title: A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.
abstract: Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole-exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with 2 affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
authors.forename: M-L
authors.initials: ML
authors.lastname: Bondeson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.|Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Ericson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Gudmundsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Ameur
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Center for Clinical Research Dalarna, Falun, Sweden.|Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Wesström
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Frykholm
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
authors.forename: M
authors.identifier: http://orcid.org/0000-0003-3000-0696
authors.initials: M
authors.lastname: Wilbe
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics*; D000483:Alleles; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D000072661:Ciliopathies / Q000235:genetics* / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics*; D004247:DNA / Q000097:blood; D004252:DNA Mutational Analysis; D003616:Dandy-Walker Syndrome / Q000000981:diagnostic imaging / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005333:Fetus / Q000002:abnormalities*; D005808:Genes, Recessive; D056426:Genetic Loci; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D010181:Pancreatic Cyst / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D011256:Pregnancy Outcome
chemical_list: D018797:Cell Cycle Proteins; C505378:Cep55 protein, human; D018389:Codon, Nonsense; D009687:Nuclear Proteins; D004247:DNA
keywords: CEP55; Meckel-like; ciliopathy; cytokinesis; whole-exome sequencing