ABCMdb

PMID: 23695285

Heathfield L, Lacerda M, Nossek C, Roberts L, Ramesar RS
Stargardt disease: towards developing a model to predict phenotype.
Eur J Hum Genet. 2013 Oct;21(10):1173-6. doi: 10.1038/ejhg.2013.92. Epub 2013 May 22., [PubMed]

Sentences

No. Mutations Sentence Comment

13 ABCA4 p.Gly863Ala ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe This study considers a South African cohort of 118 individuals who express biallelic combinations of seven founder mutations in ABCA4 (c.454C4T (p.Arg152*), c.768G4T (p.Val256Val), c.1804C4T (p.Arg602Trp), c.2588G4C (p.Gly863Ala), c.4469G4A (p.Cys1490Tyr), c.5461-10T4C, c.6079C4T (p.Leu2027Phe)), which collectively account for 36% of STGD cases studied to date in South Africa.19,20 These data, together with clinical information for each patient, were used to test the genotype-phenotype model. Login to comment 27 ABCA4 p.Cys1490Tyr The c.4469G4A (p.Cys1490Tyr) mutation, in combination with either itself or another mutation, was the most common, as it was detected in 64 of the 118 patient samples (54%). Login to comment 30 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp To illustrate the utility of this model, consider the population of individuals expressing the mutation pair c.4469G4A (p.Cys1490Tyr) and c.1804C4T (p.Arg602Trp). Login to comment 31 ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp The average AOO for this group of individuals is predicted as (0.0460 &#fe; 0.0528&#fe; 0.04680.0295)1 &#bc; 8.61 years, where 0.0460 is the intercept term, 0.0528 is the regression coefficient for c.4469G4A (p.Cys1490Tyr), 0.0468 is the regression coefficient for c.1804C4T (p.Arg602Trp) and 0.0295 is the regression coefficient for c.4469G4A (p.Cys1490Tyr): c.1804C4T (p.Arg602Trp). Login to comment 33 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe Table 1 A summary of the 23 mutation combinations observed in 118 patients with STGD, showing the number of patients per combination and the average and median AOO (in years) per combination Mutation 1 Mutation 2 Number of patients Average AOO (years) Median AOO (years) c.5461-10T4C c.768G4T (p.Val256Val) 1 6 6 c.5461-10T4C c.5461-10T4C 2 6.5 6.5 c.1804C4T (p.Arg602Trp) c.768G4T (p.Val256Val) 3 6.7 6 c.5461-10T4C c.454C4T (p.Arg152*) 3 7 8 c.4469G4A (p.Cys1490Tyr) c.454C4T (p.Arg152*) 6 7.8 8 c.768G4T (p.Val256Val) c.454C4T (p.Arg152*) 4 8 9 c.768G4T (p.Val256Val) c.768G4T (p.Val256Val) 1 8 8 c.4469G4A (p.Cys1490Tyr) c.4469G4A (p.Cys1490Tyr) 9 8.1 8 c.6079C4T (p.Leu2027Phe) c.454 C4T (p.Arg152*) 7 8.2 7 c.4469G4A (p.Cys1490Tyr) c.1804C4T (p.Arg602Trp) 13 8.6 8 c.4469G4A (p.Cys1490Tyr) c.5461-10T4C 13 8.8 9 c.4469G4A (p.Cys1490Tyr) c.768G4T (p.Val256Val) 10 10.3 9 c.4469G4A (p.Cys1490Tyr) c.6079C4T (p.Leu2027Phe) 12 10.3 9.5 c.6079C4T (p.Leu2027Phe) c.5461-10T4C 3 11 10 c.1804C4T (p.Arg602Trp) c.5461-10T4C 1 11 11 (c.1804C4T (p.Arg602Trp) c.6079C4T (p.Leu2027Phe) 8 12 11 c.6079C4T (p.Leu2027Phe) c.768G4T (p.Val256Val) 6 12.5 13 c.768G4T (p.Val256Val) c.2588G4C (p.Gly863Ala) 3 16.7 18 c.1804C4T (p.Arg602Trp) c.2588G4C (p.Gly863Ala) 2 17.5 17.5 c.4469G4A (p.Cys1490Tyr) c.2588G4C (p.Gly863Ala) 4 18.5 19 c.5461-10T4C c.2588G4C (p.Gly863Ala) 1 20 20 c.6079C4T (p.Leu2027Phe) c.6079C4T (p.Leu2027Phe) 2 28 28 c.2588G4C (p.Gly863Ala) c.454C4T (p.Arg152*) 4 28 30 In some cases, the average AOO of a given mutation differed significantly depending on the mutational context in which it occurred. Login to comment 35 ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Leu2027Phe For example, the average AOO is significantly lower among individuals who are homozygous for the Cys1490Tyr mutation compared to individuals who express a single Cys1490Tyr mutation and the Leu2027Phe mutation. Login to comment 45 ABCA4 p.Gly863Ala ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe Table 2 Covariates included in the generalised linear model (with inverse link function) with their respective coefficients, standard errors and P-values Covariate Coefficient Standard error P-value (Intercept) 0.0460 0.0106 3.53e 05 c.4469G4A (p.Cys1490Tyr) 0.0528 0.0076 2.71e 10 c.1804C4T (p.Arg602Trp) 0.0468 0.0085 2.33e 07 c.6079C4T (p.Leu2027Phe) 0.0090 0.0089 0.3117 c.5461-10T4C 0.0562 0.0106 6.59e 07 c.768G4T (p.Val256Val) 0.0507 0.0083 2.06e 08 c.2588G4C (p.Gly863Ala) 0.0413 0.0081 1.58e 06 c.454C4T (p.Arg152*) 0.0311 0.0080 0.0002 c.4469G4A (p.Cys1490Tyr) (homozygous) 0.0336 0.0144 0.0214 c.4469G4A (p.Cys1490Tyr): c.5461-10T4C 0.0419 0.0146 0.0049 c.4469G4A (p.Cys1490Tyr): c.1804C4T (p.Arg602Trp) 0.0295 0.0145 0.0442 c.4469G4A (p.Cys1490Tyr): c.768G4T (p.Val256Val) 0.0520 0.0134 0.0002 c.6079C4T (p.Leu2027Phe): c.454C4T (p.Arg152*) 0.0519 0.0158 0.0013 Figure 1 Graph depicting the actual and predicted average AOO with 95% confidence bands for each mutation combination observed in five or more patients. Login to comment 50 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp For example, consider again the population of individuals expressing the mutation combination c.4469G4A (p.Cys1490Tyr) and c.1804C4T (p.Arg602Trp). Login to comment 52 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp However, if the regression coefficient for c.4469G4A (p.Cys1490Tyr):c.1804C4T (p.Arg602Trp) ( 0.0295) was not included, ie, (0.0460 &#fe; 0.0528 &#fe; 0.0468)1 &#bc; 6.868, the predicted average AOO would be an underestimation of the true value. Login to comment 53 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe The mutation combinations not detected in the cohort were c.454C4T (p.Arg152*) (homozygous), c.1804C4T (p.Arg602Trp) (homozygous), c.2588G4C (p.Gly863Ala) (homozygous), c.454C4T (p.Arg152*):c.1804C4T (p.Arg602Trp) and c.2588G4C (p.Gly863Ala): c.6079C4T (p.Leu2027Phe). Login to comment 57 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu2027Phe The c.2588G4C (p.Gly863Ala): c.6079C4T (p.Leu2027Phe) combination may be an example of this, as this combination has not yet been reported in the literature, to the best of our knowledge, and c.2588G4C (p.Gly863Ala) was previously proposed as a mild mutation.16 Lastly, and least likely, the mutation combination may be so severe that it leads to panretinal atrophy and therefore would not be identified in this STGD patient cohort. Login to comment