title: Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy.
abstract: Intellectual disability (ID) with cerebellar ataxia comprises a genetically heterogeneous group of neurodevelopmental disorders. We identified a homozygous frameshift mutation in CWF19L1 (c.467delC; p.(P156Hfs*33)) by a combination of linkage analysis and Whole Exome Sequencing in a consanguineous Turkish family with a 9-year-old boy affected by early onset cerebellar ataxia and mild ID. Serial MRI showed mildly progressive cerebellar atrophy. Absent C19L1 protein expression in lymphoblastoid cell lines strongly suggested that c.467delC is a disease-causing alteration. One further pregnancy of the mother had been terminated at 22 weeks of gestation because of a small cerebellum and agenesis of corpus callosum. The homozygous CWF19L1 variant was also present in the fetus. Postmortem examination of the fetus in addition showed unilateral hexadactyly and vertebral malformations. These features have not been reported and may represent an expansion of the CWF19L1-related phenotypic spectrum, but could also be due to another, possibly autosomal recessive disorder. The exact function of the evolutionarily highly conserved C19L1 protein is unknown. So far, homozygous or compound heterozygous mutations in CWF19L1 have been identified in two Turkish siblings and a Dutch girl, respectively, affected by cerebellar ataxia and ID. A zebrafish model showed that CWF19L1 loss-of-function mutations result in abnormal cerebellar morphology and movement disorders. Our report corroborates that loss-of-function mutations in CWF19Ll lead to early onset cerebellar ataxia and (progressive) cerebellar atrophy. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Evers
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kaufmann
authors.affiliation: Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Seitz
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Medical Faculty Heidelberg, Heidelberg University, Germany.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Paramasivam
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Granzow
authors.affiliation: Center for Child and Adolescent Medicine, Pediatric Neurology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Karch
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology, Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Gdynia
authors.affiliation: Department of Obstetrics and Gynecology, Prenatal Medicine, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Elsässer
authors.affiliation: Genomics and Proteomics Core Facility (GPCF), High Throughput Sequencing, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pinkert
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
mesh_terms: D001921:Brain / Q000002:abnormalities; D018797:Cell Cycle Proteins / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D055028:Comparative Genomic Hybridization; D003241:Consanguinity; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics; D059472:Exome; D056726:Genetic Association Studies; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009421:Nervous System Malformations / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011859:Radiography
chemical_list: C000595891:CWF19L1 protein, human; D018797:Cell Cycle Proteins
keywords: CWF19L1; ataxia; cerebellar atrophy; cerebellar hypoplasia; developmental delay; intellectual disability