HNRNPH1‐related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2‐related X‐linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1‐related syndromic intellectual disability.


Peer Review
The peer review history for this article is available at https://publons.com/publon/10. 1111/cge.13765. cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability. respectively. These proteins belong to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of RNA binding proteins which bind to pre-mRNA transcripts and assist in stabilizing, transporting, and targeting transcripts between the nucleus and cytoplasm for processing and alternative splicing prior to becoming mature mRNAs. 1 More than 20 hnRNPs have been identified, and hnRNP H and hnRNP H 0 share 96% homology. Both genes are ubiquitously expressed across multiple tissue types including the brain, eye, smooth muscle, small intestine, and stomach. 2 The functions of hnRNP H and H 0 on pre-mRNA processing include capping, splicing, polyadenylation, export, and translation and are mainly exerted within the nucleus. 3 Given their central role in cellular function, it is not surprising that pathogenic variants affecting genes that code for hnRNPs are an emerging cause of disease. Altered expression of hnRNPs has been linked to tumorigenesis and germline variants in genes encoding hnRNPs have been implicated as a potential causes of adult-onset neurodegenerative conditions including frontotemporal dementia/ amyotrophic lateral sclerosis, inclusion body myopathy with frontotemporal dementia (IBMPFM [MIM: 615424]), and Alzheimer disease. 1,4 Whole exome sequencing (WES) has identified multiple HNRNP genes as novel causes of early-onset syndromic intellectual disability. [5][6][7] In 2016, pathogenic variants in HNRNPH2 were reported as a novel cause for an X-linked intellectual disability syndrome in females. 6  Here, we present an additional seven cases of de novo pathogenic variants in HNRNPH1 to further characterize and expand the phenotype initially described by Pilch et al.

| MATERIALS AND METHODS
Seven individuals with HNRNPH1 pathogenic variants were identified using GeneMatcher and clinical networks. 12 One individual resides in the United States, the remaining in the European Union. DNA extracted form peripheral blood was analyzed by WES on all individuals using standard technologies. Details on case specific WES can be found in Supporting Materials. This series was reviewed by the VCU Health IRB and not found to meet the definitions of human subjects research, and thus did not require IRB review or approval. Written informed consent was obtained for individuals whose photographs are included within this report. We characterized their phenotype retrospectively and contrasted them with features reported previously by Pilch et al as well as with individuals with MRXSB.

| RESULTS
The seven individuals range in age from a fetus at 30w4d to a 23-year-old. The five surviving cases have intellectual disability, ranging from moderate to severe. Congenital anomalies were observed in this cohort, with 7/7 having abnormalities identified on brain MRI, 4/7 having palate abnormalities, and 3/7 having genitourinary malformations. Other notable features observed include ophthalmological abnormalities (6/7), short stature (5/7), microcephaly (5/7), and hypotonia (4/7). Developmental regression is not observed in this cohort.

4/6 surviving individuals are non-verbal or have very limited speech.
A complete phenotypic review can be found in Table 1 (1/11) ataxia; (1/11) athetoid movements; (1/11) involuntary movements; (1/ (11) dystonic posturing Non-ambulatory Non-ambulatory Six variants were identified in this cohort including two missense variants, two frameshift variants, an in-frame deletion, and an entire gene duplication (Figure 2). One variant, c.616C>T (p.R206W) identified in Cases 1 and 7, was previously described by Pilch et al. 11 Another, c.617G>A (p.R206Q) was identified in Case 4 and is analogous to the HNRNPH2 variant described by Bain et al. 6 The remaining four variants have not been described in either HNRNPH1 or HNRNPH2 to date. These include two small duplications, c.618dupG

| DISCUSSION
The seven individuals reported in this series suggest a unique, but var-  Figure S1). To confirm this duplication, a qPCR assay was run on fibroblasts from the proband and parents to confirm the de novo duplication ( Figure S1). Our findings suggest that pathogenic variants in HNRNPH1 represent a related, but distinct, syndrome from MRXSB with unique dysmorphic features, increased incidence of congenital anomalies, and an increased incidence of ophthalmological abnormalities. Importantly, identification of additional individuals with pathogenic HNRNPH1 variants will continue to shape the observed phenotype and provide further insights into the potential genotype/phenotype correlation.
While this represents a rare form of syndromic intellectual disability, given the severity observed in individuals with variants impacting the NLS, consideration of rapid-WES in critically ill newborns with microcephaly, congenital anomalies, and respiratory distress may identify pathogenic variants in HNRNPH1.