Case report of a novel homozygous splice site mutation in PLA2G6 gene causing infantile neuroaxonal dystrophy in a Sudanese family

Liena E O Elsayed,Inaam N Mohammed,Mutaz Amin,Ahlam A A Hamed,Mustafa I Elbashir,Ammar E Ahmed,Mustafa A M Salih,Rayan A Siddig,Alexis Brice,Giovanni Stevanin,Ashraf Yahia,Mahmoud Koko,Maha A Elseed,Muntaser E Ibrahim

doi:10.1186/s12881-018-0592-y

Abstract

BackgroundInfantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in PLA2G6. The disease commonly affects children below 3 years of age and presents with delay in motor skills, optic atrophy and progressive spastic tetraparesis. Studies of INAD in Africa are extremely rare, and genetic studies from Sub Saharan Africa are almost non-existent.Case presentationTwo Sudanese siblings presented, at ages 18 and 24 months, with regression in both motor milestones and speech development and hyper-reflexia. Brain MRI showed bilateral and symmetrical T2/FLAIR hyperintense signal changes in periventricular areas and basal ganglia and mild cerebellar atrophy. Whole exome sequencing with confirmatory Sanger sequencing were performed for the two patients and healthy family members. A novel variant (NM_003560.2 c.1427 + 2 T > C) acting on a splice donor site and predicted to lead to skipping of exon 10 was found in PLA2G6. It was found in a homozygous state in the two patients and homozygous reference or heterozygous in five healthy family members.ConclusionThis variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients’ phenotype). Therefore this variant can be currently annotated as “pathogenic”. This is the first study to report mutations in PLA2G6 gene in patients from Sudan.

Highlights

Infantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in the PLA2G6 gene [1]
More than 85% of cases are caused by mutations in PLA2G6 gene, while the remainder has unknown genetic cause
Sequencing analysis of PLA2G6 gene has identified missense, nonsense, splicing disruption variants and insertion/deletions with genotype/phenotype correlation: loss of function mutations are usually associated with more severe forms of the disease, while compound heterozygous variants have usually milder presentation [4]

Summary

Conclusion

This variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients’ phenotype). This variant can be currently annotated as “pathogenic”. This is the first study to report mutations in PLA2G6 gene in patients from Sudan

Background

Results

Discussion and conclusion