ABCMdb

ABCA4 p.Cys54Gly

ClinVar:	c.161G>A , p.Cys54Tyr ? , not provided c.161G>T , p.Cys54Phe D , Pathogenic
Predicted by SNAP2:	A: D (53%), D: D (75%), E: D (63%), F: D (91%), G: D (71%), H: D (59%), I: D (53%), K: D (66%), L: D (63%), M: D (63%), N: D (63%), P: D (71%), Q: D (66%), R: D (66%), S: D (63%), T: D (59%), V: D (95%), W: D (80%), Y: D (91%),
Predicted by PROVEAN:	A: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Homozygosity mapping in patients with cone-rod dys... Invest Ophthalmol Vis Sci. 2010 Nov;51(11):5943-51. Epub 2010 Jun 16. Littink KW, Koenekoop RK, van den Born LI, Collin RW, Moruz L, Veltman JA, Roosing S, Zonneveld MN, Omar A, Darvish M, Lopez I, Kroes HY, van Genderen MM, Hoyng CB, Rohrschneider K, van Schooneveld MJ, Cremers FP, den Hollander AI
Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations.
Invest Ophthalmol Vis Sci. 2010 Nov;51(11):5943-51. Epub 2010 Jun 16., [PMID:20554613]

Abstract [show]
PURPOSE: To determine the genetic defect and to describe the clinical characteristics in a cohort of mainly nonconsanguineous cone-rod dystrophy (CRD) patients. METHODS: One hundred thirty-nine patients with diagnosed CRD were recruited. Ninety of them were screened for known mutations in ABCA4, and those carrying one or two mutations were excluded from further research. Genome-wide homozygosity mapping was performed in the remaining 108. Known genes associated with autosomal recessive retinal dystrophies located within a homozygous region were screened for mutations. Patients in whom a mutation was detected underwent further ophthalmic examination. RESULTS: Homozygous sequence variants were identified in eight CRD families, six of which were nonconsanguineous. The variants were detected in the following six genes: ABCA4, CABP4, CERKL, EYS, KCNV2, and PROM1. Patients carrying mutations in ABCA4, CERKL, and PROM1 had typical CRD symptoms, but a variety of retinal appearances on funduscopy, optical coherence tomography, and autofluorescence imaging. CONCLUSIONS: Homozygosity mapping led to the identification of new mutations in consanguineous and nonconsanguineous patients with retinal dystrophy. Detailed clinical characterization revealed a variety of retinal appearances, ranging from nearly normal to extensive retinal remodeling, retinal thinning, and debris accumulation. Although CRD was initially diagnosed in all patients, the molecular findings led to a reappraisal of the diagnosis in patients carrying mutations in EYS, CABP4, and KCNV2.

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101 The p.C54G change in ABCA4 (family W04-009) is a known mutation that was not yet present on the 2001 version of the ABCA4 APEX array at the time that the patient`s DNA was screened.31 The other mutation in ABCA4 (c.6729ϩ5_19del15) is new and was not detected in 180 control alleles. Login to comment
75 T ABLE 1. Overview of the Genes in Which Mutations Were Detected, and the Size Ranking of the Homozygous Regions in Which These Genes Resided Retinal Dystrophy Gene Patient or Family ID (Siblings, n) Consanguinity Country (Origin) Ranking of Region (n) Size (Mb) % of Genome That Is Homozygous (Regions > b03; 3 Mb) Homozygous Mutations Reference for Mutation ABCA4 W00-409 (3) Yes Germany (Iraq) 1st (1) 27.8 5.7* c.160Tb0e;G; p.C54G Ozgu &#a8; l et al. 31 ABCA4 50417 No Canada (Pakistan) 5th (10) 4.2 1.5 c.6729af9;5_19del15; splice defect This study CABP4 W03-008 (2) No Netherlands 1st (2) 8.9 0.9* c.646Cb0e;T; p.Arg216X Littink et al. 32 CERKL 50397 No Canada 1st (4) 28.4 1.6 c.375Cb0e;G; p.C125W This study CERKL 51456 No Canada (French Canadian) 1st (2) 10.6 0.5 c.847Cb0e;T; p.R283X This study EYS W05-112 (2) No Netherlands 2nd (2) 5.0 0.9* c.9468Tb0e;A; p.Y3156X Collin et al. 22 KCNV2 50222 Yes Netherlands (Morocco) 3rd (16) 10.9 7.0 c.162Cb0e;A; p.Y54X This study PROM1 W02-077 (2) No Netherlands (Greece) 2nd (6) 10.4 1.2* c.1142-1Gb0e;A; splice defect This study * In the case of multiple affected siblings, the mean percentage of the genome that is homozygous was calculated. Login to comment
99 Clinical Features of Patients in Which a Genetic Defect Was Identified Patient ID (Family Number) Gene Defect Age (y) Age of Diagnosis Visual Acuity (Best Eye) Color Vision Goldmann Perimetry ERG, Rod* ERG, Coneߤ CRD Patients 16875 (W00-409) ABCA4, p.C54G 17 15 20/200 Diffuse errors Small central scotoma Subnormal NR 16876 (W00-409) ABCA4, p.C54G 15 14 20/400 Diffuse errors, mostly protan axis Large central scotoma 2 22 16877 (W00-409) ABCA4, p.C54G 13 8 20/300 Diffuse errors NP 22 NR 50417 ABCA4, c.6729af9;5_19del15 48 30 20/400 Abnormal Central scotoma and decreased sensitivity NR NR 50397 (W09-0340) CERKL, p.C125W 48 30 20/50 Abnormal Central scotoma 22 22 54684 (W09-0340) CERKL, p.C125W 51 28 3/400 Abnormal Central scotoma NR NR 51456 CERKL, p.R283X 53 29 LP NP Not measurable NR NR 20695 (W02-077) PROM1, c.1142-1Gb0e;A 18 13 20/200 Severely disturbed Substantial central scotoma 22 NR 20696 (W02-077) PROM1, c.1142-1Gb0e;A 16 9 20/125 Severely disturbed Central scotoma with relative ring scotoma NR NR Patient Affected by Cone Dystrophy with Supernormal Rod ERG Responses 50222 KCNV2, p.Y54X 11 10 20/32 Moderately disturbed Normal 1, delayed 2 * Isolated rod response. Login to comment
108 The p.C54G change in ABCA4 (family W04-009) is a known mutation that was not yet present on the 2001 version of the ABCA4 APEX array at the time that the patient`s DNA was screened.31 The other mutation in ABCA4 (c.6729af9;5_19del15) is new and was not detected in 180 control alleles. Login to comment
145 The percentage of homozygous regions in nonconsanguineous T ABLE 4. Overview of Funduscopy, Autofluorescence Imaging and SD-OCT of CRD Patients Patient ID (Family Number) Gene Defect Funduscopy Autofluorescence Spectralis OCT 16875 (W00-409) ABCA4, c.160Tb0e;G, p.C54G Central glittering maculopathy and some peripheral fishtail pigment clusters NP NP 16876 (W00-409) ABCA4, c.160Tb0e;G, p.C54G Central glittering maculopathy and some peripheral fishtail pigment clusters NP NP 16877 (W00-409) ABCA4, c.160Tb0e;G, p.C54G Granular macular changes with irregular RPE NP NP 50417 ABCA4, c.6729af9;5_19del15, splice defect Advanced pigmentary maculopathy Striking macular absence of FAF Loss of the IS-OS junction, massive debris accumulation between the retina and RPE, retinal thickening and foveal thinning 50397 (W09-0340) CERKL, c.375Cb0e;G, p.C125W Perifoveal atrophy with a central RPE island Striking macular absence of FAF with remaining central island Single retinal cyst formation 54684 (W09-0340) CERKL, c.375Cb0e;G, p.C125W Advanced foveal and macular atrophy, choroidal sclerosis, and sclerosis in the macula Striking macular absence of FAF Extensive retinal remodeling, severe diffuse retinal thinning of one to two layers 51456 CERKL, c.874Cb0e;T, p.R283X Choroidal sclerosis and sclerosis in the macula Striking macular absence of FAF RPE thinning 20695 (W02-007) PROM1, c.1142-1Gb0e;A, splice defect Central atrophic lesions in the macula, severely attenuated retinal vessels NP NP 20696 (W02-007) PROM1, c.1142-1Gb0e;A, splice defect Discrete central atrophy in the macula, severely attenuated retinal vessels, granular pigmentation in periphery NP NP NP, not performed. Login to comment