Cornelia de Lange syndrome: Congenital heart disease in 149 patients

Casas, A. Ayerza; Uriol, Beatriz Puisac; Rodrigo, M.E.; Marcos, María Hernández; Fuentes, Feliciano Jesús Ramos; Juste, Juan Pié

doi:10.1016/j.medcle.2017.03.024

Cited by 7 publications

(7 citation statements)

References 9 publications

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“…In addition, the reduction in FHF cell number could contribute to the presence of CHDs in Nipbl +/− mice and individuals with CdLS ( 24 , 125 ). In a prior study in Nipbl +/− mice, most CHDs observed were in heart regions (right ventricle and atrial/ventricular septa) considered to be derivatives of the SHF ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Gastrulation-stage gene expression in Nipbl ^+/− mouse embryos foreshadows the development of syndromic birth defects

Chea,

Kreger,

Lopez-Burks

et al. 2024

Sci. Adv.

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In animal models, Nipbl deficiency phenocopies gene expression changes and birth defects seen in Cornelia de Lange syndrome, the most common cause of which is Nipbl haploinsufficiency. Previous studies in Nipbl +/− mice suggested that heart development is abnormal as soon as cardiogenic tissue is formed. To investigate this, we performed single-cell RNA sequencing on wild-type and Nipbl +/− mouse embryos at gastrulation and early cardiac crescent stages. Nipbl +/− embryos had fewer mesoderm cells than wild-type and altered proportions of mesodermal cell subpopulations. These findings were associated with underexpression of genes implicated in driving specific mesodermal lineages. In addition, Nanog was found to be overexpressed in all germ layers, and many gene expression changes observed in Nipbl +/− embryos could be attributed to Nanog overexpression. These findings establish a link between Nipbl deficiency, Nanog overexpression, and gene expression dysregulation/lineage misallocation, which ultimately manifest as birth defects in Nipbl +/− animals and Cornelia de Lange syndrome.

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Section: Discussionmentioning

confidence: 99%

Gastrulation-stage gene expression in Nipbl ^+/− mouse embryos foreshadows the development of syndromic birth defects

Chea,

Kreger,

Lopez-Burks

et al. 2024

Sci. Adv.

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show abstract

“…In addition, the reduction in FHF cell number could contribute to the presence of CHDs in Nipbl +/- mice and individuals with CdLS ( 40, 99 ). In a prior study in Nipbl +/- mice, the majority of CHDs observed were in heart regions (right ventricle, atrial/ventricular septa) considered to be derivatives of the second heart field (SHF) ( 40, 100 ).…”

Section: Discussionmentioning

confidence: 99%

Gastrulation-stage gene expression inNipbl^+/-mouse embryos foreshadows the development of syndromic birth defects

Chea,

Kreger,

Lopez-Burks

et al. 2023

Preprint

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In animal models, Nipbl-deficiency phenocopies gene expression changes and birth defects seen in Cornelia de Lange Syndrome (CdLS), the most common cause of which is Nipbl-haploinsufficiency. Previous studies in Nipbl+/- mice identified aberrant gene expression and heart defects as early as cardiac crescent (CC) stage. Here, we performed single-cell RNA-sequencing on wildtype (WT) and Nipbl+/- mouse embryos at CC- and earlier (gastrulation) stages. Nipbl+/- embryos had fewer mesoderm cells than WT and altered proportions of mesodermal cell subpopulations. These findings were associated with an underexpression of genes implicated in driving specific mesodermal lineages. Nipbl+/- embryos also misexpressed developmentally-critical genes, including the transcription factor, Nanog, and genes governing left-right and anterior-posterior patterning. These events of cell misallocation and transcriptional dysregulation foreshadowed defects in tissue composition and patterning that arise later in Nipbl+/- mice, offering insights into early developmental contributions to birth defects in CdLS.

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“…These abnormalities have been described in syndromes caused both by chromosomal aneuploidies and CNVs [ 36 , 37 , 38 ], as well as by pathogenic variation of single genes [ 39 ]. In fact, in syndromic disorders that are clinically comparable to PACS1 -NDD, such as CdLS, Kabuki syndrome, and WDR37 syndrome, the prevalence of CHD has been estimated to be 33%, 50%, and 70%, respectively [ 40 , 41 , 42 ]. In our study, the prevalence of heart disease was high, and although several patients required intervention, they had good subsequent evolution without repercussions on cardiac function to date.…”

Section: Discussionmentioning

confidence: 99%

Heart Disease Characterization and Myocardial Strain Analysis in Patients with PACS1 Neurodevelopmental Disorder

Latorre-Pellicer,

Trujillano,

del Rincón

et al. 2023

JCM

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Background: PACS1 neurodevelopmental disorder (PACS1-NDD) (MIM# 615009) is a rare autosomal dominant disease characterized by neurodevelopmental delay, dysmorphic facial features, and congenital malformations. Heart disease (HD) is frequently present in individuals with PACS1-NDD, but a compressive review of these anomalies and an evaluation of cardiac function in a cohort of patients are lacking. Methods: (i) Cardiac evaluation in 11 PACS1-NDD patients was conducted using conventional echocardiography. (ii) Heart function was assessed by tissue Doppler imaging, and two-dimensional speckle tracking was performed in seven patients and matched controls. (iii) This systematic review focused on determining HD prevalence in individuals with PACS1-NDD. Results: In our cohort, 7 of 11 patients presented HD. (Among them, three cases of ascending aortic dilatation (AAD) were detected and one mitral valve prolapse (MVP).) None of the patients showed echocardiographic pathological values, and the left global longitudinal strain was not significantly different between patients and controls (patients −24.26 ± 5.89% vs. controls −20.19 ± 1.75%, p = 0.3176). In the literature review, almost 42% (42/100) of individuals with PACS1-NDD reportedly experienced HD. Septal defects were the most common malformation, followed by patent ductus arteriosus. Conclusions: Our results show a high prevalence of HD in PACS1-NDD patients; in this way, AAD and MVP are reported for the first time in this syndrome. Furthermore, a detailed cardiac function evaluation in our cohort did not reveal evidence of cardiac dysfunction in individuals with PACS1-NDD. Cardiology evaluation should be included for all individuals with Schuurs-Hoeijmakers syndrome.

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Cornelia de Lange syndrome: Congenital heart disease in 149 patients

Cited by 7 publications

References 9 publications

Gastrulation-stage gene expression in Nipbl ^+/− mouse embryos foreshadows the development of syndromic birth defects

Gastrulation-stage gene expression in Nipbl ^+/− mouse embryos foreshadows the development of syndromic birth defects

Gastrulation-stage gene expression inNipbl^+/-mouse embryos foreshadows the development of syndromic birth defects

Heart Disease Characterization and Myocardial Strain Analysis in Patients with PACS1 Neurodevelopmental Disorder

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Cornelia de Lange syndrome: Congenital heart disease in 149 patients

Cited by 7 publications

References 9 publications

Gastrulation-stage gene expression in Nipbl +/− mouse embryos foreshadows the development of syndromic birth defects

Gastrulation-stage gene expression in Nipbl +/− mouse embryos foreshadows the development of syndromic birth defects

Gastrulation-stage gene expression inNipbl+/-mouse embryos foreshadows the development of syndromic birth defects

Heart Disease Characterization and Myocardial Strain Analysis in Patients with PACS1 Neurodevelopmental Disorder

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Product

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Gastrulation-stage gene expression in Nipbl ^+/− mouse embryos foreshadows the development of syndromic birth defects

Gastrulation-stage gene expression in Nipbl ^+/− mouse embryos foreshadows the development of syndromic birth defects

Gastrulation-stage gene expression inNipbl^+/-mouse embryos foreshadows the development of syndromic birth defects