Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Lecoquierre, François; Bréhin, Anne-Claire; Coutant, Sophie; Coursimault, Juliette; Bazin, Anne; Finck, Wilfrid; Benoist, G.; Begorre, Marianne; Bénéteau, Claire; Cailliez, Daniel; Chenal, Pierre; Jong, Mirjam de; Degré, Sophie; Devisme, Louise; Francannet, Christine; Gerard, Bénédicte; Jeanne, Corinne; Joubert, Madeleine; Journel, Hubert; Delmas, Hélène Laurichesse; Layet, Valérie; Liquier, Alain; Mangione, R.; Patrier, Sophie; Pelluard, Fanny; Petit, Florence; Tillouche, N.; Ravenswaaij-Arts, Conny M. A. van; Frébourg, Thierry; Saugier-Veber, Pascale; Gruchy, Nicolas; Nicolas, Gaël; Gérard, Marion

doi:10.1002/humu.23998

Cited by 9 publications

(19 citation statements)

References 37 publications

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“…The reasoning is that vasculature develops only as there is a need for nutrition by tissues. Evidence, genetic or otherwise, that there is a deficiency of caudal mesoderm or early damage to the allantois necessary to support this concept is currently limited to the CDX2 variants found in two cases of sirenomelia from the literature and the intragenic deletion of CDX2 in case 1 of the present report (Lecoquierre et al, 2020). The possibility that different pathogenic mechanisms operating in early embryogenesis could lead to the same anatomical consequences cannot as yet be dismissed.…”

Section: Discussionmentioning

confidence: 71%

“…Fewer genetic/genomic alterations have been noted in sirenomelia, OEIS complex, and LBWD. In sirenomelia, sequence variants in CDX2 and cytogenetic aberrations (mosaic 1qdup, mosaic 69,XXX/46,XX, and Xp:16p translocation) have been reported (Kurosawa et al, 2012; Lecoquierre et al, 2020; Stevenson et al, 1986; Tonni & Grisolia, 2013). Deletions at 1p36 and 9q34 have been reported in OEIS complex and a missense variant in IQCK has been noted in LBWD (El‐Hattab et al, 2010; Kruszka et al, 2015; Thauvin‐Robinet et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Deletions at 1p36 and 9q34 have been reported in OEIS complex and a missense variant in IQCK has been noted in LBWD (El‐Hattab et al, 2010; Kruszka et al, 2015; Thauvin‐Robinet et al, 2004). Although most of these genetic and genomic changes have been noted in single case, CDX2 alterations have been found in two cases of sirenomelia and three biallelic TRAP1 variants, two biallelic HAAO variants, two biallelic KYNU variants, and multiple ZIC3 variants have been reported in cases with VACTERL anomalies (Chung et al, 2011; Dworschak et al, 2013; Hilger et al, 2015; Lecoquierre et al, 2020; Saisawat et al, 2014; Shi et al, 2017; Wessels et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The fetal karyotype was 46,XX and whole exome sequencing identified no variants of significance. Genomic microarray identified a 3.4 Mb deletion of 13q12.2q12.3 which included exon 3 of CDX2 , a gene that is critical for development of the caudal somites and allantois and which has been implicated as a cause of sirenomelia (Lecoquierre et al, 2020).…”

Section: Case Reportsmentioning

confidence: 99%

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Common pathogenesis for sirenomelia, OEIS complex, limb‐body wall defect, and other malformations of caudal structures

Stevenson

2021

American J of Med Genetics Pt A

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Decades of clinical, pathological, and epidemiological study and the recent application of advanced microarray and gene sequencing technologies have led to an understanding of the causes and pathogenesis of most recognized patterns of malformation. Still, there remain a number of patterns of malformation whose pathogenesis has not been established. Six such patterns of malformation are sirenomelia, VACTERL association, OEIS complex, limb‐body wall defect (LBWD), urorectal septum malformation (URSM) sequence, and MURCS association, all of which predominantly affect caudal structures. On the basis of the overlap of the component malformations, the co‐occurrence in individual fetuses, and the findings on fetal examination, a common pathogenesis is proposed for these patterns of malformation. The presence of a single artery in the umbilical cord provides a visible clue to the pathogenesis of all cases of sirenomelia and 30%–50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWD. The single artery is formed by a coalescence of arteries that supply the yolk sac, arises from the descending aorta high in the abdominal cavity, and redirects blood flow from the developing caudal structures of the embryo to the placenta. This phenomenon during embryogenesis is termed vitelline vascular steal.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Case Reportsmentioning

confidence: 99%

See 2 more Smart Citations

Common pathogenesis for sirenomelia, OEIS complex, limb‐body wall defect, and other malformations of caudal structures

Stevenson

2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

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“…The combinatorial analyses of data from mouse embryonic developmental have identi ed cores of common differentially-expressed genes and chromatin regions responsive to the Cdx2 homeoprotein at three steps where this transcription factor plays pivotal roles: trophectoderm differentiation, posterior growth of the embryonic body and intestinal determination. Similar functions are anticipated for the CDX2 gene in human embryonic development, because of its speci c expression in the trophectoderm lineage at the blastula stage [35], the association of gene mutations with sirenomelia [33], and its abnormal expression linked to gut-type differentiation in congenital endoderm-derived lesions [34].…”

Section: Resultsmentioning

confidence: 66%

BioData Mining | Short Report (Biomedcentral.Com) Combinatorial Analyses Identify A Core Response to the CDX2 Homeoprotein During Development and In Pathologies

Gourain

Duluc

Domon‐Dell

et al. 2021

Preprint

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Whether a gene involved in distinct tissue or cell functions exerts a core of common molecular activities is a relevant topic in the evolutionary, developmental and therapeutic perspective. Here, we addressed this question by focusing on the CDX2 homeobox gene that encodes a transcription factor with important functions during embryonic development and in adult pathologies. By analysing RNAseq data and ChIPseq data, we unveiled the existence of a core of genes whose expression is responsive to the Cdx2 homeoprotein and also a core of chromosomal regions targeted by Cdx2 at three important steps of mouse development: trophectoderm formation, posterior body elongation and intestinal specification. In addition, based on human cancer data, we highlighted the relevance of the core of responsive genes by displaying a significant number of human orthologues exhibiting an altered expression along with CDX2 in human malignancies.

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Clinically diverse and perinatally lethal syndromes with urorectal septum malformation sequence

Nayak

Harkness

Shukla

et al. 2022

American J of Med Genetics Pt A

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Urorectal septum malformation sequence (URSMS) is characterized by a spectrum of anomalies of the urogenital system, hindgut and perineum. It is presumed to be a constellation of an embryonic defect. Herein, we analyzed the clinically diverse syndromes associated with URSMS in our perinatal evaluation unit. We reviewed fetuses with URSMS in referrals for perinatal autopsy over a period of 3 years. Chromosomal microarray and genome sequencing were performed whenever feasible. Literature was reviewed for syndromes or malformations with URSMS. We ascertained URSMS in 12 of the 215 (5%) fetuses. Nine fetuses (75%) had complete URSMS and remainder had partial/intermediate URSMS. Eleven fetuses had malformations of other systems that included: cerebral ventriculomegaly; right aortic arch with double outlet right ventricle; microcephaly with fetal akinesia deformation sequence; ventricular septal defect and radial ray anomaly; thoraco-abdominoschisis and limb defects; myelomeningocele; spina bifida and fused iliac bones; omphalocele; occipital encephalocele; lower limb amelia and cleft foot. We report on six fetuses with recurrent and five fetuses with unique malformations/patterns where URSMS is a component.Exome sequencing (one family) and genome sequencing (eight families) were performed and were nondiagnostic. Additionally, we review the literature for genetic basis of this condition. URMS is a clinically heterogeneous condition and is a component of several multiple malformation syndromes. We describe several unique and recurrent malformations associated with URSMS.

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Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Cited by 9 publications

References 37 publications

Common pathogenesis for sirenomelia, OEIS complex, limb‐body wall defect, and other malformations of caudal structures

Common pathogenesis for sirenomelia, OEIS complex, limb‐body wall defect, and other malformations of caudal structures

BioData Mining | Short Report (Biomedcentral.Com) Combinatorial Analyses Identify A Core Response to the CDX2 Homeoprotein During Development and In Pathologies

Clinically diverse and perinatally lethal syndromes with urorectal septum malformation sequence

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