Genetic, Environmental and Synergistic Gene-Environment Contributions to Craniofacial Defects

Editorial

24 March 2022

Editorial: Genetic, Environmental and Synergistic Gene-Environment Contributions to Craniofacial Defects

Peter J. Anderson

Karen J. Liu

Mary L. Marazita

and

Sebastian Dworkin

1,638 views

0 citations

Editors

Sebastian Dworkin

La Trobe University

Peter John ANDERSON

University of South Australia

Karen Liu

King's College London

Mary L Marazita

University of Pittsburgh

Impact

Review

12 August 2021

Depression and Antidepressants During Pregnancy: Craniofacial Defects Due to Stem/Progenitor Cell Deregulation Mediated by Serotonin

Natalia Sánchez

, 7 more and

Marcia Gaete

Depression is a common and debilitating mood disorder that increases in prevalence during pregnancy. Worldwide, 7 to 12% of pregnant women experience depression, in which the associated risk factors include socio-demographic, psychological, and socioeconomic variables. Maternal depression could have psychological, anatomical, and physiological consequences in the newborn. Depression has been related to a downregulation in serotonin levels in the brain. Accordingly, the most commonly prescribed pharmacotherapy is based on selective serotonin reuptake inhibitors (SSRIs), which increase local serotonin concentration. Even though the use of SSRIs has few adverse effects compared with other antidepressants, altering serotonin levels has been associated with the advent of anatomical and physiological changes in utero, leading to defects in craniofacial development, including craniosynostosis, cleft palate, and dental defects. Migration and proliferation of neural crest cells, which contribute to the formation of bone, cartilage, palate, teeth, and salivary glands in the craniofacial region, are regulated by serotonin. Specifically, craniofacial progenitor cells are affected by serotonin levels, producing a misbalance between their proliferation and differentiation. Thus, it is possible to hypothesize that craniofacial development will be affected by the changes in serotonin levels, happening during maternal depression or after the use of SSRIs, which cross the placental barrier, increasing the risk of craniofacial defects. In this review, we provide a synthesis of the current research on depression and the use of SSRI during pregnancy, and how this could be related to craniofacial defects using an interdisciplinary perspective integrating psychological, clinical, and developmental biology perspectives. We discuss the mechanisms by which serotonin could influence craniofacial development and stem/progenitor cells, proposing some transcription factors as mediators of serotonin signaling, and craniofacial stem/progenitor cell biology. We finally highlight the importance of non-pharmacological therapies for depression on fertile and pregnant women, and provide an individual analysis of the risk–benefit balance for the use of antidepressants during pregnancy

7,214 views

10 citations

Regional association plots of the GE test with interaction plots (A) 6q22 (rs706954) interaction with alcohol use. (B) 6p22.3 (rs35097027) interaction with smoking. (C) 3q27.3 (rs61069053) with vitamin use. Note, only one individual is homozygous for the G allele in the no vitamin use stratum.

Original Research

10 February 2022

Genome-wide Interaction Study Implicates VGLL2 and Alcohol Exposure and PRL and Smoking in Orofacial Cleft Risk

Jenna C. Carlson

, 8 more and

Elizabeth J. Leslie

2,304 views

4 citations

Original Research

08 July 2021

Identification of Novel Variants in Cleft Palate-Associated Genes in Brazilian Patients With Non-syndromic Cleft Palate Only

Renato Assis Machado

, 5 more and

Ricardo D. Coletta

4,354 views

6 citations

Cleft palate-associated genes suppressed by overexpression of miR-27a-3p, miR-27b-3p, or miR-124-3p in MEPM cells. (A–C) Quantitative RT-PCR for the indicated genes after treatment with control or miR-27a-3p mimic (A), control or miR-27b-3p mimic (B), and control or miR-124a-3p mimic (C). Multiple t-tests adjusted by Bonferroni (n = 3). *Adjusted p < 0.00132 in A (38 genes), adjusted p < 0.00135 in B (37 genes), adjusted p < 0.000909 in C (55 genes), **adjusted p < 0.000263 in A (38 genes), adjusted p < 0.000270 in B (37 genes), adjusted p < 0.000182 in C (55 genes), ***adjusted p < 0.0000182 in C (55 genes).

Original Research

09 June 2021

MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

Hiroki Yoshioka

, 3 more and

Junichi Iwata

3,640 views

19 citations

Bone formation rate sensitivity at various stages, sagittal and dorsal views.

Original Research

26 May 2021

Using Sensitivity Analysis to Develop a Validated Computational Model of Post-operative Calvarial Growth in Sagittal Craniosynostosis

Connor Cross

, 5 more and

Mehran Moazen

2,650 views

9 citations

Review

20 May 2021

Diabetes, Oxidative Stress, and DNA Damage Modulate Cranial Neural Crest Cell Development and the Phenotype Variability of Craniofacial Disorders

Sharien Fitriasari

and

Paul A. Trainor

Craniofacial malformations are among the most common birth defects in humans and they often have significant detrimental functional, aesthetic, and social consequences. To date, more than 700 distinct craniofacial disorders have been described. However, the genetic, environmental, and developmental origins of most of these conditions remain to be determined. This gap in our knowledge is hampered in part by the tremendous phenotypic diversity evident in craniofacial syndromes but is also due to our limited understanding of the signals and mechanisms governing normal craniofacial development and variation. The principles of Mendelian inheritance have uncovered the etiology of relatively few complex craniofacial traits and consequently, the variability of craniofacial syndromes and phenotypes both within families and between families is often attributed to variable gene expression and incomplete penetrance. However, it is becoming increasingly apparent that phenotypic variation is often the result of combinatorial genetic and non-genetic factors. Major non-genetic factors include environmental effectors such as pregestational maternal diabetes, which is well-known to increase the risk of craniofacial birth defects. The hyperglycemia characteristic of diabetes causes oxidative stress which in turn can result in genotoxic stress, DNA damage, metabolic alterations, and subsequently perturbed embryogenesis. In this review we explore the importance of gene-environment associations involving diabetes, oxidative stress, and DNA damage during cranial neural crest cell development, which may underpin the phenotypic variability observed in specific craniofacial syndromes.

7,845 views

25 citations

Meta-analysis of the 2 df joint test for G and G × E interaction on all OFC case–parent trios across both the GENEVA and POFC studies. Numerous genes/regions show strong evidence of influencing risk to OFC largely through the main gene effect (βG) with very subtle differences that could be attributed to G × E interaction effect (βGE). Most of these strong signals represent recognized risk genes for CL/P. (A) Meta-analysis of 2 df test for G and G × Smoking interaction. (B) Meta-analysis of the 2 df test for G and G × Alcohol interaction. (C) Meta-analysis of the 2 df test for G and G × Vitamin interaction. The red dashed line represents the conventional threshold for genome-wide significance (5 × 10–8).

Original Research

16 April 2021

Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft

Wanying Zhang

, 10 more and

Terri H. Beaty

3,543 views

7 citations

Original Research

09 April 2021

Genome-Wide Association Study of Non-syndromic Orofacial Clefts in a Multiethnic Sample of Families and Controls Identifies Novel Regions

Nandita Mukhopadhyay

, 19 more and

Mary L. Marazita

Association peak in 1q32.2 (IRF6) consistent with category 2. SNPs are ordered by base-pair position; Q-statistic p-value noted under each SNP in forest plot; lead variant and sample with highest p-value shown in red in heatmap and FST values noted under each SNP. The top 10 associated variants fall below our MAF filter in the EUR and ASIA groups.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (~ 1/2,500), Asians have the highest prevalence (~1/500), Europeans and Latin Americans lie somewhere in the middle (~1/800 and 1/900, respectively). Thus, ethnicity appears to be a major determinant of the risk of developing OFC. The Pittsburgh Orofacial Clefts Multiethnic study was designed to explore this ethnic variance, comprising a large number of families and individuals (~12,000 individuals) from multiple populations worldwide: US and Europe, Asians, mixed Native American/Caucasians, and Africans. In this current study, we analyzed 2,915 OFC cases, 6,044 unaffected individuals related to the OFC cases, and 2,685 controls with no personal or family history of OFC. Participants were grouped by their ancestry into African, Asian, European, and Central and South American subsets, and genome-wide association run on the combined sample as well as the four ancestry-based groups. We observed 22 associations to cleft lip with or without cleft palate at 18 distinct loci with p-values < 1e-06, including 10 with genome-wide significance (<5e-08), in the combined sample and within ancestry groups. Three loci - 2p12 (rs62164740, p = 6.27e-07), 10q22.2 (rs150952246, p = 3.14e-07), and 10q24.32 (rs118107597, p = 8.21e-07) are novel. Nine were in or near known OFC loci - PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, NTN1, WNT3-WNT9B, TANC2, and RHPN2. The majority of the associations were observed only in the combined sample, European, and Central and South American groups. We investigated whether the observed differences in association strength were (a) purely due to sample sizes, (b) due to systematic allele frequency difference at the population level, or (c) due to the fact certain OFC-causing variants confer different amounts of risk depending on ancestral origin, by comparing effect sizes to observed allele frequencies of the effect allele in our ancestry-based groups. While some of the associations differ due to systematic differences in allele frequencies between groups, others show variation in effect size despite similar frequencies across ancestry groups.

4,238 views

26 citations

Apoptosis level was restored by combinatorial treatment with teratogen and Wnt agonists. (A) Immunofluorescence images of apoptotic cells in the palate at 96 hpf. Experimental time course is the same as in Figure 4A. WAF (30 μM) exposure induced cleft palate and increased the number of active Cas3-positive cells in the palate. The number of active Cas3-positive cells was restored to normal by combinatorial treatment with BIO (100 nM), CHIR99021 (300 nM) or WAY-262611 (250 nM). White indicates cartilage cells double stained with anti-coll2 antibody and lectin PNA. Green dotted lines trace the shape of the palate. Yellow indicates apoptotic cells stained with anti-caspase3 antibody. (B) Quantification of the number of active Cas3-positive cells in the palate. Numerical value is normalized to 104 μm2. (C) VPA (20 μM) exposure induced cleft palate and increased the number of active Cas3-positive cells. The number of active Cas3-positive cells was restored to normal by combinatorial treatment with BIO (100 nM), CHIR99021 (300 nM) or WAY-262611 (250 nM). (D) Quantification of the number of active Cas3-positive cells in the palate. Numerical value is normalized to 104 μm2. n = 15 (Control), 15 (WAF), 14 (WAF + BIO), 14 (WAF + CHIR), 14 (WAF + WAY) in (B), n = 15 (Control), 15 (VPA), 14 (VPA + BIO), 13 (VPA + CHIR), 11 (VPA + WAY) in (D), *P < 0.05, **P < 0.01, ***P < 0.001 (one-way ANOVA followed by Dunnett’s multiple comparison test). Scale bar, 50 μm.

Original Research

14 December 2020

Chemical-Induced Cleft Palate Is Caused and Rescued by Pharmacological Modulation of the Canonical Wnt Signaling Pathway in a Zebrafish Model

Rika Narumi

, 3 more and

Junichi Tasaki

Cleft palate is one of the most frequent birth defects worldwide. It causes severe problems regarding eating and speaking and requires long-term treatment. Effective prenatal treatment would contribute to reducing the risk of cleft palate. The canonical Wnt signaling pathway is critically involved in palatogenesis, and genetic or chemical disturbance of this signaling pathway leads to cleft palate. Presently, preventative treatment for cleft palate during prenatal development has limited efficacy, but we expect that zebrafish will provide a useful high-throughput chemical screening model for effective prevention. To achieve this, the zebrafish model should recapitulate cleft palate development and its rescue by chemical modulation of the Wnt pathway. Here, we provide proof of concept for a zebrafish chemical screening model. Zebrafish embryos were treated with 12 chemical reagents known to induce cleft palate in mammals, and all 12 chemicals induced cleft palate characterized by decreased proliferation and increased apoptosis of palatal cells. The cleft phenotype was enhanced by combinatorial treatment with Wnt inhibitor and teratogens. Furthermore, the expression of tcf7 and lef1 as a readout of the pathway was decreased. Conversely, cleft palate was prevented by Wnt agonist and the cellular defects were also prevented. In conclusion, we provide evidence that chemical-induced cleft palate is caused by inhibition of the canonical Wnt pathway. Our results indicate that this zebrafish model is promising for chemical screening for prevention of cleft palate as well as modulation of the Wnt pathway as a therapeutic target.

5,747 views

10 citations