Mutations in MFSD8 can indeed cause a nonsyndromic recessive macular dystrophy.

Abstract

Purpose: To identify the genetic basis of macular dystrophy in three affected siblings of a non-consanguineous Caucasian family living in the UK.

Methods: Whole-exome sequencing (WES) was performed using SureSelectXT Human V4 target enrichment reagent followed by paired-end sequencing on a HiSeq2500.The data files were processed on the Galaxy platform, aligned to the human reference genome (hg19/GRCh37) and the reported variants annotated using Annovar. Variants were excluded if they were outside the exon and flanking splice recognition sites, were synonymous or had a minor allele frequency >1% in the exome variant server database. Variants were confirmed by PCR and Sanger sequencing.

Results: Genomic DNA from an affected family member was analysed by WES and the list filtered for prioritization of variants that are in the known RetNet genes. We identified 5 heterozygous and 1 homozygous variant though none segregated with the disease phenotype in the family. WES analysis of a second affected siblingand comparison of the full lists for common variantsidentified 15 homozygous and 4 genes with compound heterozygous variants. It was noted that mutations in one of these candidates MFSD8 (major facilitator superfamily domain-containing protein 8) had recently been reported in 2 families to cause nonsyndromic recessive macular dystrophy (Roosing et al., Ophthalmology, 2014). Sanger sequencing of the MFSD8 variants, c.1006G>C, p.E336Q and c.1394G>A, p.R465Q, in the UK family confirmed that all the affected members were indeed compound heterozygous for the mutations. These results are surprising since all publications to date on mutations in this gene except the one above showed that recessive MFSD8 mutations cause a severe multisystem lysosomal storage disorder, neuronal ceroidlipofuscinosis.

Conclusions: This is the second study and only the third family describing biallelic MFSD8 mutations causing a nonsyndromic eye phenotype, and independently confirms the findings of the recent report.It is worth highlighting that one of these mutations, p.E336Q, exists in a heterozygous state in all three families and may act as a modifier of disease symptoms resulting in the less severe phenotype.