title: GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.
abstract: We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.
authors.affiliation: Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Alberta, Canada.
authors.forename: P Y Billie
authors.initials: PYB
authors.lastname: Au
authors.affiliation: Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: You
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Oana
authors.initials: O
authors.lastname: Caluseriu
authors.affiliation: Department of Human Genetics, McGill and Genome Quebec Innovation Center, McGill University, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Department of Human Genetics, McGill and Genome Quebec Innovation Center, McGill University, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Alberta, Canada.|Alberta Children's Hospital, Research Institute for Child and Maternal Health, University of Calgary, Alberta, Canada.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.affiliation: Harvey Institute for Human Genetics, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD.
authors.forename: Marcia
authors.initials: M
authors.lastname: Ferguson
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.affiliation: Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Alberta, Canada.|Alberta Children's Hospital, Research Institute for Child and Maternal Health, University of Calgary, Alberta, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nara
authors.initials: N
authors.lastname: Sobreira
authors.affiliation: Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Alberta, Canada.|Alberta Children's Hospital, Research Institute for Child and Maternal Health, University of Calgary, Alberta, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Harvey Institute for Human Genetics, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD.
authors.forename: Antonie D
authors.initials: AD
authors.lastname: Kline
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D002648:Child; D019465:Craniofacial Abnormalities / Q000235:genetics*; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D006801:Humans; D033181:Information Dissemination; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009133:Muscular Atrophy / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012261:Ribonucleoproteins / Q000235:genetics*; D012984:Software; D064878:Web Browser
chemical_list: D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D012261:Ribonucleoproteins; C072074:HNRNPK protein, human
keywords: GeneMatcher; HNRNPK; WES; matchmaker exchange; reverse phenotyping