title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder that typically exhibits autosomal dominant inheritance. Genomic strategies enable discovery of novel, unsuspected molecular underpinnings of familial DCM. We performed genome-wide mapping and exome sequencing in a unique family wherein DCM segregated as an autosomal recessive (AR) trait.
  
  
  RESULTS
  Echocardiography in 17 adult descendants of first cousins revealed DCM in 2 female siblings and idiopathic left ventricular enlargement in their brother. Genotyping and linkage analysis mapped an AR DCM locus to chromosome arm 7q21, which was validated and refined by high-density homozygosity mapping. Exome sequencing of the affected sisters was then used as a complementary strategy for mutation discovery. An iterative bioinformatics process was used to filter >40,000 genetic variants, revealing a single shared homozygous missense mutation localized to the 7q21 critical region. The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched controls, altered a conserved residue of GATAD1, encoding GATA zinc finger domain-containing protein 1. Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages. Immunohistochemistry demonstrated nuclear localization of GATAD1 in left ventricular myocytes, yet subcellular expression and nuclear morphology were aberrant in the proband.
  
  
  CONCLUSIONS
  Linkage analysis and exome sequencing were used as synergistic genomic strategies to identify GATAD1 as a gene for AR DCM. GATAD1 binds to a histone modification site that regulates gene expression. Consistent with murine DCM caused by genetic disruption of histone deacetylases, the data implicate an inherited basis for epigenetic dysregulation in human heart failure.
authors.affiliation: Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jeanne L
authors.initials: JL
authors.lastname: Theis
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Sharpe
authors.forename: Martha E
authors.initials: ME
authors.lastname: Matsumoto
authors.forename: High Seng
authors.initials: HS
authors.lastname: Chai
authors.forename: Asha A
authors.initials: AA
authors.lastname: Nair
authors.forename: Jason D
authors.initials: JD
authors.lastname: Theis
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
authors.forename: Virginia V
authors.initials: VV
authors.lastname: Michels
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D059472:Exome; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D044465:White People; D055815:Young Adult
chemical_list: D005136:Eye Proteins; C464454:GATAD1 protein, human