title: Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome.
abstract: Ritscher-Schinzel syndrome (RSS)/3C (cranio-cerebro-cardiac) syndrome (OMIM#220210) is a rare and clinically heterogeneous developmental disorder characterized by intellectual disability, cerebellar brain malformations, congenital heart defects, and craniofacial abnormalities. A recent study of a Canadian cohort identified homozygous sequence variants in the KIAA0196 gene, which encodes the WASH complex subunit strumpellin, as a cause for a form of RSS/3C syndrome. We have searched for genetic causes of a phenotype similar to RSS/3C syndrome in an Austrian family with two affected sons. To search for disease-causing variants, whole-exome sequencing (WES) was performed on samples from two affected male children and their parents. Before WES, CGH array comparative genomic hybridization was applied. Validation of WES and segregation studies was done using routine Sanger sequencing. Exome sequencing detected a missense variant (c.1670A>G; p.(Tyr557Cys)) in exon 15 of the CCDC22 gene, which maps to chromosome Xp11.23. Western blots of immortalized lymphoblastoid cell lines (LCLs) from the affected individual showed decreased expression of CCDC22 and an increased expression of WASH1 but a normal expression of strumpellin and FAM21 in the patients cells. We identified a variant in CCDC22 gene as the cause of an X-linked phenotype similar to RSS/3C syndrome in the family described here. A hypomorphic variant in CCDC22 was previously reported in association with a familial case of syndromic X-linked intellectual disability, which shows phenotypic overlap with RSS/3C syndrome. Thus, different inactivating variants affecting CCDC22 are associated with a phenotype similar to RSS/3C syndrome.
authors.affiliation: 1] Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Kolanczyk
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Krawitz
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Hupalowska
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Miaczynska
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Marschner
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Schlack
authors.affiliation: 1] Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Emmerich
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kobus
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.affiliation: Division of Child Neurology, University Children's Hospital Zurich, Zürich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.affiliation: Department of Pediatrics, Medical University Graz, Graz, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Grangl
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Uhrig
authors.affiliation: 1] Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Max Planck Institute for Molecular Genetics, Berlin, Germany [3] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D000293:Adolescent; D000595:Amino Acid Sequence; D002460:Cell Line; D002648:Child; D055028:Comparative Genomic Hybridization; D019465:Craniofacial Abnormalities / Q000175:diagnosis* / Q000235:genetics*; D003616:Dandy-Walker Syndrome / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D015870:Gene Expression; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D006344:Heart Septal Defects, Atrial / Q000175:diagnosis* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: C571908:CCDC22 protein, human; D011506:Proteins