Abstract
Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype–phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.
Highlights
Heterogeneous nuclear ribonucleoproteins constitute a large group of RNA-binding proteins with multiple roles in RNA metabolism including the regulation of transcription, translation, mRNA stability, mRNA decay, and splicing (Geuens et al 2016)
Pathogenic variants in HNRNPU (OMIM #602869) (Carvill et al 2013; Bramswig et al 2017), HNRNPK (OMIM #600712) (Au et al 2015), HNRNPH2 (OMIM #300610) (Bain et al 2016), HNRNPH1 (OMIM #601035) (Pilch et al 2018; Reichert et al 2020), and HNRNPR (OMIM #607201) (Duijkers et al 2019) were identified in individuals affected by various neurodevelopmental disorders
We report eight individuals including a pair of monozygotic twin brothers harboring likely causative variants in HNRNPH2 (Fig. 1A and Table 1)
Summary
Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a large group of RNA-binding proteins with multiple roles in RNA metabolism including the regulation of transcription, translation, mRNA stability, mRNA decay, and splicing (Geuens et al 2016). Previous studies established pathogenic variants in several genes encoding for hnRNPs as the underlying cause of neurodegenerative and neurodevelopmental disorders. HNRNPA1 (OMIM #164017) and HNRNPA2B1 (OMIM #600124) identified in individuals affected by neurodegenerative diseases including amyotrophic lateral sclerosis (Kim et al 2013). Pathogenic variants in HNRNPU (OMIM #602869) (Carvill et al 2013; Bramswig et al 2017), HNRNPK (OMIM #600712) (Au et al 2015), HNRNPH2 (OMIM #300610) (Bain et al 2016), HNRNPH1 (OMIM #601035) (Pilch et al 2018; Reichert et al 2020), and HNRNPR (OMIM #607201) (Duijkers et al 2019) were identified in individuals affected by various neurodevelopmental disorders. A recent large-scale sequencing study implicated a role for HNRNPAB (OMIM #602688), HNRNPD (OMIM #601324), HNRNPF (OMIM #601037), HNRNPH3 (OMIM #602324), HNRNPUL1 (OMIM #605800), HNRNPUL2 (currently no OMIM #), and HNRNPQ/SYNCRIP (OMIM #616686) in human
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