NKX2-5 mutations in an inbred consanguineous population: genetic and phenotypic diversity.
NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2-5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population.
1] Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon [2] Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
Ossama K
OK
Abou Hassan
1] Department of Genetics, Harvard Medical School, Boston, MA [2] Department of Medicine, Massachusetts General Hospital, Boston, MA.
Akl C
AC
Fahed
Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
Manal
M
Batrawi
Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
Mariam
M
Arabi
1] Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon [2] Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
Marwan M
MM
Refaat
Department of Genetics, Harvard Medical School, Boston, MA.
Steven R
SR
DePalma
Department of Genetics, Harvard Medical School, Boston, MA.
J G
JG
Seidman
1] Department of Genetics, Harvard Medical School, Boston, MA [2] Howard Hughes Medical Institute and Division of Cardiology, Brigham and Women's Hospital, Boston, MA.
Christine E
CE
Seidman
1] Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon [2] Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
Fadi F
FF
Bitar
Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
Georges M
GM
Nemer
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003241:Consanguinity; D004562:Electrocardiography; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D014644:Genetic Variation; D005838:Genotype; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007861:Lebanon / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D015995:Prevalence; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors