Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Gillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H, Kim CN, De Vries BBA, Vissers LELM, Nordenskjold M, Kvarnung M, Lindstrand A, Nordgren A, Gecz J, Iascone M, Cereda A, Scatigno A, Maitz S, Zanni G, Bertini E, Zweier C, Schuhmann S, Wiesener A, Pepper M, Panjwani H, Torti E, Abid F, Anselm I, Srivastava S, Atwal P, Bacino CA, Bhat G, Cobian K, Bird LM, Friedman J, Wright MS, Callewaert B, Petit F, Mathieu S, Afenjar A, Christensen CK, White KM, Elpeleg O, Berger I, Espineli EJ, Fagerberg C, Brasch-Andersen C, Hansen LK, Feyma T, Hughes S, Thiffault I, Sullivan B, Yan S, Keller K, Keren B, Mignot C, Kooy F, Meuwissen M, Basinger A, Kukolich M, Philips M, Ortega L, Drummond-Borg M, Lauridsen M, Sorensen K, Lehman A, Lopez-Rangel E, Levy P, Lessel D, Lotze T, Madan-Khetarpal S, Sebastian J, Vento J, Vats D, Benman LM, Mckee S, Mirzaa GM, Muss C, Pappas J, Peeters H, Romano C, Elia M, Galesi O, Simon MEH, Van Gassen KLI, Simpson K, Stratton R, Syed S, Thevenon J, Palafoll IV, Vitobello A, Bournez M, Faivre L, Xia K, Earl RK, Nowakowski T, Bernier RA, Eichler EE (2021)

Publication Type: Journal article

Publication year: 2021


Book Volume: 13

Journal Issue: 1

DOI: 10.1186/s13073-021-00870-6


Background 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. Methods 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. Results 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. Conclusions 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.

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Involved external institutions

University of Washington US United States (USA) (US) Odense Universitetshospital (OUH) DK Denmark (DK) Driscoll Children's Hospital US United States (USA) (US) Atwal Clinic US United States (USA) (US) University of California, San Diego US United States (USA) (US) Indiana University Health / Clarian Health Partners US United States (USA) (US) Gillette Childrens Specialty Care US United States (USA) (US) Houston Texas Medical Center US United States (USA) (US) University Hospital Ghent BE Belgium (BE) University of Missouri-Columbia (Mizzou) US United States (USA) (US) ASST Papa Giovanni XXIII IT Italy (IT) Baylor Genetics US United States (USA) (US) Indiana University – Purdue University Indianapolis US United States (USA) (US) Cook Children's Health Care System US United States (USA) (US) Samson Assuta Ashdod University Hospital / Assuta Ashdod Medical Center IL Israel (IL) University of Antwerp / Universiteit Antwerpen BE Belgium (BE) University of British Columbia CA Canada (CA) Azienda Ospedaliera San Gerardo (ASST Monza) IT Italy (IT) Karolinska Institute SE Sweden (SE) Universiteit Utrecht (UU) / Utrecht University NL Netherlands (NL) Harvard University US United States (USA) (US) Hebrew University of Jerusalem IL Israel (IL) Children’s National Health System US United States (USA) (US) University of Adelaide AU Australia (AU) Children's Mercy Hospital US United States (USA) (US) Ospedale Pediatrico Bambino Gesu IT Italy (IT) University of Illinois at Urbana-Champaign US United States (USA) (US) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) FR France (FR) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Assistance Publique-Hôpitaux de Paris (AP-HP) FR France (FR) Oregon Health and Science University (OSHU) US United States (USA) (US) University of Paris 4 - Paris-Sorbonne / Université paris IV Paris-Sorbonne FR France (FR) University of Pittsburgh US United States (USA) (US) Children’s Hospital at Montefiore US United States (USA) (US) Belfast City Hospital / Ospidéal Chathair Bhéal Feirste GB United Kingdom (GB) GeneDX US United States (USA) (US) Radboud University Nijmegen NL Netherlands (NL) Nemours/Alfred I. duPont Hospital for Children US United States (USA) (US) Istituto di ricovero e cura a carattere scientifico (IRCCS) IT Italy (IT) Kaiser Permanente US United States (USA) (US) Kaiser Permanente US United States (USA) (US) University of California San Francisco (UCSF) US United States (USA) (US) New York University (NYU) US United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) Seattle Children's Hospital US United States (USA) (US) Central South University CN China (CN) Université Bourgogne Franche-Comté FR France (FR) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron ES Spain (ES) Centre hospitalier universitaire (CHU) de Dijon Bourgogne FR France (FR) Centre hospitalier universitaire de Grenoble FR France (FR)

How to cite


Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P., Guo, H.,... Eichler, E.E. (2021). Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome Medicine, 13(1). https://doi.org/10.1186/s13073-021-00870-6


Gillentine, Madelyn A., et al. "Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders." Genome Medicine 13.1 (2021).

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