TY - JOUR
T1 - A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q
AU - Van De Meerakker, Judith B.A.
AU - Van Engelen, Klaartje
AU - Mathijssen, Inge B.
AU - Lekanne Dit Deprez, Ronald H.
AU - Lam, Jan
AU - Wilde, Arthur A.M.
AU - Baars, Marieke J.H.
AU - Mannens, Marcel M.A.M.
AU - Mulder, Barbara J.M.
AU - Moorman, Antoon F.M.
AU - Postma, Alex V.
N1 - Funding Information: We thank all family members for their kind participation. We also thank A Ilgun, A Mul, D van Gent, S de Jong, F Salehi and F Asidah for their excellent technical assistance, S Romeih, and M Groenink for the assessment of the MRI and CT images, and HACM de Bruin-Bon for performing echocardiographic examinations. We thank Dr RJ Oostra for helpful discussions. AFMM is supported by grants from the Netherlands Heart Foundation (96.002) and the European Community’s Sixth Framework Program contract (‘HeartRepair’ LSHM-CT-2005-018630). Copyright: Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/7
Y1 - 2011/7
N2 - Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.
AB - Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.
KW - atrium
KW - congenital heart defects
KW - sinus node
UR - http://www.scopus.com/inward/record.url?scp=79959229675&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/ejhg.2011.33
DO - https://doi.org/10.1038/ejhg.2011.33
M3 - Article
C2 - 21386876
SN - 1018-4813
VL - 19
SP - 820
EP - 826
JO - European journal of human genetics
JF - European journal of human genetics
IS - 7
ER -