Anneke I. den Hollander, Robert K

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Mutations in the CEP290 (NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis Anneke I. den Hollander, Robert K. Koenekoop, Suzanne Yzer, Irma Lopez, Maarten L. Arends, Krysta E.J. Voesenek, Marijke N. Zonneveld, Tim M. Strom, Thomas Meitinger, Han G. Brunner, Carel B. Hoyng, L. Ingeborgh van den Born, Klaus Rohrschneider, Frans P.M. Cremers The American Journal of Human Genetics Volume 79, Issue 3, Pages 556-561 (September 2006) DOI: 10.1086/507318 Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree and clinical features of the French Canadian LCA-affected family. A, Pedigree of the family. Four siblings are affected with LCA (blackened symbols), and the parents are first cousins. Haplotypes are shown for the chromosome 12 interval containing CEP290. B–E, Color fundus photographs of the right eye of affected sib IV-8 at age 45 years. B, Posterior pole, showing myopic changes, choroidal show, mild optic disc pallor, very significant arteriolar and venular narrowing, a poorly developed fovea, and peri-papillary atrophy, which extends along the superior arcade. C, Superior retina, showing a small isolated area of pigmentation, one bone spicule, and diffuse choroidal show. D, Inferior retina, showing small clumps of round pigmentation. E, Inferotemporal retina, showing more extensive small, round intraretinal pigmentation (nummular pigmentation). Images are slightly blurred because of a mild nuclear cataract. F, CT scan at the level of the midbrain of proband IV-7 at age 40 years. The axial view of the brain shows the normal structures of the midbrain and the cerebellum, without the molar tooth sign. G, CT scan of proband IV-7 at age 40 years at the level of the basal ganglia and the ventricles, depicting normal brain architecture, with no cerebellar atrophy. H and I, Kidney ultrasounds of affected sibling IV-6 at age 51 years. At the level of the parenchyma, both kidneys show isolated tiny foci of marked increased echogenicity, but without definite posterior shadowing. These are located mostly on the left side at the level of the cortex, but a few are also identified near the medulla on both sides and may indicate the presence of nephrocalcinosis. On both images, there are neither definite cysts nor dilatation of the collecting system or ureteral dilatation. There is no evidence of nephronophthisis. The American Journal of Human Genetics 2006 79, 556-561DOI: (10.1086/507318) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 2 Molecular characterization of the CEP290 mutation in the consanguineous LCA-affected family. A, Reverse transcription of CEP290 mRNA and subsequent PCR using primers situated in exons 26–29 in two affected family members (IV-6 and IV-7), revealing a fragment of normal size and a larger aberrant fragment (upper panel). The aberrant fragment was not present in eight control individuals (C1–C8). RT-PCR using primers situated in the cryptic exon (X) and in exon 29 revealed an aberrant fragment in the patients with LCA but not in the controls (lower panel). Lane M contains a 100-bp marker. B, Sequencing of the aberrant RT-PCR product, showing that a cryptic exon (X) is spliced in between exons 26 and 27. The cryptic exon introduces a premature stop codon immediately downstream of exon 26. C, Cryptic exon X located 1.5 kb downstream of exon 26. Sequencing of the genomic DNA (gDNA) surrounding exon X revealed a mutation 5 bp downstream of the cryptic exon (c.2991+1655A→G). The mutation introduces a strong splice-donor site. Nucleotides in the cryptic exon are in uppercase letters, and intronic sequences are in lowercase letters. D, Allele-specific PCR showed that the c.2991+1655A→G mutation segregates with the disease in the family. All affected family members (IV-6, IV-7, IV-8, and IV-9) are homozygous for the mutation, whereas unaffected individuals are heterozygous or do not carry the mutation. Lane C represents a control individual. The American Journal of Human Genetics 2006 79, 556-561DOI: (10.1086/507318) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 3 Segregation analysis of CEP290 mutations in nine LCA-affected families. In all nine families, segregation of the mutations is in agreement with autosomal recessive inheritance. For each family, the proband is indicated (arrow). M1 = c.2991+1655A→G; M2 = p.Glu1956X; M3 = p.Arg1272X; M4 = p.Thr89AsnfsX1; M5 = c.180+1G→T; M6 = p.Leu517X; M7 = p.Ile1372LysfsX3; M8 = p.Glu1656X; + = wild type. The American Journal of Human Genetics 2006 79, 556-561DOI: (10.1086/507318) Copyright © 2006 The American Society of Human Genetics Terms and Conditions