Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
Creators: name: Gillentine, Madelyn A
name: Wang, Tianyun
name: Hoekzema, Kendra
name: Rosenfeld, Jill
name: Liu, Pengfei
name: Guo, Hui
name: Kim, Chang N
name: De Vries, Bert B A
name: Vissers, Lisenka E L M
name: Nordenskjold, Magnus
name: Kvarnung, Malin
name: Lindstrand, Anna
name: Nordgren, Ann
name: Gecz, Jozef
name: Iascone, Maria
name: Cereda, Anna
name: Scatigno, Agnese
name: Maitz, Silvia
name: Zanni, Ginevra
name: Bertini, Enrico
name: Zweier, Christiane
name: Schuhmann, Sarah
name: Wiesener, Antje
name: Pepper, Micah
name: Panjwani, Heena
name: Torti, Erin
name: Abid, Farida
name: Anselm, Irina
name: Srivastava, Siddharth
name: Atwal, Paldeep
name: Bacino, Carlos A
name: Bhat, Gifty
name: Cobian, Katherine
name: Bird, Lynne M
name: Friedman, Jennifer
name: Wright, Meredith S
name: Callewaert, Bert
name: Petit, Florence
name: Mathieu, Sophie
name: Afenjar, Alexandra
name: Christensen, Celenie K
name: White, Kerry M
name: Elpeleg, Orly
name: Berger, Itai
name: Espineli, Edward J
name: Fagerberg, Christina
name: Brasch-Andersen, Charlotte
name: Hansen, Lars K
name: Feyma, Timothy
name: Hughes, Susan
name: Thiffault, Isabelle
name: Sullivan, Bonnie
name: Yan, Shuang
name: Keller, Kory
name: Keren, Boris
name: Mignot, Cyril
name: Kooy, Frank
name: Meuwissen, Marije
name: Basinger, Alice
name: Kukolich, Mary
name: Philips, Meredith
name: Ortega, Lucia
name: Drummond-Borg, Margaret
name: Lauridsen, Mathilde
name: Sorensen, Kristina
name: Lehman, Anna
name: Lopez-Rangel, Elena
name: Levy, Paul
name: Lessel, Davor
name: Lotze, Timothy
name: Madan-Khetarpal, Suneeta
name: Sebastian, Jessica
name: Vento, Jodie
name: Vats, Divya
name: Benman, L. M
name: Mckee, Shane
name: Mirzaa, Ghayda M
name: Muss, Candace
name: Pappas, John
name: Peeters, Hilde
name: Romano, Corrado
name: Elia, Maurizio
name: Galesi, Ornella
name: Simon, Marleen E H
name: Van Gassen, Koen L I
name: Simpson, Kara
name: Stratton, Robert
name: Syed, Sabeen
name: Thevenon, Julien
name: Palafoll, Irene V
name: Vitobello, Antonio
name: Bournez, Marie
name: Faivre, Laurence
name: Xia, Kun
name: Earl, Rachel K
name: Nowakowski, Tomasz
name: Bernier, Raphael A
name: Eichler, Evan E
Publisher: name: BioMed Central
Year: 2021

description: 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.