Dataset Information

Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene.

ABSTRACT: IMPORTANCE:The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS. OBJECTIVE:To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases. DESIGN:Whole-exome sequencing and follow up-screening by Sanger sequencing. SETTING:Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France. PARTICIPANTS:A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype. INTERVENTIONS:Whole-exome sequencing in a family and Sanger sequencing of CSF1R. MAIN OUTCOMES AND MEASURES:Mutations in CSF1R. RESULTS:We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS. CONCLUSIONS AND RELEVANCE:These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.

SUBMITTER: Guerreiro R

PROVIDER: S-EPMC4204151 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene.

Guerreiro Rita R Kara Eleanna E Le Ber Isabelle I Bras Jose J Rohrer Jonathan D JD Taipa Ricardo R Lashley Tammaryn T Dupuits Céline C Gurunlian Nicole N Mochel Fanny F Warren Jason D JD Hannequin Didier D Sedel Frédéric F Depienne Christel C Camuzat Agnès A Golfier Véronique V Du Boisguéheneuc Foucaud F Schottlaender Lucia L Fox Nick C NC Beck Jonathan J Mead Simon S Rossor Martin N MN Hardy John J Revesz Tamas T Brice Alexis A Houlden Henry H

JAMA neurology 20130701 7

<h4>Importance</h4>The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. R ...[more]

PMID: 23649896

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Project description:Background Inherited retinal diseases (IRD) represent a prominent etiology of visual impairment on a global scale. The lack of a clear definition of the etiology and genotypic spectrum of IRD is attributed to the significant genetic variability seen. Additionally, there is a scarcity of available data about the correlations between genotypes and phenotypes in this context. This study aimed to clarify the range of mutations and the associations between genotypes and phenotypes in IRD. Methods This cohort consists of 223 patients who have been diagnosed with a range of retinal illnesses, such as retinitis pigmentosa (RP), Stargardt (STGD)/STGD-like disease, Usher syndrome, and Leber congenital amaurosis (LCA). The validation of each mutation and its pathogenicity was conducted by bioinformatics analysis, Sanger sequencing-based co-segregation testing, and computational assessment. The link between genotype and phenotype was analyzed in all patients who possessed mutations as described in the recommendations established by the American College of Medical Genetics. Results A total of 223 cases, comprising Turkish and Syrian families, were examined, revealing the presence of 175 distinct mutations in the IRD gene. Among these mutations, 58 were identified as unique, indicating that they had not been previously reported. A total of 119 mutations were identified to be likely pathogenic, while 104 mutations were classified as pathogenic. The study identified patterns of heredity, namely autosomal recessive, dominant, and X-linked inheritance. Conclusions The findings of this study broaden the clinical and molecular aspects of IRD and further enhance our understanding of its complex nature. The discovery of previously unknown relationships between genetic variations and observable traits, as well as the wide range of genetic variants associated with IRD, significantly contributes to our existing understanding of the diverse phenotypic and genotypic characteristics of IRD. This new information will prove invaluable in facilitating accurate clinical diagnoses as well as personalized therapeutic interventions for individuals affected by IRD.

Dataset Information

Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene.

Publications

Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene.

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