title: Novel genes and variants associated with IgA nephropathy by co-segregating with the disease phenotypes in 10 IgAN families.
abstract: BACKGROUND
  Previously, a large proportion of the genetic components predisposing individuals to IgA nephropathy (IgAN) have been unidentified. Familial IgAN is enriched with genetic variations predisposing individuals to the disease. Whole exome sequencing is an effective way to explore disease-causing genes and gene variants.
  
  
  METHODS
  We performed exome sequencing on the probands from each of ten IgAN families, and on one of the unaffected member from 7 of the families. Sanger sequencing, bioinformatics and co-segregation analysis were performed for all available family members to detect deleterious genetic variation. The relatedness of the families was tested by haplotype analyses.
  
  
  RESULTS
  Six deleterious variants in 4 genes were observed to be associated with IgA nephropathy by co-segregating with the disease phenotypes in study families. MYCT1 p.Asp22Glufs*34 was associated with IgAN by co-segregating with its phenotypes in families 2, 7, and 9; DEFA4 p.Ala8Pro, p.Ala8Val, c.172+1G>T co-segregated in families 1, 2, and 3; ZNF543 p.Pro226Ala co-segregated in families 3, 5, and 6 and CARD8 p.Val98Lysfs*26 co-segregated in families 7 and 8. Among these genes, MYCT1, CARD8 and ZNF543 are novel. Our haplotype analyses showed that families in which the same variation(s) were co-segregating with IgAN were unrelated, except for DEFA4. Of the families carrying DEFA4, families 2 and 3 were possibly related, but not family 1, indicating that common genes/variations in these families were not due to the same founder. Interfamilial sharing of different co-segregating genes was also observed, demonstrating the polygenic nature of this disease.
  
  
  CONCLUSIONS
  We discovered 6 deleterious variants in 4 genes associated with familial IgAN. These genes are good candidate genes that appear to be causally related to IgAN and warrant further study.
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Center for Genome Research, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ruihong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Center for Genome Research, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Qibin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Prenatal Diagnosis Center, Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Jing
authors.affiliation: Center for Reproductive Medicine, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Center for Genome Research, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Man F
authors.initials: MF
authors.lastname: Lam
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Kar N
authors.initials: KN
authors.lastname: Lai
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Center for Genome Research, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; BGI-Shenzhen, Shenzhen, China. Electronic address: ywzhong@hotmail.com.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005192:Family Health; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000473:pathology; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods; D023084:alpha-Defensins / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D004268:DNA-Binding Proteins; C477074:MYCT1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C000602810:ZNF543 protein, human; D023084:alpha-Defensins; C406428:human neutrophil peptide 4
keywords: Caspase recruitment domain-containing protein 8 (CARD8); Defensin, Alpha 4 (DEFA4); Familial; IgA nephropathy (IgAN); Myc Target 1 (MYCT1); Zinc Finger Protein 543 (ZNF543)