JAM2 variants can be more common in primary familial brain calcification (PFBC) cases than those appear; may be due to a founder mutation.

INTRODUCTION: Mutations in JAM2 have been linked to ~ 2% of primary familial brain calcification (PFBC) cases. PFBC is a rare neurological disorder characterized by excessive calcium deposition in the brain. It causes movement disorders and psychiatric problems. Six other genes were identified as causing PFBC. However, the genetic basis of ~ 50% of PFBC cases remains unknown. This study presented the results of a comprehensive analysis of five unrelated Iranian PFBC families. METHODS: Clinical and paraclinical features of all patients were recorded. Whole-exome sequencing (WES) was done on the DNAs of probands. Data was analyzed, and haplotypes were determined. RESULTS: WES identified two homozygous variants in JAM2 across four families: a novel variant, c.426dup:p.Ser143Leufs*23, in one family and a known mutation, c.685C > T:p.Arg229*, in the remaining three families. Haplotype analysis using six intragenic single-nucleotide polymorphisms (SNPs) in JAM2 revealed an identical haplotype in probands who carried the same mutation, whereas two other probands presented diverse haplotypes. CONCLUSION: Based on our results, p.Arg229* may be a founder mutation in the Iranian population. The variant has been detected in two out of seven other reported JAM2-related families who may originate from the Middle East and exhibit an identical haplotype. Even though this particular mutation may not be classified as a founder mutation, it does appear to be a hotspot, given that it has been observed in 45% of the 11 JAM2-associated families. Our study expanded the clinical features and mutation spectrum of JAM2 and revealed that mutations in JAM2 may be more common than previously reported.

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

Introduction: Homozygous and compound heterozygous variants in GJC2, 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 GJC2-related family with intrafamilial phenotypic heterogeneity and review the literatures. Methods: 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 GJC2-related families. Results: A novel homozygous variant, c.G14T:p.Ser5Ile, in the GJC2 gene was identified. The variant was co-segregated with the disease status in the family members. Clinical evaluation of all patients showed two distinct GJC2-related phenotypes in this family; the proband presented a complicated form of HSP, whereas both his affected sisters presented a HLD2 phenotype. Discussion: Up to now, correlation between HSP and GJC2 variants has been reported once. Here, the second case of SPG44 was identified that emphasizes on GJC2 as a HSP-causing gene. So, the screening of GJC2 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 GJC2-related phenotypes: HLD2 and HSP" was reported. Such intrafamilial phenotypic heterogeneity for GJC2 can emphasize on the shared pathophysiology of these disorders.