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.

Keywords: HNRNPH2; X chromosome; alternative splicing; autism; developmental delay; microcephaly; neurodevelopment; pre-mRNA.

Figure 1

HNRNPH2 Domains and Conservation among Various Family Members and across Species (A) HNRNPH2 domains. The numbers above (100, 200, 300, and 400) represent the amino acid sequence. Dotted arrows indicate the location of de novo variants at amino acid positions 206 and 209. Abbreviations are as follows: NLS, nuclear localization sequence; RRM, RNA recognition motifs; G, glycine-rich domain; Y, tyrosine-rich domain; R, arginine-rich domain. (B) Highly conserved sequences among members of the HNRNPH family, including HNRNPs H1 (H), H2 (H’), and F proteins. Highlighted boxes indicate amino acid residues 206 and 209 reported. (C) Cross species conservation of amino acids 206 and 209. Highlighted boxes indicate amino acid residues 206 and 209 reported.

Figure 2

Magnetic Resonance Images of Affected Individuals Axial T1-weighted (A) and coronal (B) STIR images of individual 2 demonstrating hypoplasia of cerebellar vermis at age 7 years old. Images obtained on a 1.5 Tesla MRI.

Figure 3

Dysmorphic Features in Affected Individuals Photographs of individual 1 (A–C) and individual 5 (D–F) with dysmorphic features including almond shaped eyes, short palpebral fissures, short philtrum, full lower lip, long columella, and hypoplastic alae nasi. Individual 1 is shown at 5 years of age (A) and 34 years of age (B, C). Individual 5 is shown at 21 years of age. Individual 2 (G) is shown at 8 years of age.