Description of Phenotypic Heterogeneity in a GJC2-Related Family and Literature Review

Abstract

<b><i>Introduction:</i></b> Homozygous and compound heterozygous variants in <i>GJC2</i>, the gene encoding connexin-47 protein, cause Pelizaeus-Merzbacher-like disease type 1 or hypomyelinating leukodystrophy 2 (HLD2), a severe infantile-onset hypomyelinating leukodystrophy, and rarely some milder phenotypes like hereditary spastic paraplegia (HSP) type 44 (SPG44) and subclinical leukodystrophy. Herein, we report an Iranian <i>GJC2</i>-related family with intrafamilial phenotypic heterogeneity and review the literatures. <b><i>Methods:</i></b> Whole-exome sequencing was performed for an Iranian proband, who was initially diagnosed as HSP case. Data were analyzed and the candidate variant was confirmed by PCR and Sanger sequencing subsequently checked in family members to co-segregation analysis. A careful clinical and paraclinical evaluation of all affected individuals of the family was done and compared with previous reported <i>GJC2</i>-related families. <b><i>Results:</i></b> A novel homozygous variant, c.G14T:p.Ser5Ile, in the <i>GJC2</i> gene was identified. The variant was co-segregated with the disease status in the family members. Clinical evaluation of all patients showed two distinct <i>GJC2</i>-related phenotypes in this family; the proband presented a complicated form of HSP, whereas both his affected sisters presented a HLD2 phenotype. <b><i>Discussion:</i></b> Up to now, correlation between HSP and <i>GJC2</i> variants has been reported once. Here, the second case of SPG44 was identified that emphasizes on <i>GJC2</i> as a HSP-causing gene. So, the screening of <i>GJC2</i> in patients with HSP or HSP-like phenotypes especially with hypomyelination in their brain MRI is recommended. Also, for the first time, intrafamilial phenotypic heterogeneity for “two distinct <i>GJC2</i>-related phenotypes: HLD2 and HSP” was reported. Such intrafamilial phenotypic heterogeneity for <i>GJC2</i> can emphasize on the shared pathophysiology of these disorders.