pécs, School of Medicine; Molecular Medicine (B.K.), Markusovszky University Teaching Hospital, Szombathely, Hungary; Immunology and Molecular Biology Laboratory of Experimental and Clinical Medicine Institute at the O'Bogomolets National Medical University (D.M.), Kyiv, Ukraine; General Practice (C.M.), Brisbane, Queensland, Australia; Department of Cognitive Neurology and Neurodegenerative Diseases (G.N.), University Clinic of Neurology, Medical Faculty, University "Ss. Cyril and Methodius", Institute for Alzheimer's Disease and Neuroscience-Skopje; Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov" (D.P.-K.), Macedonian Academy of Sciences and Arts, Skopje, North Macedonia; Postgraduate Program in Child and Adolescent (S.R.), Department of Pediatrics, Federal University of Paraná, Curitiba; School of Medicine (J.S.), Pontificia Universidade Católica do Paraná (PUCPR); Department of Genetics (J.S.), Hospital Infantil Pequeno Príncipe; and Universidade Federal do Paraná (H.A.T.), Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Setor de Distúrbios do Movimento, Curitiba, Brazil.
Objectives:
To highlight the worldwide presence of CSF1R-related disorder (CSF1R-RD), discuss its penetrance, and provide the first haplotype analysis.
Methods:
Data on patients worldwide were collected, including demographics, genotype, family history, and clinical status. For haplotype analysis, polymorphisms of short tandem repeats in 3 distinct families with CSF1R p.Ile794Thr variant were examined.
Results:
Nineteen new patients were included, at a mean age of 38.7 years (ranging from 11 to 74 years), from 14 families from the Americas, Asia, Australia, and Europe, including the first from Mexico, North Macedonia, and Ukraine. Fifteen CSF1R variants were found, including 8 novel. Three patients were compound heterozygotes with disease onset at 1, 4, and 22 years. Patients with heterozygous CSF1R variants developed symptoms at a mean of 39.0 years (range 8-71 years). Four patients died at a mean of 3.3 years from onset (range 2-5 years). Negative family history was noted in 7 patients. In haplotype analysis, 2 families exhibited shared haplotype encompassing ∼6-Mb region downstream of the CSF1R while the third family displayed a different haplotype.
Discussion:
CSF1R-RD has a global prevalence. The reasons for negative family history include de novo variants (as shown by the haplotype analysis), mosaicism, and incomplete penetrance, which are possibly modulated by environmental and genetic factors.
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