Identification of mutations causing inherited retinal degenerations in the israeli and palestinian populations using homozygosity mapping.
OBJECTIVE
The Israeli and Palestinian populations are known to have a relatively high level of consanguineous marriages, leading to a relatively high frequency of autosomal recessive (AR) diseases. Our purpose was to use the homozygosity mapping approach, aiming to prioritize the set of genes and identify the molecular genetic causes underlying AR retinal degenerations in the Israeli and Palestinian populations.


METHODS
Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping and mutation analysis of candidate genes.


RESULTS
We recruited for the study families with AR nonsyndromic retinal degenerations, including mainly retinitis pigmentosa (RP), cone-rod degeneration (CRD), and Leber congenital amaurosis (LCA). With the aim to identify the causative genes in these families, we performed homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays in 125 families. The analysis revealed the identification of 14 mutations, 5 of which are novel, in 16 of the families. The mutations were identified in the following eight genes: RDH12, PROM1, MFRP, TULP1, LCA5, CEP290, NR2E3, and EYS. While most patients had a retinal disease that is compatible with the causing gene, in some cases new clinical features are evident.


CONCLUSIONS
Homozygosity mapping is a powerful tool to identify genetic defects underlying heterogeneous AR disorders, such as RP and LCA, in consanguineous and nonconsanguineous patients. The identification of significant and large homozygous regions, which do not include any known retinal disease genes, may be a useful tool to identify novel disease-causing genes, using next generation sequencing.
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Avigail
A
Beryozkin
Lina
L
Zelinger
Dikla
D
Bandah-Rozenfeld
Elia
E
Shevach
Anat
A
Harel
Tim
T
Storm
Michal
M
Sagi
Dalia
D
Eli
Saul
S
Merin
Eyal
E
Banin
Dror
D
Sharon
D018912:Arabs / Q000208:ethnology; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007557:Israel / Q000453:epidemiology; D007585:Jews / Q000208:ethnology; D008297:Male; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012162:Retinal Degeneration / Q000208:ethnology / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000208:ethnology / Q000235:genetics*
D005136:Eye Proteins
homozygosity mapping; retinal degeneration; retinitis pigmentosa