The Arg99Gln Substitution in HNRNPC Is Associated with a Distinctive Clinical Phenotype Characterized by Facial Dysmorphism and Ocular and Cochlear Anomalies

Abstract

Background/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)/intellectual disability (ID) is also wide, ranging from mild to severe. The mutational spectrum is relatively broad with exon deletions and splice site and frameshift variants distributed along the entire length of the gene leading to HNRNPC loss of function. Only two missense changes located within the RNA-binding motif (RBM) and adjacent linker region of the more abundant isoform (Arg64Trp and Arg99Gln) have been described. Notably, the Arg99Gln amino acid substitution was reported in a subject presenting with a more complex and unique clinical phenotype characterized by distinctive facial features, DD/ID, cochlear aplasia, and bilateral colobomatous microphthalmia, suggesting the possible occurrence of phenotypic heterogeneity. Results: Here, we report the second individual carrying the Arg99Gln change in HNRNPC and having clinical features with a significant overlap with the peculiar phenotype of the previously described subject, supporting the occurrence of a genotype-phenotype correlation. Conclusions: Due to the concomitant occurrence of ocular and cochlear involvement as recognizable diagnostic handles, we propose that the HNRNPC^Arg99Gln-related phenotype should be considered as a potential differential diagnosis in subjects with ID and major signs of CHARGE syndrome not fulfilling the minimum criteria for a clinical diagnosis.

Keywords: CHARGE syndrome; HNRNPC; MRD74; cochlear aplasia; coloboma; genotype-phenotype correlations; microphthalmia; phenotypic heterogeneity.

Figure 1

Clinical features of the subject carrying the missense HNRNPC pathogenic variant predicting the Arg99Gln amino acid substitution. Facial features (top panels). Note a broad and slightly receding forehead, high hairline, thick eyebrows, narrow and wave-shaped lids, bilateral microphthalmia, sharp nose, long philtrum, thin upper lip, prominent malar region, dimple chin, slightly posteriorly rotated ears, large triangular dimple, and fleshy lobes. CT scan of mastoids and petrous bone (bottom panel). Note aplasia of the left internal auditory canal (IAC), marked hypoplasia of the right IAC, and severe malformation of the vestibule, semicircular canals, and cochleae, bilaterally.

Figure 2

Intramolecular interactions involving Arg⁹⁹ and perturbations introduced by the pathogenic Arg99Gln substitution. (A) The 3D structures of the single-stranded RNA-binding motif (RBM) of HNRNPC complexed with RNA consensus sequences (PDB ID 2MXY, submodel 18, 5′-AUUUUUC-3′, left; PDB ID 2MZ1, submodel 9, 5′-UUUUC-3′, right) are shown, with secondary structures and loops colored in sky blue and grey, respectively (top panel). The RNA consensus sequences are plum-colored. H-bonds (black dashed lines) and van der Waals bonds (orange lines) involving Arg⁹⁹ are shown. The two most frequent H-bonds observed in the NMR spectrometry models (i.e., involving Val⁹⁷ and Glu¹⁰³) are also indicated (left and right, respectively). The plot (bottom panel) shows all the intramolecular H-bonds involving Arg⁹⁹, colored by H-bond length. (B) By considering the same 3D structures, the substitution of the arginine residue by a non-charged polar residue, glutamine, abolishes binding to Val⁹⁷ (left) and weakens binding to Glu¹⁰³ (right) (top panel). The plot (bottom panel) shows all the intramolecular H-bonds involving Gln⁹⁹, colored by H-bond length.