A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report.

Researchers found two sisters who have changes in a gene called NEUROG1 that affects their cranial nerves (nerves in the head). Both girls have autism, developmental delays, hearing problems, and eye issues including no blinking. This is only the fourth case like this ever reported worldwide, and the first time autism has been seen with this genetic condition. The findings suggest this gene might be important for understanding some forms of autism.

This case report describes two sisters with homozygous variants in the NEUROG1 gene presenting with cranial dysinnervation disorder alongside autism spectrum disorder. The 6-year-old proband showed global developmental delay, autism, hearing loss, corneal opacity, and absent eye blinking, while her 4-year-old sister had similar features. Whole exome sequencing identified a novel homozygous frameshift variant (c.228_231dup) in NEUROG1. This represents only the fourth reported case worldwide of NEUROG1-related cranial dysinnervation, and the first to document autism as an additional phenotype.

The authors propose a hypothetical framework linking dysfunctional NEUROG1 protein to both cranial nerve dysfunction and autism development.

This case suggests NEUROG1 should be considered in genetic testing panels for individuals with autism accompanied by cranial nerve abnormalities, hearing loss, or eye movement disorders. However, more research is needed to confirm this association and understand the underlying mechanisms before clinical recommendations.

Single family case report with only two affected individuals. Lacks functional validation of the variant's pathogenicity. Hypothesis for autism mechanism is theoretical without experimental support. No comparison with larger patient cohorts or control groups.

NEUROG1 gene is yet to be associated with a set of human phenotypes in the OMIM database. Three cases have previously been diagnosed with cranial dysinnervation due to biallelic variants in the NEUROG1 gene. This is the fourth and a novel report of a sibling pair harboring a homozygous variant in the NEUROG1 gene with autism as an additional phenotype. A brief review of the literature in conjunction with a genotype-phenotype correlation has been described.

A potential hypothesis for the presence of the autistic phenotype in the present case has also been elucidated. A female aged 6 years and 9 months born to endogamous and phenotypically healthy parents was diagnosed with global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her MRI of the brain revealed mild peritrigonal white matter hyperintensity, and MRI and CT scan of the temporal bones showed abnormal cranial nerves. The proband's younger sister, aged 4-years, was similarly affected.

Whole exome sequencing was performed in the proband, which revealed a novel homozygous, likely pathogenic, truncating frameshift variant, c.228_231dup (p.Thr78ProfsTer122) in exon 1 of the NEUROG1 gene (ENST00000314744.4). Segregation analysis by Sanger sequencing showed the proband and her younger sister to be homozygotes and their parents to be heterozygous carriers. This is the fourth report across the globe with a variant identified in the NEUROG1 gene to be associated with cranial dysinnervation phenotype. An additional phenotype of autism in two female siblings was a novel observation.

We provide a hypothetical framework which could explain the pleiotropic effect of a dysfunctional NEUROG1 protein leading to autism and posit it as a candidate for diagnosis of autism spectrum disorder with congenital cranial dysinnervation disorder.