Journal article
Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
Genome medicine, Vol.13(1), 63
04/19/2021
DOI: 10.1186/s13073-021-00870-6
PMCID: PMC8056596
PMID: 33874999
Abstract
With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.
We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.
We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.
Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
Details
- Title: Subtitle
- Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
- Creators
- Madelyn A Gillentine - University of Washington School of MedicineTianyun Wang - University of Washington School of MedicineKendra Hoekzema - University of Washington School of MedicineJill Rosenfeld - Baylor College of MedicinePengfei Liu - Baylor GeneticsHui Guo - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaChang N Kim - University of California, San FranciscoBert B A De Vries - Radboud University NijmegenLisenka E L M Vissers - Department of Human Genetics, Radboud University Medical Center, Nijmegen, The NetherlandsMagnus Nordenskjold - Department of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenMalin Kvarnung - Karolinska University HospitalAnna Lindstrand - Karolinska University HospitalAnn Nordgren - Karolinska University HospitalJozef Gecz - South Australian Health and Medical Research Institute, Adelaide, South Australia, AustraliaMaria Iascone - Ospedale Papa Giovanni XXIIIAnna Cereda - Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, ItalyAgnese Scatigno - Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, ItalySilvia Maitz - Genetic Unit, Department of Pediatrics, Fondazione MBBM S. Gerardo Hospital, Monza, ItalyGinevra Zanni - Bambino Gesù Children's HospitalEnrico Bertini - Bambino Gesù Children's HospitalChristiane Zweier - Institut de Génétique HumaineSarah Schuhmann - Institut de Génétique HumaineAntje Wiesener - Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, GermanyMicah Pepper - Seattle Children's Autism Center, Seattle, WA, USAHeena Panjwani - Seattle Children's Autism Center, Seattle, WA, USAErin Torti - GeneDX, Gaithersburg, MD, USAFarida Abid - Texas Children's Hospital, Houston, TX, USAIrina Anselm - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USASiddharth Srivastava - Boston Children's HospitalPaldeep Atwal - The Atwal Clinic: Genomic & Personalized Medicine, Jacksonville, FL, USACarlos A Bacino - Baylor College of MedicineGifty Bhat - University of Illinois ChicagoKatherine Cobian - University of Illinois ChicagoLynne M Bird - Genetics/Dysmorphology, Rady Children's Hospital San Diego, San Diego, CA, USAJennifer Friedman - University of California San DiegoMeredith S Wright - Rady Children's Institute for Genomic Medicine, San Diego, CA, USABert Callewaert - Ghent University HospitalFlorence Petit - Clinique de Génétique, Hôpital Jeanne de Flandre, Bâtiment Modulaire, CHU, 59037, Lille Cedex, FranceSophie Mathieu - Assistance Publique – Hôpitaux de ParisAlexandra Afenjar - Assistance Publique – Hôpitaux de ParisCelenie K Christensen - Indiana UniversityKerry M White - Indiana University HealthOrly Elpeleg - Department of Genetics, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelItai Berger - Ben-Gurion University of the NegevEdward J Espineli - Texas Children's Hospital, Houston, TX, USAChristina Fagerberg - Odense University HospitalCharlotte Brasch-Andersen - Odense University HospitalLars Kjærsgaard Hansen - Odense University HospitalTimothy Feyma - Gillette Children's Specialty HealthcareSusan Hughes - University of Missouri–Kansas CityIsabelle Thiffault - Sisters of Mercy Health SystemBonnie Sullivan - Sisters of Mercy Health SystemShuang Yan - Sisters of Mercy Health SystemKory Keller - Oregon Health & Science UniversityBoris Keren - Birmingham Women’s and Children’s NHS Foundation TrustCyril Mignot - Université Paris CitéFrank Kooy - Department of Medical Genetics, University of Antwerp, Antwerp, BelgiumMarije Meuwissen - University of AntwerpAlice Basinger - Cook Children's Medical CenterMary Kukolich - Genetics Department, Cook Children's Hospital, Fort Worth, TX, USAMeredith Philips - Genetics Department, Cook Children's Hospital, Fort Worth, TX, USALucia Ortega - Genetics Department, Cook Children's Hospital, Fort Worth, TX, USAMargaret Drummond-Borg - Cook Children's Medical CenterMathilde Lauridsen - Odense University HospitalKristina Sorensen - Odense University HospitalAnna Lehman - BC Children's Hospital and BC Women's Hospital, Vancouver, BC, CanadaElena Lopez-Rangel - Sunny Hill Health Centre for ChildrenPaul Levy - Children's Hospital at MontefioreDavor Lessel - University Medical Center Hamburg-EppendorfTimothy Lotze - Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USASuneeta Madan-Khetarpal - UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USAJessica Sebastian - University of PittsburghJodie Vento - University of PittsburghDivya Vats - Kaiser PermanenteL Manace Benman - The Permanente Medical Group, Oakland, CA, USAShane Mckee - Belfast City HospitalGhayda M Mirzaa - Brotman Baty Institute for Precision Medicine, Seattle, WA, USACandace Muss - Community Health Systems - Dupont HospitalJohn Pappas - New York UniversityHilde Peeters - Center for Human GeneticsCorrado Romano - Oasi Maria SSMaurizio Elia - Oasi Research Institute-IRCCS, Troina, ItalyOrnella Galesi - Oasi Research Institute-IRCCS, Troina, ItalyMarleen E H Simon - University Medical Center UtrechtKoen L I van Gassen - Department of Genetics, University Medical Center, Utrecht University, Utrecht, The NetherlandsKara Simpson - Rare Disease Institute, Children's National Health System, Washington, DC, USARobert Stratton - Driscoll Children's HospitalSabeen Syed - Driscoll Children's HospitalJulien Thevenon - Vall d'Hebron Hospital UniversitariIrene Valenzuela Palafoll - Centre de référence Anomalies du développement, CHU Grenoble-Alpes, Grenoble, FranceAntonio Vitobello - Université Bourgogne Franche-ComtéMarie Bournez - Université Bourgogne Franche-ComtéLaurence Faivre - Centre de Référence Maladies Rares « Anomalies du Développement et Syndromes malformatifs » Université Bourgogne Franche-Comté, Dijon, FranceKun Xia - Chinese Academy of SciencesRachel K Earl - University of WashingtonTomasz Nowakowski - University of California, San FranciscoRaphael A Bernier - University of WashingtonEvan E Eichler - Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. eee@gs.washington.eduSPARK Consortium
- Contributors
- Tanner S Koomar (Contributor)Jacob J Michaelson (Contributor) - University of Iowa, Iowa Neuroscience Institute
- Resource Type
- Journal article
- Publication Details
- Genome medicine, Vol.13(1), 63
- DOI
- 10.1186/s13073-021-00870-6
- PMID
- 33874999
- PMCID
- PMC8056596
- NLM abbreviation
- Genome Med
- ISSN
- 1756-994X
- eISSN
- 1756-994X
- Grant note
- Wellcome Trust Department of Health P30 ES010126 / NIEHS NIH HHS Howard Hughes Medical Institute T32 HG000035 / NHGRI NIH HHS K08 NS092898 / NINDS NIH HHS R01 MH101221 / NIMH NIH HHS
- Language
- English
- Date published
- 04/19/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984530558702771
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