title: Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy.
abstract: OBJECTIVE
  This study aimed to identify the genetic defects in 2 families with autosomal recessive macular dystrophy with central cone involvement.
  
  
  METHODS
  Case series.
  
  
  METHODS
  Two families and a cohort of 244 individuals with various inherited maculopathies and cone disorders.
  
  
  METHODS
  Genome-wide linkage analysis and exome sequencing were performed in 1 large family with 5 affected individuals. In addition, exome sequencing was performed in the proband of a second family. Subsequent analysis of the identified mutations in 244 patients was performed by Sanger sequencing or restriction enzyme digestion. The medical history of individuals carrying the MFSD8 variants was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), multifocal ERG (mfERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence, and fundus photography.
  
  
  METHODS
  MFSD8 variants, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, mfERG, fundus autofluorescence, and OCT findings.
  
  
  RESULTS
  Compound heterozygous variants in MFSD8, a gene encoding a lysosomal transmembrane protein, were identified in 2 families with macular dystrophy with a normal or subnormal ERG, but reduced mfERG. In both families, a heterozygous missense variant p.Glu336Gln was identified, which was predicted to have a mild effect on the protein. In the first family, a protein-truncating variant (p.Glu381*) was identified on the other allele, and in the second family, a variant (c.1102G>C) was identified that results in a splicing defect leading to skipping of exon 11 (p.Lys333Lysfs*3). The p.Glu336Gln allele was found to be significantly enriched in patients with maculopathies and cone disorders (6/488) compared with ethnically matched controls (35/18 682; P < 0.0001), suggesting that it may act as a genetic modifier.
  
  
  CONCLUSIONS
  In this study, we identified variants in MFSD8 as a novel cause of nonsyndromic autosomal recessive macular dystrophy with central cone involvement. Affected individuals showed no neurologic features typical for variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a severe and devastating multisystem lysosomal storage disease previously associated with mutations in MFSD8. We propose a genotype-phenotype model in which a combination of a severe and a mild variant cause nonsyndromic macular dystrophy with central cone involvement, and 2 severe mutations cause vLINCL.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands; Current affiliation: Howard Hughes Medical Institute, The Rockefeller University, Department for Pediatric Brain Diseases, New York, New York.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roosing
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sangermano
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy; Medical Genetics, Department of Biochemistry, Biophysics, and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Banfi
authors.affiliation: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marijke N
authors.initials: MN
authors.lastname: Zonneveld-Vrieling
authors.affiliation: Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.affiliation: Department of Ophthalmology, St. Elisabeth Ziekenhuis, Tilburg, The Netherlands.
authors.forename: Janneke J C
authors.initials: JJ
authors.lastname: van Lith-Verhoeven
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Anneke.denHollander@radboudumc.nl.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
mesh_terms: D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D004596:Electroretinography; D059472:Exome / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D041623:Tomography, Optical Coherence; D058609:Visual Field Tests
chemical_list: D051907:Lysosomal Membrane Proteins; C522398:MFSD8 protein, human; D026901:Membrane Transport Proteins