ABCA4 p.Phe642Ile
| Predicted by SNAP2: | A: D (66%), C: N (61%), D: D (71%), E: D (53%), G: D (75%), H: N (57%), I: N (72%), K: D (53%), L: N (66%), M: N (78%), N: D (59%), P: D (71%), Q: N (57%), R: D (53%), S: D (53%), T: N (53%), V: N (57%), W: N (61%), Y: N (82%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: 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: N, Y: N, |
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[hide] Detecting genetic variations in hereditary retinal... Mol Vis. 2014 Apr 26;20:553-60. eCollection 2014. Jin X, Qu LH, Meng XH, Xu HW, Yin ZQ
Detecting genetic variations in hereditary retinal dystrophies with next-generation sequencing technology.
Mol Vis. 2014 Apr 26;20:553-60. eCollection 2014., [PMID:24791140]
Abstract [show]
PURPOSE: To identify pathogenic mutations responsible for retinal dystrophies (RDs) in three unrelated Chinese families. METHODS: Three probands from unrelated families with RDs were recruited. Genomic DNA prepared from leukocytes was analyzed using gene chip-based next-generation sequencing (NGS) to capture and sequence all of the exons of 100 known RD-associated genes. Candidate variants were validated with PCR and Sanger sequencing in the respective families. Thorough ophthalmic examinations including best-corrected visual acuity, funduscopic examination, and full-field electroretinograms were performed in the affected individuals. RESULTS: We successfully identified causative mutations in patients from the Chinese families with RDS: the known mutation IMPDH1 c.942_944delGAA in a family with retinitis pigmentosa, the novel mutation ABCA4 c.1924T>A in a family with Stargardt disease, and the novel mutation NMNAT1 c.272A>G and known mutation NMNAT1 c.196C>T in a family with Leber congenital amaurosis. All variations segregated with the disease phenotypes in the respective families and were absent from ethnically matched control chromosomes. Prediction analysis demonstrated the two novel missense mutations might be damaging. CONCLUSIONS: The results strongly suggested these mutations were responsible for different RD phenotypes in the Chinese families. NGS technology provides an accurate and economic method for identifying causative genes for RDs.
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No. Sentence Comment
81 After filtering against these databases, four variants that might be associated with RDs diseases were left: The first was a heterozygous nucleotide deletion variation c.942_944delGAA in IMPDH1, which was predicted to result in lysine deletion at position 314 (p.Lys314del p.K314del) in the proband of Family-012; the second was a homozygous single-nucleotide-polymorphic site c.1924T>A in ABCA4 leading to amino acid substitution of phenylalanine for isoleucine at position 642 (p.Phe642Ile p.F642I) in the proband of Family-024; the third and fourth were compound heterozygous mutations of c.272A>G and c.196C>T in NMNAT1 that caused glutamic acid substitution for glycine at position 91 (p.Glu91Gly p.E91G) and amino acid substitution of arginine for tryptophan at position 66 (p.Arg66Trp p.R66W) in the proband of Family-035.
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ABCA4 p.Phe642Ile 24791140:81:434
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ABCA4 p.Phe642Ile 24791140:81:482
status: NEWX
ABCA4 p.Phe642Ile 24791140:81:494
status: NEW120 Thus, in total, we have identified four mutants in three Chinese families associated with adRP, STGD, and LCA, including a deletion mutation encoding p.K314del in IMPDH1 and three missense mutations encoding p.F642I in ABCA4, p.E91G, and p.R66W in NMNAT1 with gene panel-based NGS.
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ABCA4 p.Phe642Ile 24791140:120:210
status: NEW125 Sample Disease Inheritance mannera Gene Exon Nucleotide change Amino acid change Mutation typeb SIFT/ Polyphen2c Family-012 RP AD IMPDH1 10 c.942_944delGAA p.K314del het N.P. Family-024 STD AR ABCA4 13 c.1924T>A p.Phe642Ile hom 0.03/ 0.278 Family-035 LCA AR NMNAT1 3 c.272A>G p.Glu91Gly het 0.2/0.745 NMNAT1 3 c.196C>T p.Arg66Trp het N.P a Inheritance manner: AR (autosomal recessive), AD (autosomal dominant);b Mutation type: het (heterozygous), hom (homozygous); c SIFT/ Polyphen2: N.P. (not predicted) APPENDIX 1.
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ABCA4 p.Phe642Ile 24791140:125:214
status: NEW[hide] Next-generation sequencing applied to a large Fren... Orphanet J Rare Dis. 2015 Jun 24;10:85. doi: 10.1186/s13023-015-0300-3. Boulanger-Scemama E, El Shamieh S, Demontant V, Condroyer C, Antonio A, Michiels C, Boyard F, Saraiva JP, Letexier M, Souied E, Mohand-Said S, Sahel JA, Zeitz C, Audo I
Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation.
Orphanet J Rare Dis. 2015 Jun 24;10:85. doi: 10.1186/s13023-015-0300-3., [PMID:26103963]
Abstract [show]
BACKGROUND: Cone and cone-rod dystrophies are clinically and genetically heterogeneous inherited retinal disorders with predominant cone impairment. They should be distinguished from the more common group of rod-cone dystrophies (retinitis pigmentosa) due to their more severe visual prognosis with early central vision loss. The purpose of our study was to document mutation spectrum of a large French cohort of cone and cone-rod dystrophies. METHODS: We applied Next-Generation Sequencing targeting a panel of 123 genes implicated in retinal diseases to 96 patients. A systematic filtering approach was used to identify likely disease causing variants, subsequently confirmed by Sanger sequencing and co-segregation analysis when possible. RESULTS: Overall, the likely causative mutations were detected in 62.1 % of cases, revealing 33 known and 35 novel mutations. This rate was higher for autosomal dominant (100 %) than autosomal recessive cases (53.8 %). Mutations in ABCA4 and GUCY2D were responsible for 19.2 % and 29.4 % of resolved cases with recessive and dominant inheritance, respectively. Furthermore, unexpected genotype-phenotype correlations were identified, confirming the complexity of inherited retinal disorders with phenotypic overlap between cone-rod dystrophies and other retinal diseases. CONCLUSIONS: In summary, this time-efficient approach allowed mutation detection in the most important cohort of cone-rod dystrophies investigated so far covering the largest number of genes. Association of known gene defects with novel phenotypes and mode of inheritance were established.
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99 Table 1 Summary of 43 patients carrying pathogenic and likely pathogenic mutations in known CCRD genes ID Type Consang. Gene NM Allele State Exon cDNA Protein Coseg. Conservation Polyphen2 Sift Mutation taster References High confidence CIC00137 simplex ABCA4 NM_000350.2 Ho 47 c.6394G>A p.(E2132K) + Highly Prd D Dc Novel CIC00765 Ar + ABCA4 NM_000350.2 Ho 47 c.6445C>T p.(R2149*) + - - - - (Lewis et al. 1999) (rs61750654) CIC03436 Ar + ABCA4 NM_000350.2 Ho 42 c.5892del p.(G1965Efs*9) Np - - - - a CIC04412 simplex ABC4A NM_000350.2 Het 34 c.4793C>A p.(A1598D) + Weakly Pd T Dc (Maugeri et al. 2000) (rs61750155) ABCA4 NM_000350.2 Het 28 c.4234C>T p.(Q1412*) + - - - - (Maugeri et al. 2000) (rs61750137) CIC04645 Ar + ABCA4 NM_000350.2 Ho 13 c.1924T>C p.(F642L) Np Moderately B D Dc Novel, but c.1924T>A p.F642I in (Jin et al. 2014) [80] CIC05087 simplex ABCA4 NM_000350.2 Ho IVS 11 c.1554+1G>C r.(spl?)
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ABCA4 p.Phe642Ile 26103963:99:809
status: NEW