Congenital diaphragmatic hernia and a complex heart defect in association with Wolf–Hirschhorn syndrome

Tautz, Juliane; Veenma, Danielle; Eussen, Bert; Joosen, Linda; Poddighe, Pino J.; Tibboel, Dick; Klein, Annelies de; Schaible, Thomas

doi:10.1002/ajmg.a.33660

Cited by 15 publications

(9 citation statements)

References 20 publications

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“…Diaphragmatic hernias can develop in isolation or in association with other developmental abnormalities [1]. CDH that arises in association with other abnormalities is often associated with recognized syndromes, commonly including Fryns syndrome, Denys-Drash syndrome, Cornelia de Lange syndrome, Donnai-Barrow syndrome, Wolf-Hirschhorn syndrome, Ehlers-Danlos syndrome and focal dermal hypoplasia [50][51][52][53][54][55][56].…”

Section: Cdhmentioning

confidence: 99%

Development of the diaphragm – a skeletal muscle essential for mammalian respiration

2013

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The mammalian diaphragm muscle is essential for respiration, and thus it is among the most critical of the skeletal muscles in the human body. Defects in diaphragm development, leading to congenital diaphragmatic hernias (CDH), are common birth defects and result in severe morbidity or mortality. Given its functional importance and the frequency of congenital defects, an understanding of diaphragm development normally and during herniation is important. We review the current knowledge of the embryological origins of the diaphragm, diaphragm development and morphogenesis, and the genetic and developmental etiology of diaphragm birth defects.

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Section: Cdhmentioning

confidence: 99%

Development of the diaphragm – a skeletal muscle essential for mammalian respiration

2013

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“…The deletion identified in Subject 1 defines the CDH critical region on 4p16.3 that is associated with Wolf‐Hirschhorn syndrome. A schematic representation of molecularly defined, isolated 4p16 deletions associated with CDH (Callaway et al, 2018; Casaccia et al, 2006; Slavotinek et al, 2006; Tautz et al, 2010; Van Buggenhout et al, 2004). In all cases, the maximal deletion is depicted.…”

Section: Resultsmentioning

confidence: 99%

Evidence that FGFRL1 contributes to congenital diaphragmatic hernia development in humans

Gofin

Mackay

Machol

et al. 2021

American J of Med Genetics Pt A

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Fibroblast growth factor receptor‐like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf‐Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf‐Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left‐sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.

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“…In mouse embryos, Fgfrl1, Ctbp1, and Nsd2 transcripts have been detected in the pleuroperitoneal folds (PPF) at E11.5 and E12.5 as well as the developing diaphragm at E16.5. 16,[35][36][37][38] FGFRL1 is thought to act as a decoy receptor that can bind and sequester fibroblast growth factor ligands and may be involved in cell-cell adhesion. 39,40 Initial studies by Trueb and Taeschler showed that FGFRL1 expression increased during development, particularly within the diaphragm.…”

Section: Discussionmentioning

confidence: 99%

“…4 A small subset of individuals with WHS also have congenital diaphragmatic hernia (CDH). [5][6][7][8][9][10][11][12][13][14][15][16][17][18] The WHS critical region has been defined as a 1.5-to1.6-Mb region on chromosome 4p16.3 encompassing a region between $0.4 and 1.9 Mb from the 4p terminus that includes LETM1, SLBP, NSD2 (previously known as WHSC1), and NELFA (previously known as WHSC2). 17,[19][20][21] However, it remains unclear whether deletion of this region is sufficient to cause CDH and which genes on 4p16.3 potentially contribute to the development of the diaphragm.…”

Section: Introductionmentioning

confidence: 99%

Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm

et al. 2018

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Wolf–Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified FGFRL1, CTBP1, NSD2, FGFR3, CPLX1, MAEA, CTBP1-AS2, and ZNF141 as genes whose haploinsufficiency may contribute to the development of CDH.

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Congenital diaphragmatic hernia and a complex heart defect in association with Wolf–Hirschhorn syndrome

Cited by 15 publications

References 20 publications

Development of the diaphragm – a skeletal muscle essential for mammalian respiration

Development of the diaphragm – a skeletal muscle essential for mammalian respiration

Evidence that FGFRL1 contributes to congenital diaphragmatic hernia development in humans

Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm

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