A boy with homozygous microdeletion of NEUROG1 presents with a congenital cranial dysinnervation disorder [Moebius syndrome variant]

Abstract

Background: We report on a 6-year-old Turkish boy with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild developmental delay. Further findings included scaphocephaly, plagiocephaly, long palpebral fissures, high narrow palate, low-set posteriorly rotated ears, torticollis, hypoplastic genitalia and faulty foot posture. Parents were consanguineous.

Methods and results: Computed tomography and magnetic resonance imaging showed bilateral single widened cochlear turn, narrowing of the internal auditory canal, and bilateral truncation of the vestibulo-cochlear nerve. Microarray analysis and next generation sequencing showed a homozygous deletion of chromosome 5q31.1 spanning 115.3 kb and including three genes: NEUROG1 (encoding neurogenin 1), DCNP1 (dendritic cell nuclear protein 1, C5ORF20) and TIFAB (TIFA-related protein). The inability to chew and swallow, deafness and balance disorder represented congenital palsies of cranial nerves V (trigeminal nerve) and VIII (vestibulo-cochlear nerve) and thus a congenital cranial dysinnervation disorder.

Conclusions: Based on reported phenotypes of neurog1 null mutant mice and other vertebrates, we strongly propose NEUROG1 as the causative gene in this boy. The human NEUROG1 resides within the DFNB60 locus for non-syndromic autosomal recessive deafness on chromosome 5q22-q31, but linkage data have excluded it from being causative in the DFNB60 patients. Given its large size (35 Mb, >100 genes), the 5q22-q31 area could harbor more than one deafness gene. We propose NEUROG1 as a new gene for syndromic autosomal recessive hearing loss and congenital cranial dysinnervation disorder including cranial nerves V and VIII.

Figure 1

High resolution CT of the left petrosus bone. The coronal view demonstrates the widened single basal cochlear turn (black arrow) and the narrowing of the auditory canal (white arrow). The patient did not show an enlarged vestibular aqueduct (EVA) but similar findings of the right petrosus bone.

Figure 2

The proband at age 3 ½ years. Note (A) hypotonic appearance, balance disorder and torticollis, (B, C) scaphocephaly, high arched eyebrows, elongated palpebral fissures and low-set posteriorly rotated ears, and (D) orthopedic aids for correction of faulty foot posture.

Figure 3

Definition of the homozygous deletion by NGS and breakpoint-spanning PCR analysis. (A) The locus, showing aligned reads (black bars) and RefSeq genes (blue). (B) A plot showing a p-value representing the likelihood that a genomic position is not in a homozygous deletion. (C) The sequence at the start and stop of the homozygous deletion; the black bars represent the location of primer sequences.

Figure 4

Results of microarray analysis in the patient. The homozygous deletion of chromosome 5q31.1 spans from 110.787 kb to 116.796 kb and includes three genes, C5ORF20 (DCNP1), TIFAB and NEUROG1. Both parents carried the same chromosomal microdeletion in heterozygous state.