Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-Phenotype Correlations

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Fältnamn	Indikatorer	Metadata
000		05524naa a2200781 4500
001		oai:DiVA.org:umu-82273
003		SwePub
008		131029s2013 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-822732 URI
024	7	a https://doi.org/10.1002/humu.223982 DOI
040		a (SwePub)umu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Mackay, Donna S4 aut
245	1 0	a Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-Phenotype Correlations
264		c 2013-09-17
264	1	b John Wiley & Sons,c 2013
338		a print2 rdacarrier
520		a This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
653		a LCA
653		a RP
653		a retinal dystrophy
653		a blindness
653		a LCA5
653		a lebercilin
700	1	a Borman, Arundhati Dev4 aut
700	1	a Sui, Ruifang4 aut
700	1	a van den Born, L Ingeborgh4 aut
700	1	a Berson, Eliot L4 aut
700	1	a Ocaka, Louise A4 aut
700	1	a Davidson, Alice E4 aut
700	1	a Heckenlively, John R4 aut
700	1	a Branham, Kari4 aut
700	1	a Ren, Huanan4 aut
700	1	a Lopez, Irma4 aut
700	1	a Maria, Maleeha4 aut
700	1	a Azam, Maleeha4 aut
700	1	a Henkes, Arjen4 aut
700	1	a Blokland, Ellen4 aut
700	1	a Andreasson, Sten4 aut
700	1	a de Baere, Elfride4 aut
700	1	a Bennett, Jean4 aut
700	1	a Chader, Gerald J4 aut
700	1	a Berger, Wolfgang4 aut
700	1	a Golovleva, Irinau Umeå universitet,Medicinsk och klinisk genetik4 aut0 (Swepub:umu)irgo0001
700	1	a Greenberg, Jacquie4 aut
700	1	a den Hollander, Anneke I4 aut
700	1	a Klaver, Caroline C W4 aut
700	1	a Klevering, B Jeroen4 aut
700	1	a Lorenz, Birgit4 aut
700	1	a Preising, Markus N4 aut
700	1	a Ramsear, Raj4 aut
700	1	a Roberts, Lisa4 aut
700	1	a Roepman, Ronald4 aut
700	1	a Rohrschneider, Klaus4 aut
700	1	a Wissinger, Bernd4 aut
700	1	a Qamar, Raheel4 aut
700	1	a Webster, Andrew R4 aut
700	1	a Cremers, Frans P M4 aut
700	1	a Moore, Anthony T4 aut
700	1	a Koenekoop, Robert K4 aut
710	2	a Umeå universitetb Medicinsk och klinisk genetik4 org
773	0	t Human Mutationd : John Wiley & Sonsg 34:11, s. 1537-1546q 34:11<1537-1546x 1059-7794x 1098-1004
856	4	u https://europepmc.org/articles/pmc4337959?pdf=render
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-82273
856	4 8	u https://doi.org/10.1002/humu.22398

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