OBJECTIVES: This study was designed to identify disease loci for hypoplastic left heart syndrome (HLHS) and evaluate the genetic relationship between HLHS and bicuspid aortic valve (BAV). BACKGROUND: Previously, we identified that HLHS and BAV exhibit complex inheritance, and both HLHS and BAV kindreds are enriched for BAV. However, the genetic basis of HLHS and its relationship to BAV remains unclear. METHODS: Family-based nonparametric genome-wide linkage analysis was performed in kindreds ascertained by either an HLHS or BAV proband. Echocardiograms were performed on 1,013 participants using a sequential sampling strategy (33 HLHS kindreds, 102 BAV kindreds). RESULTS: The recurrence risk ratio of BAV in HLHS families (8.05) was nearly identical to that in BAV families (8.77). Linkage to chromosomal regions 10q22 and 6q23 with maximum logarithm of odds scores of 3.2 and 3.1, respectively, was identified in HLHS kindreds. In addition, 5 suggestive loci were identified (7q31, 11q22, 12q13, 14q23, and 20q11). We previously identified loci at chromosomes 18q22, 13q34, and 5q21 in BAV kindreds. The relationship between these loci was examined in the combined HLHS and BAV cohort and associations between loci were demonstrated (5q21, 13q34, and 14q23; 6q23 and 10q22; 7q31 and 20q11). Subsequent subsets linkage analysis showed a significant improvement in the logarithm of odds score at 14q23 only (4.1, p < 0.0001). CONCLUSIONS: These studies demonstrate linkage to multiple loci identifying HLHS as genetically heterogeneous. Subsets linkage analyses and recurrence risk ratios in a combined cohort provide evidence that some HLHS and BAV are genetically related.
OBJECTIVES: This study was designed to identify disease loci for hypoplastic left heart syndrome (HLHS) and evaluate the genetic relationship between HLHS and bicuspid aortic valve (BAV). BACKGROUND: Previously, we identified that HLHS and BAV exhibit complex inheritance, and both HLHS and BAV kindreds are enriched for BAV. However, the genetic basis of HLHS and its relationship to BAV remains unclear. METHODS: Family-based nonparametric genome-wide linkage analysis was performed in kindreds ascertained by either an HLHS or BAV proband. Echocardiograms were performed on 1,013 participants using a sequential sampling strategy (33 HLHS kindreds, 102 BAV kindreds). RESULTS: The recurrence risk ratio of BAV in HLHS families (8.05) was nearly identical to that in BAV families (8.77). Linkage to chromosomal regions 10q22 and 6q23 with maximum logarithm of odds scores of 3.2 and 3.1, respectively, was identified in HLHS kindreds. In addition, 5 suggestive loci were identified (7q31, 11q22, 12q13, 14q23, and 20q11). We previously identified loci at chromosomes 18q22, 13q34, and 5q21 in BAV kindreds. The relationship between these loci was examined in the combined HLHS and BAV cohort and associations between loci were demonstrated (5q21, 13q34, and 14q23; 6q23 and 10q22; 7q31 and 20q11). Subsequent subsets linkage analysis showed a significant improvement in the logarithm of odds score at 14q23 only (4.1, p < 0.0001). CONCLUSIONS: These studies demonstrate linkage to multiple loci identifying HLHS as genetically heterogeneous. Subsets linkage analyses and recurrence risk ratios in a combined cohort provide evidence that some HLHS and BAV are genetically related.
Authors: Damini Jawaheer; Michael F Seldin; Christopher I Amos; Wei V Chen; Russell Shigeta; Carol Etzel; Aarti Damle; Xiangli Xiao; Dong Chen; Raymond F Lum; Joanita Monteiro; Marlene Kern; Lindsey A Criswell; Salvatore Albani; J Lee Nelson; Daniel O Clegg; Richard Pope; Harry W Schroeder; S Louis Bridges; David S Pisetsky; Ryk Ward; Daniel L Kastner; Ronald L Wilder; Theodore Pincus; Leigh F Callahan; Donald Flemming; Mark H Wener; Peter K Gregersen Journal: Arthritis Rheum Date: 2003-04
Authors: David A Elliott; Edwin P Kirk; Thomas Yeoh; Suchitra Chandar; Fiona McKenzie; Peter Taylor; Paul Grossfeld; Diane Fatkin; Owen Jones; Peter Hayes; Michael Feneley; Richard P Harvey Journal: J Am Coll Cardiol Date: 2003-06-04 Impact factor: 24.094
Authors: James S Tweddell; George M Hoffman; Kathleen A Mussatto; Raymond T Fedderly; Stuart Berger; Robert D B Jaquiss; Nancy S Ghanayem; Stephanie J Frisbee; S Bert Litwin Journal: Circulation Date: 2002-09-24 Impact factor: 29.690
Authors: Christopher A Loffredo; Anand Chokkalingam; Anne M Sill; Joann A Boughman; Edward B Clark; Janet Scheel; Joel I Brenner Journal: Am J Med Genet A Date: 2004-01-30 Impact factor: 2.802
Authors: Helen N Jones; Stephanie K Olbrych; Kathleen L Smith; James F Cnota; Mounira Habli; Osniel Ramos-Gonzales; Kathryn J Owens; Andrea C Hinton; William J Polzin; Louis J Muglia; Robert B Hinton Journal: Placenta Date: 2015-08-07 Impact factor: 3.481
Authors: M Carmen Fernández; Ana C Durán; Borja Fernández; Josep M Arqué; Robert H Anderson; Valentín Sans-Coma Journal: J Anat Date: 2012-05-17 Impact factor: 2.610
Authors: Laura E Mitchell; A J Agopian; Angela Bhalla; Joseph T Glessner; Cecilia E Kim; Michael D Swartz; Hakon Hakonarson; Elizabeth Goldmuntz Journal: Hum Mol Genet Date: 2014-08-18 Impact factor: 6.150