title: Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females.
abstract: Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bain
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Telegrafi
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Department of Pediatrics, Rutgers Robert Wood Johnson Medical Group, New Brunswick, NJ 08901, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Brooks
authors.affiliation: Department of Pediatrics, Rutgers Robert Wood Johnson Medical Group, New Brunswick, NJ 08901, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Botti
authors.affiliation: Weisskopf Child Evaluation Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Gowans
authors.affiliation: Weisskopf Child Evaluation Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Autullo
authors.affiliation: Pediatrics & Genetics, Alpharetta, GA 30005, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Krishnamurthy
authors.affiliation: Division of Genetics & Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Willing
authors.affiliation: Division of Genetics & Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Tomi L
authors.initials: TL
authors.lastname: Toler
authors.affiliation: Pediatric Neurology, Edmond and Lily Safra Children's Hospital at Sheba, Derech Sheba 2, Tel Hashomer, Ramat Gan, Israel.
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zev
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Departments of Biomedical Informatics and Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: wkc15@columbia.edu.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics; D020964:Embryo Loss / Q000235:genetics; D059472:Exome / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D005787:Gene Frequency; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D019913:Nuclear Localization Signals; D010641:Phenotype; D012640:Seizures / Q000235:genetics; D012727:Sex Characteristics
chemical_list: C116747:HNRNPH2 protein, human; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D019913:Nuclear Localization Signals
keywords: HNRNPH2; X chromosome; alternative splicing; autism; developmental delay; microcephaly; neurodevelopment; pre-mRNA