Case report: Identification of a novel variant p.Gly215Arg in the CHN1 gene causing Moebius syndrome

Abstract

Background: Moebius Syndrome (MBS) is a rare congenital neurological disorder characterized by paralysis of facial nerves, impairment of ocular abduction and other variable abnormalities. MBS has been attributed to both environmental and genetic factors as potential causes. Until now only two genes, PLXND1 and REV3L have been identified to cause MBS. Results: We present a 9-year-old male clinically diagnosed with MBS, presenting facial palsy, altered ocular mobility, microglossia, dental anomalies and congenital torticollis. Radiologically, he lacks both abducens nerves and shows altered symmetry of both facial and vestibulocochlear nerves. Whole-exome sequence identified a de novo missense variant c.643G>A; p.Gly215Arg in CHN1, encoding the α2-chimaerin protein. The p.Gly215Arg variant is located in the C1 domain of CHN1 where other pathogenic gain of function variants have been reported. Bioinformatic analysis and molecular structural modelling predict a deleterious effect of the missense variant on the protein function. Conclusion: Our findings support that pathogenic variants in the CHN1 gene may be responsible for different cranial congenital dysinnervation syndromes, including Moebius and Duane retraction syndromes. We propose to include CHN1 in the genetic diagnoses of MBS.

Keywords: CHN1; congenital dysinnervation syndromes; genetic diagnosis; moebius syndrome; novel variant.

FIGURE 1

(A), Patient at 3 years 10 month old. Microglossia and dental anomalies. (B), Patient at 10 months of age showing limited outward gaze (abduction) of the right eye. (C–F). Patient at 9 years old. Ocular motility patterns. (C), Straight gaze showing mild esotropia of the right eye. (D), Horizontal left gaze showing limited abduction on the left eye. (E), Horizontal right gaze showing limited abduction on the right eye. (F), Full vertical eye movement. Exotropia in upper gaze.

FIGURE 2

(A), Patient at 4 years 10 month old. Movements of the lower part of the forehead are reduced. (B,C), Patient at 9 years old showing mild facial palsy. (B), the patient cannot fully smile and when he smiles there is a mild asymmetry. (C), Limited mouth movements (he cannot blow). (D), Patient at 9 years old. Microglossia and dental anomalies.

FIGURE 3

(A), 3D-constructive interference in steady State (CISS) sequences. Note the absence of bilateral VI nerves (yellow arrows). (B), 3D-CISS sequences with reconstructions perpendicular to the bilateral internal auditory channel show an asymmetry in the position of VII (blue arrows) and VIII nerves (orange arrows). The left side is normal. (C), 3D-CISS sequences in the axial plane with reconstructions in the coronal plane demonstrate the presence of a cisternal segment of bilateral facial (VII) (blue arrows) and vestibulocochlear nerve (VIII).

FIGURE 4

Molecular characterisation of the c.643G>A; p. Gly215Arg variant. (A), De novo inheritance pattern of CHN1 c.643G>A variant. A red asterisk indicates the variant. (B), Schematic structure of the human CHN1 protein. The upper black arrows indicate previously reported pathogenic variants in the C1 domain. (C), Multiple-sequence alignment showing the conservation of Gly215 residue in CHN1 across evolution. (D), Cartoon representation of the protein structure CHN1. Insets show close-up views of (left) the interaction mediated by CHN1 Gly215 with nearby amino acid residues in stick representation.