Modern Ultrasonography of the Umbilical Cord: Prenatal Diagnosis of Umbilical Cord Abnormalities and Assessement of Fetal Wellbeing

Krzyżanowski, Arkadiusz; Kwiatek, Maciej; Gęca, Tomasz; Stupak, Aleksandra; Kwaśniewska, Anna

doi:10.12659/msm.913762

Cited by 19 publications

(29 citation statements)

References 62 publications

(77 reference statements)

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“…Mutations with a depth ≥ of 100x, Minor Allele Frequency (MAF) in the control population < 1%, and p -value of ≤ 5 × 10 –5 were included for further analysis. We designated umbilical cord tissue as a control for defining somatic mutations, as it is one of the earliest developed fetal tissues during embryonic development ( Krzyzanowski et al, 2019 ). A mutation at lesion site tissue but not in the same individual’s umbilical cord tissue was defined as a somatic mutation ( Knudson, 1971 ).…”

Section: Methodsmentioning

confidence: 99%

Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects

Tian

Cao

Chen

et al. 2021

Front. Cell Dev. Biol.

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BackgroundNeural tube defects (NTDs) are among the most common and severe congenital defects in humans. Their genetic etiology is complex and remains poorly understood. The Mediator complex (MED) plays a vital role in neural tube development in animal models. However, no studies have yet examined the role of its human homolog in the etiology of NTDs.MethodsIn this study, 48 pairs of neural lesion site and umbilical cord tissues from NTD and 21 case-parent trios were involved in screening for NTD-related somatic and germline de novo variants. A series of functional cell assays were performed. We generated a Med12 p.Arg1784Cys knock-in mouse using CRISPR/Cas9 technology to validate the human findings.ResultsOne somatic variant, MED12 p.Arg1782Cys, was identified in the lesion site tissue from an NTD fetus. This variant was absent in any other normal tissue from different germ layers of the same case. In 21 case-parent trios, one de novo stop-gain variant, MED13L p.Arg1760∗, was identified. Cellular functional studies showed that MED12 p.Arg1782Cys decreased MED12 protein level and affected the regulation of MED12 on the canonical-WNT signaling pathway. The Med12 p.Arg1784Cys knock-in mouse exhibited exencephaly and spina bifida.ConclusionThese findings provide strong evidence that functional variants of MED genes are associated with the etiology of some NTDs. We demonstrated a potentially important role for somatic variants in the occurrence of NTDs. Our study is the first study in which an NTD-related variant identified in humans was validated in mice using CRISPR/Cas9 technology.

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Section: Methodsmentioning

confidence: 99%

Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects

Tian

Cao

Chen

et al. 2021

Front. Cell Dev. Biol.

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“…Umbilical cord tissue was designated as control tissue, as it is one of the earliest embryonic tissues to develop post-conception (Krzyzanowski et al 2019). The mutation that occurred in the tissue at the site of the neural tube lesion but did not occur in the umbilical cord tissue of the same NTD case was defined as a somatic mutation (Knudson 1971).…”

Section: Definition Of Somatic Mutationmentioning

confidence: 99%

Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects

et al. 2020

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Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in the development of NTDs. Torrent™ Personal Genome Machine™ (PGM) sequencing was designed for selected PCP genes in paired DNA samples extracted from the tissues of lesion sites and umbilical cord from 48 cases. Sanger sequencing was used to validate the detected mutations. The source and distribution of the validated mutations in tissues from different germ layers were investigated. Subcellular location, western blotting, and luciferase assays were performed to better understand the effects of the mutations on protein localization, protein level, and pathway signaling. ix somatic mutations were identified and validated, which showed diverse distributions in different tissues. Three somatic mutations were novel/rare: CELSR1 p.Gln2125His, FZD6 p.Gln88Glu, and VANGL1 p.Arg374His. FZD6 p.Gln88Glu caused mislocalization of its protein from the cytoplasm to the nucleus, and disrupted the colocalization of CELSR1 and FZD6. This mutation affected non-canonical WNT signaling in luciferase assays. VANGL1 p.Arg374His impaired the co-localization of CELSR1 and VANGL1, increased the protein levels of VANGL1, and influenced cell migration. In all, 7/48 (14.5%) of the studied NTD cases contained somatic PCP mutations. Somatic mutations in PCP genes (e.g., FZD6 and VANGL1) are associated with human NTDs, and they may occur in different stages and regions during embryonic development, resulting in a varied distribution in fetal tissues/organs.

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“…8 To ensure normal intrauterine growth, there are some conditions that must be met: normal umbilical cord architecture and function; adequate placental perfusion; a healthy fetus and a favorable maternal condition; availability of nutrients and absence of pregnancy-related or non-related diseases. 1,8,9 Any abnormality in any of these prerequisites can potentially lead to intrauterine growth restriction (IUGR), with its inherent increased risk of perinatal mortality and morbidity in the short and long term. 1,[9][10][11][12][13][14] The main cause of IUGR is placental insufficiency, 9 which is associated with an increased resistance to blood flow in the placental vasculature, restricting the blood supply to the fetus and inducing compensatory responses with hemodynamic changes.…”

Section: Introductionmentioning

confidence: 99%

Doppler Ultrasound of the Umbilical Artery: Clinical Application

Rocha

Andrade

Moleiro

et al. 2022

Rev Bras Ginecol Obstet

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Objective To provide a survey of relevant literature on umbilical artery Doppler ultrasound use in clinical practice, technical considerations and limitations, and future perspectives. Methods Literature searches were conducted in PubMed and Medline, restricted to articles written in English. Additionally, the references of all analyzed studies were searched to obtain necessary information. Results The use of this technique as a routine surveillance method is only recommended for high-risk pregnancies with impaired placentation. Meta-analyses of randomized trials have established that obstetric management guided by umbilical artery Doppler findings can improve perinatal mortality and morbidity. The values of the indices of Umbilical artery Doppler decrease with advancing gestational age; however, a lack of consensus on reference ranges prevails. Conclusion Important clinical decisions are based on the information obtained with umbilical artery Doppler ultrasound. Future efforts in research are imperative to overcome the current limitations of the technique.

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Modern Ultrasonography of the Umbilical Cord: Prenatal Diagnosis of Umbilical Cord Abnormalities and Assessement of Fetal Wellbeing

Cited by 19 publications

References 62 publications

Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects

Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects

Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects

Doppler Ultrasound of the Umbilical Artery: Clinical Application

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