A disease‐causing variant in HNRNPH2 inherited from an unaffected mother with skewed X‐inactivation

To the Editor HNRNPH2-related disorder (MIM: 300986) is an X-linked dominant neurodevelopmental disorder caused by disruption of the regulation of heterogeneous nuclear ribonucleoproteins (hnRNPs) (Bain et al., 2016). These ribonucleoproteins are involved in splicing regulation and alternative splicing and thereby play an important role in the developmental and cell-type-specific control of gene expression (Chou, Rooke, Turck, & Black, 1999; Honore et al., 1995). The HNRNPH2-related disorder is characterized by global developmental delay, intellectual disability, behavioral and psychiatric issues, cerebellar hypoplasia, ataxia, seizures, and dysmorphic features (Bain et al., 2016). Additional features include musculoskeletal abnormalities, such as hypotonia and joint laxity, as well as acquired microcephaly and feeding problems with poor overall growth (Peron et al., 2020). Bain et al. (2016) first reported six unrelated females who all carried de novo missense variants in HNRNPH2 (MIM: 300610) five of which were located at amino acid position 206 and a sixth de novo variant located at the nearby amino acid position 209. The variants reside within a glycine-rich nuclear localization sequence (NLS); the NLS is critical for the localization of the HNRNPH2 protein to the nucleus where it can bind to heterogeneous nuclear RNA (Bain et al., 2016). While there are no studies specifically demonstrating HNRNPH2 expression throughout development, mechanisms associated with pre-mRNA alternative splicing and aberrations in splicing have been increasingly recognized as a cause of developmental disorders (Bain et al., 2016; Homsy et al., 2015). To date, 33 individuals with 11 different de novo missense variants in HNRNPH2 have been reported in the literature with a phenotype consistent with the clinical spectrum of HNRNPH2-related disorder (Bain et al., 2021). The majority of patients presented with a similar history of developmental delay/intellectual disability, severe language impairment, motor deficits, and musculoskeletal issues including joint laxity, low tone, and scoliosis (Bain et al., 2021; Sanchis-Juan et al., 2019; Somashekar et al., 2020). Some individuals were also reported to have dysmorphic features, epilepsy, autism spectrum disorder, cortical visual impairment, and rarely, early stroke and premature death (Bain et al., 2021). It was previously hypothesized that males with HNRNPH2-related disorder were embryonic lethal but there are now four male individuals reported in the literature with HNRNPH2 variants associated with the condition (Bain et al., 2021; Harmsen, Buchert, Mayatepek, Haack, & Distelmaier, 2019; Jepsen et al., 2019; Sanchis-Juan et al., 2019). Here, we report an additional affected adult female with a known pathogenic missense variant in HNRNPH2 [GRCh37/hg19: NM_019597. 4: c.616C>T, p.(Arg206Trp)] which was identified by research reanalysis of singleton exome sequencing (ES) data. The pathogenic p.(Arg206Trp) variant was inherited from her biological mother who does not present with any symptoms associated with the HNRNPH2-related disorder but does show markedly skewed Xchromosome inactivation. The proband is a 22-year-old female of French-Canadian ancestry with a noncontributory family history. She was born following an unremarkable pregnancy to nonconsanguineous parents. She presented at 18 months of age with developmental concerns including severe fine and gross motor delays. She walked unassisted at 3 years of age. She also presented with deficits in language skills with only 5– 6 words at 4 years of age. There was a maternally reported regression in expressive language at 8 years of age and today she is nonverbal. Received: 6 October 2021 Accepted: 11 October 2021