Abstract
BackgroundWith 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.MethodsWe 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.ResultsWe 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.ConclusionsOverall, 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.
Highlights
With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs)
Clinical assessment of probands (n = 188–221) expands the phenotypes associated with Heterogeneous nuclear ribonucleoprotein (HNRNP) rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs
Twelve HNRNPs are NDD candidates based on literature search, protein homology, Copy number variant (CNV) intersection, and identification of new probands In order to identify NDD candidate HNRNPs, we initially considered cases with De novo variant (DNV) in the literature
Summary
With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). Among the hundreds of candidate genes proposed for neurodevelopmental disorders (NDDs), genes involved in RNA metabolic processing and regulation of gene expression have been shown to be enriched for de novo variants (DNVs) among probands with NDDs [1]. There are tissue-specific changes in alternative splicing from RBPs resulting in cell-specific phenotypes [4]. As RBPs are necessary for many steps of neuronal RNA metabolism, there are multiple opportunities for dysfunction, which is highlighted by the range of neurological phenotypes resulting from variation in RBP-encoding genes, including neurodegenerative diseases, muscular atrophies, and various cancers. RBPs have been implicated in NDDs, most notably FMR1 in fragile X syndrome
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