MFSD8 gene mutations; evidence for phenotypic heterogeneity

Background: Cone-rod dystrophies are a group of genetically and phenotypically heterogeneous inherited degenerative retinal diseases primarily affecting macular and cone system function. MFSD8 loss-of-function variants are mainly related to the variant late-infantile neuronal ceroid lipofuscinoses which present with progressive motor and mental regression in combination with seizures, ataxia, and visual impairment.

Material and methods: Clinical examination and genomic DNA extraction were collected from two unrelated Iranian families presenting with autosomal recessive cone-rod dystrophy. The candidate disease-causing variant was screened with whole-exome sequencing and bioinformatics analyses. Sanger sequencing was used for validation and co-segregation analysis.

Results: Two previously reported variants (c.1361T>C; p.M454T and c.1235C>T; p.P412L) and in a compound heterozygous pattern in one family and a homozygous variant (c.1361T>C; p.M454T) identical to one of the variants in the first family in MFSD8 gene were identified. Both confirmed by Sanger sequencing and co-segregated with disease status.

Conclusions: Here and for the first time, we reported on two previously variant late-infantile neuronal ceroid lipofuscinoses-associated variants in MFSD8 but in association with a form of cone-rod dystrophy known as non-syndromic macular dystrophy with central cone involvement. Our results support this concept that variant late-infantile neuronal ceroid lipofuscinoses and non-syndromic macular dystrophy with central cone involvement are not different disease entities, but rather allelic diseases and phenotypic variants of the same mutation. Consideration of the milder MFSD8 phenotypes is important against the potentially severe consequences of life-threatening conditions associated with MFSD8 mutations in order to prevent the danger of misdiagnosis as well as the accuracy of genetic counseling.