Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females

Abstract

Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.

Missense variants in the Arg206 residue of HNRNPH2: Further evidence of causality and expansion of the phenotype

“…Of note, she exhibited progressive deterioration in adulthood, particularly affecting her motor skills with regression in her ability to walk, and increasing movement disorder consisting of tremors and dystonia. This regression would support the hypothesis of a neurodegenerative pathogenesis of the disease caused by the accumulation of dysfunctional proteins in the cytoplasm as suggested by Bain et al (), also in the long term.…”

“…Focused exome sequencing identified the following heterozygous variant in HNRNPH2 [NM_019597.4]: c.617G>T, de novo . The c.617G>T substitution causes amino acid change at codon 206 (p.Arg206Leu), which is located within the glycine‐rich domain containing the nuclear localization sequence (NLS) (Bain et al, ). The variant is absent from the public population databases, was predicted as damaging by all three in silico prediction tools, and had a PHRED score of 24.4.…”

“…Six females and three males have been described in the literature (Bain et al, ; Harmsen et al, ; Jepsen et al, ). All have a common neurodevelopmental phenotype with no clear differences in severity between males and females, although our analysis of the clinical manifestations suggests that males may exhibit a more severe neurological phenotype with profound ID and inability to walk (Table ).…”

Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases

“…More recently, a novel missense mutation in the NLS of hnRNPA1, which causes redistribution of hnRNPA1 from the nucleus to the cytoplasm, was identified as a cause of familial ALS (Liu et al, 2016), expanding the repertoire of NLS mutations in ALS-associated proteins. Interestingly, mutations that disrupt the NLS in a related protein, hnRNPH2, cause neurodevelopmental delay and autism (Bain et al, 2016). …”

Bain type of X‐linked syndromic mental retardation in boys

“…Pilch et al recently reported that mutations in HNRNPH1 may cause Bain type syndromic mental retardation (MRXSB) in boys . So far, this syndrome has been only described in females caused by de novo mutations in the X‐linked HNRNPH2 gene . It was thought that the disease is embryonic lethal in hemizygous males.…”