Netrin G1 mutations are an uncommon cause of atypical Rett syndrome with or without epilepsy

Mutations in the methyl-cytosine-phosphate-guanosine dinucleotide (CpG) binding protein 2 gene are identified in up to 90% of patients with classic Rett syndrome. However, the lack of methyl-CpG binding protein 2 mutations in a small group of classic Rett syndrome cases, and the low frequency of these mutations in atypical Rett syndrome patients, suggest that other gene defects may play a role in this disorder. One report described a patient with atypical Rett syndrome who presented with early epilepsy and a de novo translocation which disrupted the Netrin G1 gene. This study tested a sample of 91 female patients with a clinically heterogeneous phenotype ranging from encephalopathy with epilepsy to atypical Rett syndrome without epilepsy for mutations in the Netrin G1 gene, to evaluate its involvement in this condition. Nine sequence variations (including six novel variations) were identified, all of which were unlikely to be pathogenic. One was a novel C to G transversion, resulting in a p.Leu537Val amino-acid substitution in one patient. The same substitution was detected in the asymptomatic mother, suggesting an absence of biological significance. Our study suggests that Netrin G1 is not involved in atypical Rett syndrome or in unexplained encephalopathy with epilepsy, but in specific forms to be delineated better in the future.