title: Whole exome sequencing combined with integrated variant annotation prediction identifies asymptomatic Tangier disease with compound heterozygous mutations in ABCA1 gene.
abstract: OBJECTIVE
  Molecular diagnosis for subjects with extremely low HDL-C through candidate-gene approaches requires huge effort. Whole exome-sequencing (WES) has already shown approximately ∼30% success in the diagnosis of Mendelian disorders. Moreover, novel in silico prediction software for the pathogenicity of novel missense variants named Combined Annotation Dependent Depletion (CADD) has recently been developed, enabling the objective integration of many diverse annotations into a single measure (C-score) for each variant. Here, we investigated whether WES combined with integrated variant annotation prediction could facilitate the molecular diagnosis of this rare condition.
  
  
  METHODS
  WES was performed on 8 individuals including 2 individuals exhibiting extremely low HDL-C (2 mg/dl and 6 mg/dl), 2 unaffected family members, and 4 unrelated individuals as controls. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the recessive form of inheritance; 4) C-score < 10.
  
  
  RESULTS
  Among 305,202 variants found in those individuals, we found 21,708 nonsense, missense, or splice site variants, of which 5192 were rare (MAF ≤ 1% or not reported). Filtering assuming a recessive pattern of inheritance, combined with the use of the C-score, successfully narrowed down the candidates to compound heterozygous mutations in the ABCA1 gene (c.6230C > A or p.P2077H/c.6137G > A or p.S2046N, and c.2842G > A or p.G948R/c.1130C > T or p.P377L).
  
  
  CONCLUSIONS
  WES combined with integrated variant annotation prediction successfully identified asymptomatic Tangier disease with novel ABCA1 mutations. This comprehensive approach is useful to determine causative variants, especially in recessive inherited diseases.
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Hayato
authors: H
authors: Tada
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Masa-Aki
authors: MA
authors: Kawashiri
authors: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Atsushi
authors: A
authors: Nohara
authors: Department of Disease Control and Homeostasis, Kanazawa University, Graduate School of Medical Sciences, Kanazawa, Japan.
authors: Reina
authors: R
authors: Saito
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Yoshihiro
authors: Y
authors: Tanaka
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Akihiro
authors: A
authors: Nomura
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Tetsuo
authors: T
authors: Konno
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Kenji
authors: K
authors: Sakata
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Noboru
authors: N
authors: Fujino
authors: Department of Disease Control and Homeostasis, Kanazawa University, Graduate School of Medical Sciences, Kanazawa, Japan.
authors: Toshinari
authors: T
authors: Takamura
authors: Department of Laboratory Science, Molecular Biochemistry and Molecular Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Akihiro
authors: A
authors: Inazu
authors: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Hiroshi
authors: H
authors: Mabuchi
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Masakazu
authors: M
authors: Yamagishi
authors: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors: Kenshi
authors: K
authors: Hayashi
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods*; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D013631:Tangier Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D015415:Biomarkers; D008076:Cholesterol, HDL
keywords: ABCA1; Exome; Genetics; HDL; Tangier disease