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

P Y Billie Au; Jing You; Oana Caluseriu; Jeremy Schwartzentruber; Jacek Majewski; Francois P Bernier; Marcia Ferguson; Care for Rare Canada Consortium; David Valle; Jillian S Parboosingh; Nara Sobreira; A Micheil Innes; Antonie D Kline

doi:10.1002/humu.22837

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

Hum Mutat. 2015 Oct;36(10):1009-1014. doi: 10.1002/humu.22837. Epub 2015 Aug 6.

Authors

P Y Billie Au^#¹, Jing You^#^{2

3}, Oana Caluseriu⁴, Jeremy Schwartzentruber⁵, Jacek Majewski⁵, Francois P Bernier^{1

6}, Marcia Ferguson⁷; Care for Rare Canada Consortium; David Valle^{3

8

9}, Jillian S Parboosingh^{1

6}, Nara Sobreira³, A Micheil Innes^#^{1

6}, Antonie D Kline^#⁷

Affiliations

¹ Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Alberta, Canada.
² Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
⁵ Department of Human Genetics, McGill and Genome Quebec Innovation Center, McGill University, Quebec, Canada.
⁶ Alberta Children's Hospital, Research Institute for Child and Maternal Health, University of Calgary, Alberta, Canada.
⁷ Harvey Institute for Human Genetics, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD.
⁸ Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
⁹ 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.

^# Contributed equally.

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.

Keywords: GeneMatcher; HNRNPK; WES; matchmaker exchange; reverse phenotyping.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Adolescent
Child
Craniofacial Abnormalities / genetics*
Databases, Genetic*
Genetic Predisposition to Disease
Heterogeneous-Nuclear Ribonucleoprotein K
Humans
Information Dissemination
Intellectual Disability / genetics*
Male
Muscular Atrophy / genetics*
Phenotype
Polymorphism, Single Nucleotide*
Ribonucleoproteins / genetics*
Software
Web Browser

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

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Abstract

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