Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families

Background: Giant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that affects both the peripheral and central nervous systems. Disease-causing variants in the gigaxonin gene (GAN) cause autosomal recessive giant axonal neuropathy. Facial weakness, nystagmus, scoliosis, kinky or curly hair, pyramidal and cerebellar signs, and sensory and motor axonal neuropathy are the main symptoms of this disorder. Here, we report two novel variants in the GAN gene from two unrelated Iranian families.

Methods: Clinical and imaging data of patients were recorded and evaluated, retrospectively. Whole-exome sequencing (WES) was undertaken in order to detect disease-causing variants in participants. Confirmation of a causative variant in all three patients and their parents was carried out using Sanger sequencing and segregation analysis. In addition, for comparing to our cases, we reviewed all relevant clinical data of previously published cases of GAN between the years 2013-2020.

Results: Three patients from two unrelated families were included. Using WES, we identified a novel nonsense variant [NM_022041.3:c.1162del (p.Leu388Ter)], in a 7-year-old boy of family 1, and a likely pathogenic missense variant [NM_022041.3:c.370T>A (p.Phe124Ile)], in two affected siblings of the family 2. Clinical examination revealed typical features of GAN-1 in all three patients, including walking difficulties, ataxic gait, kinky hair, sensory-motor polyneuropathy, and nonspecific neuroimaging abnormalities. Review of 63 previously reported cases of GAN indicated unique kinky hair, gait problem, hyporeflexia/areflexia, and sensory impairment were the most commonly reported clinical features.

Conclusions: One homozygous nonsense variant and one homozygous missense variant in the GAN gene were discovered for the first time in two unrelated Iranian families that expand the mutation spectrum of GAN. Imaging findings are nonspecific, but the electrophysiological study in addition to history is helpful to achieve the diagnosis. The molecular test confirms the diagnosis.