Show simple item record

 
dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorGillentine, Madelyn A.
dc.contributor.authorWang, Tianyun
dc.contributor.authorHoekzema, Kendra
dc.contributor.authorRosenfeld, Jill
dc.contributor.authorLiu, Pengfei
dc.contributor.authorGuo, Hui
dc.contributor.authorThevenon, Julien
dc.date.accessioned2021-12-17T11:56:24Z
dc.date.available2021-12-17T11:56:24Z
dc.date.issued2021-04-19
dc.identifier.citationGillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H, et al. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome Med. 2021 Apr 19;13:63.
dc.identifier.issn1756-994X
dc.identifier.urihttp://hdl.handle.net/11351/6710
dc.descriptionGene families; Neurodevelopmental disorders; HnRNPs
dc.description.abstractBackground 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.
dc.language.isoeng
dc.publisherBMC
dc.relation.ispartofseriesGenome Medicine;13
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectMalalties mentals - Aspectes genètics
dc.subjectNeurogenètica
dc.subject.meshNeurodevelopmental Disorders
dc.subject.mesh/genetics
dc.subject.meshGenomics
dc.subject.mesh/methods
dc.titleRare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1186/s13073-021-00870-6
dc.subject.decstrastornos del desarrollo neurológico
dc.subject.decs/genética
dc.subject.decsgenómica
dc.subject.decs/métodos
dc.relation.publishversionhttps://doi.org/10.1186/s13073-021-00870-6
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[Gillentine MA, Wang T, Hoekzema K] Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA. [Rosenfeld J] Baylor Genetics Laboratories, Houston, TX, USA. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA. [Liu P] Baylor Genetics Laboratories, Houston, TX, USA. [Guo H] Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. [Thevenon J] Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain
dc.identifier.pmid33874999
dc.identifier.wos000641712700001
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record