Genome‐wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1‐related fundus phenotype

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 anal...

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Published in:	Clinical genetics Vol. 93; no. 1; pp. 149 - 154
Main Authors:	Khan, A.O., Budde, B.S., Nürnberg, P., Kawalia, A., Lenzner, S., Bolz, H.J.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-01-2018
Subjects:	Adolescent Age Amino Acid Sequence CCDC66 Child Chromosome Mapping cone‐rod dystrophy Eye Proteins - genetics Female Fundus Oculi Genetic Predisposition to Disease - genetics Genome-Wide Association Study - methods Genomes High-Throughput Nucleotide Sequencing - methods Humans Leber congenital amaurosis Linkage analysis Male Mutation Nicotinamide-Nucleotide Adenylyltransferase - genetics NMNAT1 Nucleotide sequence Pedigree Phenotype Retina Retinal degeneration Retinal Dystrophies - diagnosis Retinal Dystrophies - genetics Sequence Homology, Amino Acid Siblings Leber congenital amaurosis cone-rod dystrophy CCDC66 NMNAT1 retina
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Summary:	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. Retinal images of the two affected siblings.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	0009-9163 1399-0004
DOI:	10.1111/cge.13022