EPOS

European Paediatric Ophthalmological Society

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Finding Genes in Leber Congenital Amaurosis

Irene H Maumenee, Sharola Dhaing Li Johns Hopkins Center for Heredseases The Wilmer Institute, Johns Hopkins University, Baltimore, Md 21205, USA

Purpose: We undertook a study to identify the genes Leber Congenital Amaurosis, since treatment for patientd upon understanding of the underlying genetic defect. Backgffects 1:50,000 people. The phenotype is variable: the funormal, show "macular coloboma like" lesions, or be characterized igment migration; the acuities range from 20/100 to no light perception the disease may be progressive or stable. Multiple permutations ex Intuitively, the disease is heterogeneous and indeed, six causative genes have been identified to date, five of which lead to aessive disease; mutations in CRX are presumed to lead to minant disease. Material and methods: We collected 288 probands with LC and established their pedigrees. Consanguinity was 42, an additional 14 pedigrees were large potentially permittcation coinheritance of the parental haplotypes with disgosity mapping in these 56 pedigrees was performed usingfected patients and their parents and markers spaced 25 cM apequent runs adjacent markers and unaffected sibs were date, positive linkage results were found in 54 pedigrees, in five instanc in previously identified regions. Concurrently, mutis was performed for known genes. Results: 18 new loci wer using information from pedigrees. The LOD scores vary from low positi to above 4, and the size of any given locus varies dependent upon numb of families mapped to a given locus, degree of consanguinity, family size and number of available DNA samples. Discussion: The number of l - and hence genes - identified for LCA is very high given the rarity of the disease. The high frequency of consanguinity observed in our famili is compatible with a model where the disease frequencom the additive effect of monogenic homozygosity for a mutation in a numbe of rare genes. Conclusion:There may be several reasonsh gene frequency in the face of rarity of the disease: each involved ge is small and hence mutations are rare; we may be observing the mild e of the phenotypic spectrum of mutations leading tsevere mutations in the gene may be genetic lethals;ogenic inheritance may be the rule, leading to rare cliniation, dependent upon tri- or oligoallelic inheritance. In two instanc we observed heterozygous CRX mutations in patient anically normal first degree relative; the significance of mutations in C as causative of LCA should be questioned. Conclusions:.ausing LCA have been identified to date; our data gifor 17 additional loci. It is estimated that a minimum of 30 genes are the cause of LCA, and therefore LCA in a population ariof the additive effect of mono- or oligogenig inheritance of individually rare mutations in a larggenes.