Cleft Palate in Apert Syndrome

Willie, Delayna; Holmes, Greg; Jabs, Ethylin Wang; Wu, Meng

doi:10.3390/jdb10030033

Cited by 7 publications

(8 citation statements)

References 111 publications

(152 reference statements)

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“…This is likely due to the significant change that takes place when mutating serine, which is a small polar residue, to tryptophan, a bulky aromatic hydrophobic residue. The S252 residue promotes ligand affinity and specificity [ 74 ]. The two most frequent mutations identified in endometrial cancers are FGFR2 S252W and N550K, which are both activating mutations [ 75 , 76 ].…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the multiple mutations that were deemed significant in PIK3CA and TP53 were located at the same place in the primary sequence in each respective gene. The FGFR2 S252W mutation has been previously studied biochemically and shown to impact ligand binding and specificity [ 74 ]. The R130 residue in PTEN is located within the active site pocket and mutation of this residue has been implicated in various diseases and cancers [ 63 , 79 , 80 ].…”

Section: Discussionmentioning

confidence: 99%

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Detection of driver mutations and genomic signatures in endometrial cancers using artificial intelligence algorithms

Stan,

Bosart,

Kaur

et al. 2024

PLoS ONE

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Analyzed endometrial cancer (EC) genomes have allowed for the identification of molecular signatures, which enable the classification, and sometimes prognostication, of these cancers. Artificial intelligence algorithms have facilitated the partitioning of mutations into driver and passenger based on a variety of parameters, including gene function and frequency of mutation. Here, we undertook an evaluation of EC cancer genomes deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC), with the goal to classify all mutations as either driver or passenger. Our analysis showed that approximately 2.5% of all mutations are driver and cause cellular transformation and immortalization. We also characterized nucleotide level mutation signatures, gross chromosomal re-arrangements, and gene expression profiles. We observed that endometrial cancers show distinct nucleotide substitution and chromosomal re-arrangement signatures compared to other cancers. We also identified high expression levels of the CLDN18 claudin gene, which is involved in growth, survival, metastasis and proliferation. We then used in silico protein structure analysis to examine the effect of certain previously uncharacterized driver mutations on protein structure. We found that certain mutations in CTNNB1 and TP53 increase protein stability, which may contribute to cellular transformation. While our analysis retrieved previously classified mutations and genomic alterations, which is to be expected, this study also identified new signatures. Additionally, we show that artificial intelligence algorithms can be effectively leveraged to accurately predict key drivers of cancer. This analysis will expand our understanding of ECs and improve the molecular toolbox for classification, diagnosis, or potential treatment of these cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Detection of driver mutations and genomic signatures in endometrial cancers using artificial intelligence algorithms

Stan,

Bosart,

Kaur

et al. 2024

PLoS ONE

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“…In our study, we identified a variant in FGFR2 , c.755C>G (p.(Ser252Trp)), in case 11, which is associated with the development of Apert syndrome (OMIM #101200). Apert syndrome is a rare genetic disorder characterized by an array of clinical features, including craniosynostosis, midface retrusion, and limb anomalies ( Willie et al, 2022 ). A cleft palate is present in a subset of Apert syndrome patients.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing improves genetic diagnosis of congenital orofacial clefts

Yan,

Fu,

et al. 2023

Front. Genet.

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Objective: This retrospective study aims to evaluate the utility of exome sequencing (ES) in identifying genetic causes of congenital orofacial clefts (OFCs) in fetuses with or without other structural abnormalities, and to further explore congenital OFCs genetic causes.Methods: The study enrolled 107 singleton pregnancies diagnosed with fetal OFCs between January 2016 and May 2022, and categorized them into two groups: isolated cleft lip and/or palate (CL/CP) and syndromic CL/CP. Cases with positive karyotyping and chromosomal microarray analysis results were excluded. Whole-exome sequencing was performed on eligible fetuses and their parents. Monogenic variants identified by ES and perinatal outcomes were recorded and evaluated during postnatal follow-up.Results: Clinically significant variants were identified in 11.2% (12/107) of fetuses, with no significant difference in detection rate between the isolated CL/CP group and the syndromic CL/CP group (8/83, 9.6% vs. 4/24, 16.7%, p = 0.553). Additionally, sixteen (16/107, 15.0%) fetuses had variants of uncertain significance. We identified 12 clinically significant variations that correlated with clinical phenotypes in 11 genes from 12 fetuses, with CHD7 being the most frequently implicated gene (n = 2). Furthermore, we observed a significant difference in termination rates and survival rates between the isolated CL/CP and syndromic CL/CP groups (41.0% vs. 70.8% and 56.6% vs. 20.8%, p < 0.05 for both).Conclusion: Based on our findings, it is clear that ES provides a significant increase in diagnostic yield for the molecular diagnosis of congenital OFCs, thereby substantially improving the existing prenatal diagnostic capabilities. This study also sheds light on seven novel pathogenic variants, broadening our understanding of the genetic underpinnings of OFCs and expanding the disease spectrums of relevant genes.

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“…Wnt1-Cre;pMes-caBmpr1a mice showed reduced proliferation and ectopic cartilage formation at the palatal mesenchyme ( Li et al, 2013 ). NC-specific deletion of Tak1 in mice ( Wnt1-Cre;Tak1 fl/fl mice) develops cleft palate association with a higher level of fibroblast growth factor (FGF) signaling that is a known causative reason for Apert syndrome, a subset of patients with the syndrome develops cleft palate ( Song et al, 2013 ; Willie et al, 2022 ). We found that NC-specific expression of caBmpr1a with deletion of Tak1 in mice ( P0-Cre;caBmpr1a fl/+ ;Tak1 fl/fl mice) develops cleft palate while P0-Cre;caBmpr1a fl/+ mice and P0-Cre;Tak1 fl/fl mice did not develop a cleft palate.…”

Section: Orofacial Cleftmentioning

confidence: 99%

BMP signaling during craniofacial development: new insights into pathological mechanisms leading to craniofacial anomalies

Ueharu

Mishina

2023

Front. Physiol.

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Cranial neural crest cells (NCCs) are the origin of the anterior part of the face and the head. Cranial NCCs are multipotent cells giving rise to bones, cartilage, adipose-tissues in the face, and neural cells, melanocytes, and others. The behavior of cranial NCCs (proliferation, cell death, migration, differentiation, and cell fate specification) are well regulated by several signaling pathways; abnormalities in their behavior are often reported as causative reasons for craniofacial anomalies (CFAs), which occur in 1 in 100 newborns in the United States. Understanding the pathological mechanisms of CFAs would facilitate strategies for identifying, preventing, and treating CFAs. Bone morphogenetic protein (BMP) signaling plays a pleiotropic role in many cellular processes during embryonic development. We and others have reported that abnormalities in BMP signaling in cranial NCCs develop CFAs in mice. Abnormal levels of BMP signaling cause miscorrelation with other signaling pathways such as Wnt signaling and FGF signaling, which mutations in the signaling pathways are known to develop CFAs in mice and humans. Recent Genome-Wide Association Studies and exome sequencing demonstrated that some patients with CFAs presented single nucleotide polymorphisms (SNPs), missense mutations, and duplication of genes related to BMP signaling activities, suggesting that defects in abnormal BMP signaling in human embryos develop CFAs. There are still a few cases of BMP-related patients with CFAs. One speculation is that human embryos with mutations in coding regions of BMP-related genes undergo embryonic lethality before developing the craniofacial region as well as mice development; however, no reports are available that show embryonic lethality caused by BMP mutations in humans. In this review, we will summarize the recent advances in the understanding of BMP signaling during craniofacial development in mice and describe how we can translate the knowledge from the transgenic mice to CFAs in humans.

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Cleft Palate in Apert Syndrome

Cited by 7 publications

References 111 publications

Detection of driver mutations and genomic signatures in endometrial cancers using artificial intelligence algorithms

Detection of driver mutations and genomic signatures in endometrial cancers using artificial intelligence algorithms

Exome sequencing improves genetic diagnosis of congenital orofacial clefts

BMP signaling during craniofacial development: new insights into pathological mechanisms leading to craniofacial anomalies

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