title: Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.
abstract: To uncover the genotype underlying early-onset cone-rod dystrophy and central nummular macular atrophic lesion in 2 siblings from an endogamous Arab family, we performed targeted next-generation sequencing (NGS) of 44 retinal dystrophy genes, whole-exome sequencing (WES) and genome-wide linkage analysis. Targeted NGS and WES in the index patient highlighted 2 homozygous variants, a CCDC66 frameshift deletion and a novel missense NMNAT1 variant, c.500G>A (p.Asn167Ser). Linkage and segregation analysis excluded the CCDC66 variant and confirmed the NMNAT1 mutation. Biallelic NMNAT1 mutations cause Leber congenital amaurosis with a central nummular macular atrophic lesion (LCA9). The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy. Although Ccdc66 mutations have been proposed to cause retinal disease in dogs, our results and public databases challenge CCDC66 as a candidate gene for human retinal dystrophy.
authors.affiliation: Eye Institute, Cleveland Clinic Abu Dhabi (CCAD), Abu Dhabi, United Arab Emirates.
authors.forename: A O
authors.identifier: http://orcid.org/0000-0002-9921-7853
authors.initials: AO
authors.lastname: Khan
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: B S
authors.initials: BS
authors.lastname: Budde
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kawalia
authors.affiliation: Bioscientia, Center for Human Genetics, Ingelheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lenzner
authors.affiliation: Bioscientia, Center for Human Genetics, Ingelheim, Germany.|Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002874:Chromosome Mapping; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005654:Fundus Oculi; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D009154:Mutation; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D035781:Siblings
chemical_list: C000618179:CCDC66 protein, human; D005136:Eye Proteins; C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase
keywords: CCDC66; Leber congenital amaurosis; NMNAT1; cone-rod dystrophy; retina