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

Abstract

BackgroundWe 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 resultsComputed 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.ConclusionsBased 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.

Congenital facial palsy and emotion processing: The case of Moebius syndrome

“…Even if most Moebius cases are sporadic, some familial trends have been seen with both autosomal dominant and recessive patterns. [64][65][66][67][68] In particular, the risk of hereditariness is as low as 2% when MBS is linked to musculoskeletal anomalies, but it increases to 25% to 30% with clinical features suggesting a genetic etiology such as isolated facial palsy, deafness, ophthalmoplegia and digital contractures. 69 Genetic studies have mainly focused on potential chromo- Mutations in homeobox genes may also influence other genes, therefore determining the varying phenotypes characterizing the syndrome.…”

Examining the genetics of congenital facial paralysis—a closer look at Moebius syndrome

“…These cases have provided evidence for gene localization through linkage analysis and chromosomal abnormalities. Table 1 details the common chromosomal abnormalities with their associated phenotypic expressions based on existing literature [14,[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Translocations with breakpoints may lead to microdeletions or aberrant genetic sequences [44].…”

“…In addition, there are numerous other developmental genes that may interact with environmental factors during the required time period of brainstem growth [8]. Table 2 lists the proposed candidate genes and their function based on previous studies in the literature [46,48,53,54,[58][59][60][61][62][63][64][65].…”

“…It is also important in neuronal differentiation from embryonic ectodermal cells. MBS has primarily motor symptoms that make NEUROG1 less likely [48]. Uzumca et al put forward the theory of BASP1 gene mutation causing MBS.…”

The Use of Autozygosity Mapping and Next-Generation Sequencing in Understanding Anterior Segment Defects Caused by an Abnormal Development of the Lens

“…Further to this, where no potential disease-causing homozygous variants can be identified, simply altering the filtering approach applied to the exome data will allow the researcher to consider potential compound heterozygous variants in all known protein-coding genes. Similarly, copy number variations can also be detected from exome data, exons or even entire genes that receive no sequencing coverage upon NGS but may well represent a homozygous deletion and should definitely be considered as a potential cause where no SNPs are identified [220][221][222] . Recent advances in bioinformatics algorithms now allow the identification of autozygous regions directly from exome sequencing data, further increasing the efficiency of the process [223] .…”