ライフサイエンスコーパス: HLHS

1 HLHS was present in 45 patients, complex double-outlet r

2 HLHS-associated CELSR1 variants included 16 missense, on

3 HLHS-iPSC-derived cardiomyocytes are characterised by a

4 HLHS/TGA (n = 24), CHD-other (50), and CHD-related (34)

5 , transmission disequilibrium testing of 161 HLHS proband-parent trios revealed overrepresentation of

6 rformed whole genome sequencing (WGS) on 183 HLHS patient-parent trios to identify candidate genes, w

7 Whole-genome sequencing of 25 HLHS proband-parent trios similarly showed enrichment of

8 We studied LV myocardial samples from 32 HLHS and 17 structurally normal midgestation fetuses.

9 nts using a sequential sampling strategy (33 HLHS kindreds, 102 BAV kindreds).

10 S, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of

11 In 442H, a HLHS proband was compound heterozygous for MYO15A varian

12 ed-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution t

13 on whole-genome and iPSC RNA sequencing of a HLHS family-trio.

14 alysis of WGS data from an index family of a HLHS proband born to consanguineous parents prioritized

15 Five additional HLHS probands harbored rare, predicted damaging variants

16 All HLHS probands had aortic valve hypoplasia and dysplasia;

17 rformed in kindreds ascertained by either an HLHS or BAV proband.

18 cted members of 6 multiplex BAV families, an HLHS cohort of 197 probands and 546 relatives, and 813 c

19 variants in 3 index families comprised of an HLHS proband and relative(s) with cardiomyopathy.

20 factors for a reduced hyperemic MBF were an HLHS subtype with mitral stenosis and aortic atresia (P=

21 nium enhancement were assessed in 4 anatomic HLHS subtypes.

22 s a susceptibility gene for familial BAV and HLHS, further implicating planar cell polarity pathway p

23 tablish for the first time that AVS, COA and HLHS can share a common pathogenetic mechanism at the mo

24 atients, in comparison with those managed as HLHS, have not been reported.

25 nd evaluate the genetic relationship between HLHS and bicuspid aortic valve (BAV).

26 nd BAV exhibit complex inheritance, and both HLHS and BAV kindreds are enriched for BAV.

27 ant mice and identification of genes causing HLHS.

28 All patients had classic HLHS, defined as a right ventricular dependent circulati

29 ween these loci was examined in the combined HLHS and BAV cohort and associations between loci were d

30 PVD flow analysis and postnatally confirmed HLHS were studied.

31 tality were high (48%) compared with control HLHS patients, regardless of prenatal diagnosis and desp

32 associations between prenatal diagnosis, CSC HLHS volume, and mortality were also examined.

33 ical mortality was associated with lower CSC HLHS volume (odds ratio per 10 patients, 0.88; 95% confi

34 redicting which fetuses with AS will develop HLHS is essential to optimize patient selection for feta

35 er between fetuses that ultimately developed HLHS and those that maintained a biventricular circulati

36 uctures became evident in fetuses developing HLHS.

37 with AS who are at high risk for developing HLHS.

38 weight, gestational age, prenatal diagnosis, HLHS variant, associated diagnoses, ascending aortic siz

39 e midgestation aortic stenosis with evolving HLHS from March 2000 to January 2013.

40 asty for fetal aortic stenosis with evolving HLHS is important for accurate patient selection, parent

41 e studied hypoxia-associated injury in fetal HLHS and human pluripotent stem cells during cardiac dif

42 The hypoplastic LV in fetal HLHS samples demonstrates hypoxia-inducible factor-1alph

43 Compared with controls, the LV in fetal HLHS samples had higher nuclear expression of hypoxia-in

44 uced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiate

45 bidirectional cavopulmonary anastomosis for HLHS reduces second-stage mortality and improves interme

46 Hypothesizing an oligogenic basis for HLHS, we tested 60 additional prioritized candidate gene

47 reveal novel genetic insights important for HLHS pathology and shed new insights into the role of th

48 and improves hospital survival after NP for HLHS.

49 atients who underwent stage I operations for HLHS at our institution between 1983 and 1993, we identi

50 However, palliation for HLHS is a three-stage process and final judgment regardi

51 This work supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic d

52 also being associated with decreased PND for HLHS.

53 After staged reconstruction for HLHS, neo-aortic root dilation and neo-AR progress over

54 The sibling recurrence risk for HLHS was 8%, and for CVM was 22%.

55 underwent staged reconstructive surgery for HLHS (Norwood, n = 1,921 and hybrid, n = 91).

56 undergoing staged reconstructive surgery for HLHS, fewer than one-third are alive without a transplan

57 , 840 patients underwent stage I surgery for HLHS.

58 Identifying the best treatment for HLHS requires integrating individual patient risk factor

59 heart and transplantation as treatments for HLHS have been compared in treatment-received analyses,

60 enrolled 179 pregnant women into 4 groups: "HLHS/TGA" fetuses with hypoplastic left heart syndrome (

61 tients with available follow-up data, 17 had HLHS and 6 had a biventricular circulation.

62 The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were mor

63 yzed by 3 independent strategies to identify HLHS gene candidates, ranked by variant, gene, and disea

64 nstrate linkage to multiple loci identifying HLHS as genetically heterogeneous.

65 In HLHS, serial MRI shows the adaptation of the systemic RV

66 In HLHS, the pulmonary valve functions as the neo-aortic va

67 After reconstruction of the aortic arch in HLHS, the diameter of the arch continues to increase thr

68 The recurrence risk ratio of BAV in HLHS families (8.05) was nearly identical to that in BAV

69 is a contributor to transcriptome changes in HLHS patient RVs.

70 ng ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS par

71 receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target

72 of left- and right-sided valve dysplasia in HLHS probands and the increased prevalence of BAV in fam

73 ts reveal a critical role for endocardium in HLHS etiology and provide a rationale for considering en

74 ene demonstrating rare variant enrichment in HLHS probands (P=0.003575).

75 y of transcripts differentially expressed in HLHS patient hearts have validated Rbfox2 binding sites.

76 contributing to aberrant gene expression in HLHS patients.

77 Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell stat

78 hlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular pro

79 sated oxidative stress underlies early HF in HLHS.

80 3.2 and 3.1, respectively, was identified in HLHS kindreds.

81 , the Rbfox2 nonsense mutation identified in HLHS patients truncates the protein, impairs its subcell

82 onary dysfunction and myocardial ischemia in HLHS.

83 c MBF in the systemic ventricle was lower in HLHS compared with controls (1.89 0.57 versus 2.70 0.84

84 yocyte subtype differentiation/maturation in HLHS.

85 binding protein Rbfox2, which is mutated in HLHS patients, is a contributor to transcriptome changes

86 s indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects a

87 The staged palliation in HLHS may be a risk factor particularly for reduced left

88 he likely involvement of diverse pathways in HLHS.

89 , lower SEQ was associated with lower PND in HLHS and TGA, with the strongest association in the lowe

90 pmentally impaired endocardial population in HLHS through single-cell RNA profiling of hiPSC-derived

91 vel insights into RV geometric remodeling in HLHS and identify specific shape phenotypes associated w

92 the RV's complex geometry and remodeling in HLHS, limiting risk stratification.

93 The systemic right ventricle (RV) in HLHS is subject to significant changes in volume loading

94 nt on cell-ECM adhesion and that are seen in HLHS.

95 dence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights importa

96 rioritized by rare variant burden testing in HLHS cases versus controls.

97 We conclude that, in HLHS after the Norwood operation, the right ventricle to

98 cardiovascular defects overlapping those in HLHS patients including ventricular, valve, and aortic d

99 e for Rbfox2 in controlling transcriptome in HLHS.

100 Modifier variants in HLHS proband-parent trios were sought to account for the

101 To further investigate HLHS-cardiomyopathy gene associations in cases versus co

102 Further, fetuses that developed a marked HLHS phenotype had elevated serum titers of anti-beta-ad

103 olume CSC may significantly improve neonatal HLHS survival.

104 One hundred nineteen HLHS patients (median age, 4.80 years) and 34 healthy vo

105 , consistent with recently described de novo HLHS mutations associated with abnormal endocardial gene

106 However, the genetic basis of HLHS and its relationship to BAV remains unclear.

107 e editing in mice as being digenic causes of HLHS.

108 unique pathophysiological characteristics of HLHS in Fontan circulation.

109 Familial clustering of HLHS and bicuspid aortic valve (BAV) has been observed,

110 Efforts to improve prenatal diagnosis of HLHS and subsequent delivery near a large volume CSC may

111 Prenatal diagnosis of HLHS was associated with improved preoperative clinical

112 peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation c

113 several molecular and phenotypic features of HLHS.

114 cyte proliferation with cardinal features of HLHS.

115 Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are ad

116 Heritability (h2) of HLHS and associated CVM was estimated using maximum-like

117 ming left ventricle (one of the hallmarks of HLHS).

118 The heritability of HLHS alone and with associated CVM were 99% and 74% (p <

119 The high heritability of HLHS suggests that it is determined largely by genetic f

120 is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLH

121 ly, we examine new results for palliation of HLHS.

122 The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assume

123 dence, and distance of residence with PND of HLHS and TGA (aggregate and individually) using bivariat

124 Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTC

125 Neonatal mortality in the subgroup of HLHS patients with intact or highly restrictive atrial s

126 he art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal an

127 Surgical treatment of HLHS involves either transplantation (Tx) or staged pall

128 xpected to lead to a better understanding of HLHS and other CHDs.

129 Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin

130 ommended action after prenatal diagnosis, on HLHS mortality has been poorly investigated.

131 These hypothesis-generating findings on HLHS-specific risk factors for microvascular dysfunction

132 rized based on postnatal management as BV or HLHS.

133 ge of maternal autoantibodies and a prenatal HLHS phenotype in exposed fetuses.

134 tly no Rbfox2 mouse models that recapitulate HLHS.

135 eads to heart development defects resembling HLHS, but also identified RBFOX2-regulated AS networks t

136 Mutations from seven HLHS mouse lines showed multigenic enrichment in ten hum

137 f aortic valve abnormalities, both signature HLHS defects.

138 a combined cohort provide evidence that some HLHS and BAV are genetically related.

139 Data on 1862 subjects (HLHS: n=1171, 92% PND; TGA: n=691, 58% PND) were submitt

140 s. 36%) and hypoplastic left heart syndrome (HLHS) (47% vs. 13%).

141 surgery for hypoplastic left heart syndrome (HLHS) and assess current outcome for this condition.

142 se loci for hypoplastic left heart syndrome (HLHS) and evaluate the genetic relationship between HLHS

143 those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyano

144 nfants with hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), but

145 urvival for hypoplastic left heart syndrome (HLHS) and variants has improved over the past 4 decades;

146 a (COA) and hypoplastic left heart syndrome (HLHS) are congenital cardiovascular malformations that a

147 gression to hypoplastic left heart syndrome (HLHS) at birth.

148 n (S1P) for hypoplastic left heart syndrome (HLHS) has improved coincident with application of treatm

149 fetus with hypoplastic left heart syndrome (HLHS) have been correlated with restrictive interatrial

150 liation for hypoplastic left heart syndrome (HLHS) have improved in recent years; however, certain ri

151 nfants with hypoplastic left heart syndrome (HLHS) include increased inspired nitrogen (hypoxia) and

152 Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterize

153 Hypoplastic left heart syndrome (HLHS) is a congenital malformation commonly treated with

154 Hypoplastic left heart syndrome (HLHS) is a fatal congenital heart disease in which the l

155 Hypoplastic left heart syndrome (HLHS) is a severe cardiac malformation characterized by

156 Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with a

157 Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated wi

158 Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mort

159 Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart

160 Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided

161 eration for hypoplastic left heart syndrome (HLHS) is critical to early survival.

162 Hypoplastic left heart syndrome (HLHS) is frequently diagnosed prenatally, but this has n

163 culation in hypoplastic left heart syndrome (HLHS) is largely unknown.

164 Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within

165 Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD)

166 etuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diag

167 Deciphering hypoplastic left heart syndrome (HLHS) pathogenesis is confounded by its genetic heteroge

168 tified by a hypoplastic left heart syndrome (HLHS) proband.

169 sis (AS) to hypoplastic left heart syndrome (HLHS) requires identification of fetuses with salvageabl

170 ildren with hypoplastic left heart syndrome (HLHS) undergoing staged surgical reconstruction, to asse

171 rtality for hypoplastic left heart syndrome (HLHS) using intention-to-treat analysis.

172 e (BAV) and hypoplastic left heart syndrome (HLHS) was postulated.

173 Hypoplastic left heart syndrome (HLHS) with intact or very restrictive atrial septum is a

174 Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6

175 t resembles hypoplastic left heart syndrome (HLHS), a life-threatening CHD primarily affecting the le

176 e show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heter

177 onates with hypoplastic left heart syndrome (HLHS), a severe form of congenital heart disease, that c

178 liation for hypoplastic left heart syndrome (HLHS), and strategies for selective cerebral perfusion (

179 , including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood.

180 lliation of hypoplastic left heart syndrome (HLHS), the NO, includes augmentation of the aortic arch

181 diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and ot

182 sis (AS) to hypoplastic left heart syndrome (HLHS).

183 ruction for hypoplastic left heart syndrome (HLHS).

184 trategy for hypoplastic left heart syndrome (HLHS).

185 surgery for hypoplastic left heart syndrome (HLHS).

186 liation for hypoplastic left heart syndrome (HLHS).

187 tients with hypoplastic left heart syndrome (HLHS).

188 RBFOX2 and hypoplastic left heart syndrome (HLHS).

189 , including hypoplastic left heart syndrome (HLHS).

190 gression to hypoplastic left heart syndrome (HLHS).

191 ildren with hypoplastic left heart syndrome (HLHS).

192 tcomes than hypoplastic left heart syndrome (HLHS).

193 requency of hypoplastic left heart syndrome (HLHS).

194 84+/-12% at 10 years, which was better than HLHS patients (log-rank P=0.04).

195 Previously, we identified that HLHS and BAV exhibit complex inheritance, and both HLHS

196 Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesoder

197 These findings show that HLHS can arise genetically in a combinatorial fashion, t

198 Prevailing paradigm suggests that HLHS is a multigenic disease of co-occurring phenotypes.

199 lence of BAV in family members suggests that HLHS is a severe form of valve malformation.

200 ro cellular and functional correlates of the HLHS phenotype.

201 Compared with CHD-related, the HLHS/TGA group had smaller subplate (-13.3% [standard er

202 Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation

203 rvention to prevent the progression of AS to HLHS.

204 with progression of midgestation fetal AS to HLHS.

205 however, understanding their contribution to HLHS requires further investigation.

206 cardiogenesis and candidate contributors to HLHS.

207 exities and pathogenic mechanisms leading to HLHS is limited.

208 RNA binding protein RBFOX2, a gene linked to HLHS in humans, display cardiovascular defects overlappi

209 nt in ten human chromosome regions linked to HLHS.

210 alvageable left hearts who would progress to HLHS if left untreated, a successful in utero valvotomy,

211 bility that all 24 fetuses would progress to HLHS if left untreated.

212 wever, all of the fetuses that progressed to HLHS had retrograde flow in the transverse aortic arch (

213 dysfunction are predictive of progression to HLHS.

214 cardiomyocyte (CM) proliferation relevant to HLHS, we performed a genome-wide siRNA screen in human i

215 development in rbfox mutant zebrafish, while HLHS-linked RBFOX2 variants fail to rescue.

216 y, fetuses and infants <2 months of age with HLHS or TGA admitted between 2012 and 2016 to participat

217 onventional myosin genes are associated with HLHS susceptibility.

218 entify and expectantly manage the fetus with HLHS and RAS.

219 In the fetus with HLHS, a PVD forward/reverse VTI ratio of <5 is the stron

220 Infants with HLHS born far from a CSC have increased neonatal mortali

221 Infants with HLHS requiring catheter septostomy within the first 2 da

222 ized and paralyzed preoperative infants with HLHS were evaluated in a prospective, randomized, crosso

223 in the right ventricle (RV) of infants with HLHS, although the molecular mechanisms remain unknown.

224 Data on 231 infants with HLHS, born between 1989 and 1994 and intended for surger

225 In preoperative infants with HLHS, under conditions of anesthesia and paralysis, alth

226 C and neonatal mortality in 463 infants with HLHS.

227 A transcriptome profiles of 13 neonates with HLHS before and after their first palliative surgery wer

228 inflammation and metabolism in neonates with HLHS who develop LCOS after CPB, this study opens for ex

229 From 1990 to 2002, 33 newborns with HLHS (11% of newborns with HLHS managed during this peri

230 dentifying the need for EAS in newborns with HLHS and RAS.

231 tal condition, the outlook for newborns with HLHS has been altered dramatically with staged reconstru

232 33 newborns with HLHS (11% of newborns with HLHS managed during this period) underwent urgent/semiur

233 atient factors on survival for newborns with HLHS; and 2) examine functional and health outcomes, inc

234 gest that low weight alone in a patient with HLHS or an anatomic variant should not be considered a c

235 mean RV shape template of 329 patients with HLHS (mean age, 14.7+/-6.3 years) depicted a circumferen

236 omyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart develo

237 pluripotent stem cells from 3 patients with HLHS and 3 controls.

238 Patients with HLHS and coexisting atrioventricular septal defect were

239 The study cohort included patients with HLHS and variants undergoing the Norwood or hybrid proce

240 We reviewed patients with HLHS between July 1992 and March 1999 to determine the i

241 Patients with HLHS born before January 1995 who had the Fontan operati

242 iterature and a dataset of 231 patients with HLHS born between 1989 and 1994.

243 graphic data of 59 consecutive patients with HLHS operated on at our institution.

244 Examinations) was analyzed for patients with HLHS post-Fontan.

245 entricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental

246 trategy for centers that treat patients with HLHS should be guided by local organ availability, stage

247 cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased a

248 lated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and

249 intermediate-term survival for patients with HLHS undergoing staged palliation increased significantl

250 itation is a common finding in patients with HLHS undergoing staged surgical reconstruction and can r

251 e serial echocardiograms of 50 patients with HLHS who underwent NO to determine the diameter of the r

252 autopsy specimens of 10 other patients with HLHS who underwent NO were examined to determine the con

253 iomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of t

254 intermediate-term outlook for patients with HLHS.

255 hemi-Fontan procedure from 24 patients with HLHS; the first 10 had a Norwood operation with a system

256 equencing was performed in 197 probands with HLHS, 43 family members, and 813 controls.

257 In 38 probands with HLHS, a 3-generation family history was obtained; using

258 In 141H, 2 fifth-degree relatives with HLHS shared a paternally-inherited MYO5A missense varian

259 We also identified one subject with HLHS with SAP130 and PCDHA13 mutations.

260 ons are that 70% of newborns born today with HLHS may reach adulthood.

261 rculation of the systemic ventricle in young HLHS patients shows significant differences compared wit