title: Exome sequencing in suspected monogenic dyslipidemias.
abstract: 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.
  
  
  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.
authors: Nathan O
authors: NO
authors: Stitziel
authors: Gina M
authors: GM
authors: Peloso
authors: Marianne
authors: M
authors: Abifadel
authors: Angelo B
authors: AB
authors: Cefalu
authors: Sigrid
authors: S
authors: Fouchier
authors: M Mahdi
authors: MM
authors: Motazacker
authors: Hayato
authors: H
authors: Tada
authors: Daniel B
authors: DB
authors: Larach
authors: Zuhier
authors: Z
authors: Awan
authors: Jorge F
authors: JF
authors: Haller
authors: Clive R
authors: CR
authors: Pullinger
authors: Mathilde
authors: M
authors: Varret
authors: Jean-Pierre
authors: JP
authors: Rabès
authors: Davide
authors: D
authors: Noto
authors: Patrizia
authors: P
authors: Tarugi
authors: Masa-Aki
authors: MA
authors: Kawashiri
authors: Atsushi
authors: A
authors: Nohara
authors: Masakazu
authors: M
authors: Yamagishi
authors: Marjorie
authors: M
authors: Risman
authors: Rahul
authors: R
authors: Deo
authors: Isabelle
authors: I
authors: Ruel
authors: Jay
authors: J
authors: Shendure
authors: Deborah A
authors: DA
authors: Nickerson
authors: James G
authors: JG
authors: Wilson
authors: Stephen S
authors: SS
authors: Rich
authors: Namrata
authors: N
authors: Gupta
authors: Deborah N
authors: DN
authors: Farlow
authors: Benjamin M
authors: BM
authors: Neale
authors: Mark J
authors: MJ
authors: Daly
authors: John P
authors: JP
authors: Kane
authors: Mason W
authors: MW
authors: Freeman
authors: Jacques
authors: J
authors: Genest
authors: Daniel J
authors: DJ
authors: Rader
authors: Hiroshi
authors: H
authors: Mabuchi
authors: John J P
authors: JJ
authors: Kastelein
authors: G Kees
authors: GK
authors: Hovingh
authors: Maurizio R
authors: MR
authors: Averna
authors: Stacey
authors: S
authors: Gabriel
authors: Catherine
authors: C
authors: Boileau
authors: Sekar
authors: S
authors: Kathiresan
mesh_terms: D050171:Dyslipidemias / Q000235:genetics*; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*
keywords: DNA sequencing; exome; genetics; human; lipids
references: Nature. 2010 Aug 5;466(7307):707-13
references: 20686565
references: Hum Mutat. 2010 Nov;31(11):E1811-24
references: 20809525
references: N Engl J Med. 2010 Dec 2;363(23):2220-7
references: 20942659
references: Am J Hum Genet. 2011 Mar 11;88(3):273-82
references: 21353195
references: Nat Genet. 2011 May;43(5):491-8
references: 21478889
references: J Bone Miner Res. 2011 Jul;26(7):1655-61
references: 21404329
references: Nat Rev Genet. 2011 Nov;12(11):745-55
references: 21946919
references: Genome Biol. 2011;12(1):R1
references: 21205303
references: Nucleic Acids Res. 2012 Apr;40(7):e53
references: 22241780
references: Circ Cardiovasc Genet. 2012 Apr 1;5(2):217-25
references: 22319020
references: Genome Biol. 2011;12(9):R86
references: 21917142
references: Genome Biol. 2011;12(9):228
references: 21920049
references: Genome Biol. 2011;12(9):R97
references: 21958622
references: Fly (Austin). 2012 Apr-Jun;6(2):80-92
references: 22728672
references: Science. 2012 Jul 6;337(6090):64-9
references: 22604720
references: J Med Genet. 2012 Oct;49(10):644-9
references: 23054246
references: Hum Mutat. 2013 Jan;34(1):83-7
references: 22949395
references: Nat Genet. 2013 Mar;45(3):299-303
references: 23396133
references: Lancet. 2013 Apr 13;381(9874):1293-301
references: 23433573
references: Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1521-8
references: 23685560
references: Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):2021-5
references: 23723369
references: Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2909-14
references: 24072694
references: Atherosclerosis. 2013 Dec;231(2):218-22
references: 24267230
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: Hum Mutat. 2000;15(1):7-12
references: 10612815
references: Ital Heart J Suppl. 2001 Sep;2(9):997-1004
references: 11675837
references: J Hum Genet. 2002;47(6):325-9
references: 12111381
references: Nat Genet. 2003 Jun;34(2):154-6
references: 12730697
references: Science. 1986 Apr 4;232(4746):34-47
references: 3513311
references: J Intern Med. 1993 Jan;233(1):45-51
references: 8429286
references: Hum Mutat. 1992;1(6):445-66
references: 1301956
references: Clin Chem Lab Med. 1998 Jan;36(1):35-42
references: 9594084
references: Nat Genet. 1999 Aug;22(4):347-51
references: 10431237
references: Hum Mutat. 2005 Dec;26(6):550-6
references: 16250003
references: Ann Hum Genet. 2008 Jul;72(Pt 4):485-98
references: 18325082
references: Nat Biotechnol. 2008 Oct;26(10):1135-45
references: 18846087
references: Bioinformatics. 2009 Jul 15;25(14):1754-60
references: 19451168