ABCA1 p.Asn1948Ser
| Predicted by SNAP2: | A: D (85%), C: D (85%), D: D (91%), E: D (91%), F: D (91%), G: D (91%), H: D (85%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), P: D (91%), Q: D (80%), R: D (91%), S: D (85%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Exome sequencing in suspected monogenic dyslipidem... Circ Cardiovasc Genet. 2015 Apr;8(2):343-50. doi: 10.1161/CIRCGENETICS.114.000776. Epub 2015 Jan 27. Stitziel NO, Peloso GM, Abifadel M, Cefalu AB, Fouchier S, Motazacker MM, Tada H, Larach DB, Awan Z, Haller JF, Pullinger CR, Varret M, Rabes JP, Noto D, Tarugi P, Kawashiri MA, Nohara A, Yamagishi M, Risman M, Deo R, Ruel I, Shendure J, Nickerson DA, Wilson JG, Rich SS, Gupta N, Farlow DN, Neale BM, Daly MJ, Kane JP, Freeman MW, Genest J, Rader DJ, Mabuchi H, Kastelein JJ, Hovingh GK, Averna MR, Gabriel S, Boileau C, Kathiresan S
Exome sequencing in suspected monogenic dyslipidemias.
Circ Cardiovasc Genet. 2015 Apr;8(2):343-50. doi: 10.1161/CIRCGENETICS.114.000776. Epub 2015 Jan 27., [PMID:25632026]
Abstract [show]
BACKGROUND: Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. METHODS AND RESULTS: We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. CONCLUSIONS: We identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.
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No. Sentence Comment
112 An analysis using these updated phenotypes identified a candidate variant in LDLR (p.E228K, also known as FH Modena, previously shown to be pathogenic25 ) that was subsequently confirmed to Table.ߓ Genetic Etiologies Identified From Exome Sequencing Family (Trait) Gene Genomic position* Reference allele Alternate allele Effectߤ Notes Genetic etiology discovered during initial exome sequencing analysis A4 (high LDL) APOB 2:21229554 C T p.A3396T ߥ A9 (high LDL) PCSK9 1:55509689 T A p.S127R &#a7; B2 (low LDL) APOB 2:21233022 T A p.K2240* ৷ B13 (low LDL) APOB 2:21229005 - G p.T3579Hfs*34 # C1 (low HDL) ABCA1 9:107553287 T C p.N1948S ** Genetic etiology discovered from follow-up analysis A1 (high LDL) APOE 19:45412048 CTC - p.L167del ߥߥ A10 (high LDL) APOE 19:45412048 CTC - p.L167del ߥߥ A13 (high LDL) LIPA 10:90982268 C T Disruption of donor splice site ߥߥ Genetic etiology discovered based on phenotypic refinement within the family A7 (high LDL) LDLR 19:11216264 G A p.E228K &#a7;&#a7; HDL indicates high-density lipoprotein; and LDL, low-density lipoprotein.
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ABCA1 p.Asn1948Ser 25632026:112:654
status: NEW