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Molecular Genetics of Facial Traits and Malformations

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 43393

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Special Issue Editors

Dr. Kerstin Ludwig

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Guest Editor

Institute of Human Genetics, University Hospital Bonn, 53127 Bonn, Germany
Interests: human genetics; craniofacial genomics

Prof. Dr. Timothy C. Cox

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Guest Editor

Department of Oral & Craniofacial Sciences, University of Missouri-Kansas City School of Dentistry, Kansas City, MO 64108, USA
Interests: craniofacial development; epithelial cell adhesion; tissue fusions; craniofacial birth defects; cleft lip/palate; disease mechanisms; embryology; tomographic imaging

Special Issue Information

Dear colleagues,

The human face is arguably our most individual characteristic. Its morphogenesis is largely completed in the first trimester and occurs in a highly stereotypical fashion through the precise orchestration of cellular behaviors by conserved genetic programs. In the last few years, many new advances have been made in understanding the genetic contributions to population-level variation in facial form, as well as in determining the genetic basis of both rare and common malformations of the facial complex.

Furthermore, studies on the function of these genes have highlighted core biological pathways and developmental mechanisms that typically coordinate normal facial development.

Topics might include but are not necessarily limited to studies on rare (syndromic) conditions, common or isolated facial traits and anomalies, epigenetic and functional approaches in relevant tissues or cell types, and investigation or description of new animal models.

We invite submissions of original research articles that include either functional and/or genetic studies related to facial traits. A limited number of review articles will also be considered. However, authors considering a review contribution should contact the guest editors for approval before proceeding.

Dr. Kerstin Ludwig
Prof. Timothy Cox
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

face
animal models
genetic studies
embryonic development
(non-)syndromic
isolated
genetic variability
birth defect

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Published Papers (9 papers)

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15 pages, 957 KiB

Open AccessArticle

A Synonymous Exonic Splice Silencer Variant in IRF6 as a Novel and Cryptic Cause of Non-Syndromic Cleft Lip and Palate

by Beau Sylvester, Frederick Brindopke, Akiko Suzuki, Melissa Giron, Allyn Auslander, Richard L. Maas, Becky Tsai, Hanlin Gao, William Magee III, Timothy C. Cox and Pedro A. Sanchez-Lara

Genes 2020, 11(8), 903; https://doi.org/10.3390/genes11080903 - 7 Aug 2020

Cited by 6 | Viewed by 3522

Abstract

Missense, nonsense, splice site and regulatory region variants in interferon regulatory factor 6 (IRF6) have been shown to contribute to both syndromic and non-syndromic forms of cleft lip and/or palate (CL/P). We report the diagnostic evaluation of a complex multigeneration family of Honduran ancestry with a pedigree structure consistent with autosomal-dominant inheritance with both incomplete penetrance and variable expressivity. The proband’s grandmother bore children with two partners and CL/P segregates on both sides of each lineage. Through whole-exome sequencing of five members of the family, we identified a single shared synonymous variant, located in the middle of exon 7 of IRF6 (p.Ser307Ser; g.209963979 G>A; c.921C>T). The variant was shown to segregate in the seven affected individuals and through three unaffected obligate carriers, spanning both sides of this pedigree. This variant is very rare, only being found in three (all of Latino ancestry) of 251,352 alleles in the gnomAD database. While the variant did not create a splice acceptor/donor site, in silico analysis predicted it to impact an exonic splice silencer element and the binding of major splice regulatory factors. In vitro splice assays supported this by revealing multiple abnormal splicing events, estimated to impact >60% of allelic transcripts. Sequencing of the alternate splice products demonstrated the unmasking of a cryptic splice site six nucleotides 5′ of the variant, as well as variable utilization of cryptic splice sites in intron 6. The ectopic expression of different splice regulatory proteins altered the proportion of abnormal splicing events seen in the splice assay, although the alteration was dependent on the splice factor. Importantly, each alternatively spliced mRNA is predicted to result in a frame shift and prematurely truncated IRF6 protein. This is the first study to identify a synonymous variant as a likely cause of NS-CL/P and highlights the care that should be taken by laboratories when considering and interpreting variants. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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16 pages, 1930 KiB

Open AccessArticle

CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer

by Arthavan Selvanathan, Cheng Yee Nixon, Ying Zhu, Luigi Scietti, Federico Forneris, Lina M. Moreno Uribe, Andrew C. Lidral, Peter A. Jezewski, John B. Mulliken, Jeffrey C. Murray, Michael F. Buckley, Timothy C. Cox and Tony Roscioli

Genes 2020, 11(4), 391; https://doi.org/10.3390/genes11040391 - 3 Apr 2020

Cited by 10 | Viewed by 4926

Abstract

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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14 pages, 4870 KiB

Open AccessArticle

Finding the Unicorn, a New Mouse Model of Midfacial Clefting

by Brandi Lantz, Casey White, Xinyun Liu, Yong Wan, George Gabriel, Cecilia W. Y. Lo and Heather L. Szabo-Rogers

Genes 2020, 11(1), 83; https://doi.org/10.3390/genes11010083 - 11 Jan 2020

Cited by 5 | Viewed by 4631

Abstract

Human midfacial clefting is a rare subset of orofacial clefting and in severe cases, the cleft separates the nostrils splitting the nose into two independent structures. To begin to understand the morphological and genetic causes of midfacial clefting we recovered the Unicorn mouse line. Unicorn embryos develop a complete midfacial cleft through the lip, and snout closely modelling human midfacial clefting. The Unicorn mouse line has ethylnitrosourea (ENU)-induced missense mutations in Raldh2 and Leo1. The mutations segregate with the cleft face phenotype. Importantly, the nasal cartilages and surrounding bones are patterned and develop normal morphology, except for the lateral displacement because of the cleft. We conclude that the midfacial cleft arises from the failure of the medial convergence of the paired medial nasal prominences between E10.5 to E11.5 rather than defective cell proliferation and death. Our work uncovers a novel mouse model and mechanism for the etiology of midfacial clefting. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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14 pages, 1549 KiB

Open AccessArticle

Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene

by Iris ALM van Rooij, Kerstin U Ludwig, Julia Welzenbach, Nina Ishorst, Michelle Thonissen, Tessel E Galesloot, Edwin Ongkosuwito, Stefaan J Bergé, Khalid Aldhorae, Augusto Rojas-Martinez, Lambertus ALM Kiemeney, Joris Robert Vermeesch, Han Brunner, Nel Roeleveld, Koen Devriendt, Titiaan Dormaar, Greet Hens, Michael Knapp, Carine Carels and Elisabeth Mangold

Genes 2019, 10(12), 1023; https://doi.org/10.3390/genes10121023 - 7 Dec 2019

Cited by 21 | Viewed by 5138

Abstract

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10⁻⁷). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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24 pages, 810 KiB

Open AccessArticle

Meta-Analysis of Grainyhead-Like Dependent Transcriptional Networks: A Roadmap for Identifying Novel Conserved Genetic Pathways

by Nishanthi Mathiyalagan, Lee B. Miles, Peter J. Anderson, Tomasz Wilanowski, Brian L. Grills, Stuart J. McDonald, M. Cristina Keightley, Agata Charzynska, Michal Dabrowski and Sebastian Dworkin

Genes 2019, 10(11), 876; https://doi.org/10.3390/genes10110876 - 31 Oct 2019

Cited by 9 | Viewed by 4258

Abstract

The Drosophila grainyhead (grh) and vertebrate Grainyhead-like (Grhl) transcription factors are among the most critical genes for epithelial development, maintenance and homeostasis, and are remarkably well conserved from fungi to humans. Mutations affecting grh/Grhl function lead to a myriad of developmental and adult onset epithelial disease, such as aberrant skin barrier formation, facial/palatal clefting, impaired neural tube closure, age-related hearing loss, ectodermal dysplasia, and importantly, cancers of epithelial origin. Recently, mutations in the family member GRHL3 have been shown to lead to both syndromic and non-syndromic facial and palatal clefting in humans, particularly the genetic disorder Van Der Woude Syndrome (VWS), as well as spina bifida, whereas mutations in mammalian Grhl2 lead to exencephaly and facial clefting. As transcription factors, Grhl proteins bind to and activate (or repress) a substantial number of target genes that regulate and drive a cascade of transcriptional networks. A multitude of large-scale datasets have been generated to explore the grh/Grhl-dependent transcriptome, following ablation or mis-regulation of grh/Grhl-function. Here, we have performed a meta-analysis of all 41 currently published grh and Grhl RNA-SEQ, and microarray datasets, in order to identify and characterise the transcriptional networks controlled by grh/Grhl genes across disparate biological contexts. Moreover, we have also cross-referenced our results with published ChIP and ChIP-SEQ datasets, in order to determine which of the critical effector genes are likely to be direct grh/Grhl targets, based on genomic occupancy by grh/Grhl genes. Lastly, to interrogate the predictive strength of our approach, we experimentally validated the expression of the top 10 candidate grhl target genes in epithelial development, in a zebrafish model lacking grhl3, and found that orthologues of seven of these (cldn23, ppl, prom2, ocln, slc6a19, aldh1a3, and sod3) were significantly down-regulated at 48 hours post-fertilisation. Therefore, our study provides a strong predictive resource for the identification of putative grh/grhl effector target genes. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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12 pages, 1580 KiB

Open AccessArticle

Deregulated Adhesion Program in Palatal Keratinocytes of Orofacial Cleft Patients

by Aysel Mammadova, Carine E.L. Carels, Jie Zhou, Christian Gilissen, Maria P.A.C. Helmich, Zhuan Bian, Huiqing Zhou and Johannes W. Von den Hoff

Genes 2019, 10(11), 836; https://doi.org/10.3390/genes10110836 - 23 Oct 2019

Cited by 4 | Viewed by 2734

Abstract

Orofacial clefts (OFCs) are the most frequent craniofacial birth defects. An orofacial cleft (OFC) occurs as a result of deviations in palatogenesis. Cell proliferation, differentiation, adhesion, migration and apoptosis are crucial in palatogenesis. We hypothesized that deregulation of these processes in oral keratinocytes contributes to OFC. We performed microarray expression analysis on palatal keratinocytes from OFC and non-OFC individuals. Principal component analysis showed a clear difference in gene expression with 24% and 17% for the first and second component, respectively. In OFC cells, 228 genes were differentially expressed (p < 0.001). Gene ontology analysis showed enrichment of genes involved in β1 integrin-mediated adhesion and migration, as well as in P-cadherin expression. A scratch assay demonstrated reduced migration of OFC keratinocytes (343.6 ± 29.62 μm) vs. non-OFC keratinocytes (503.4 ± 41.81 μm, p < 0.05). Our results indicate that adhesion and migration are deregulated in OFC keratinocytes, which might contribute to OFC pathogenesis. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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9 pages, 859 KiB

Open AccessArticle

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

by Bénédicte Demeer, Nicole Revencu, Raphael Helaers, Cica Gbaguidi, Stéphanie Dakpe, Geneviève François, Bernard Devauchelle, Bénédicte Bayet and Miikka Vikkula

Genes 2019, 10(10), 833; https://doi.org/10.3390/genes10100833 - 22 Oct 2019

Cited by 9 | Viewed by 4597

Abstract

Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palate is associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuous cleft. Although this phenotype may represent 5% of clefts of the lip and/or palate (CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducted whole exome sequencing (WES) and apply a candidate gene approach to non-syndromic discontinuous CLP individuals in order to identify genes and deleterious variants that could underlie this phenotype. We discovered loss-of-function variants in two out of the seven individuals, implicating FGFR1 and DLG1 genes, which represents almost one third of this cohort. Whole exome sequencing of clinically well-defined subgroups of CLP, such as discontinuous cleft, is a relevant approach to study CLP etiopathogenesis. It could facilitate more accurate clinical, epidemiological and fundamental research, ultimately resulting in better diagnosis and care of CLP patients. Non-syndromic discontinuous cleft lip and palate seems to have a strong genetic basis. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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9 pages, 1462 KiB

Open AccessCase Report

Pitt-Hopkins Syndrome: Clinical and Molecular Findings of a 5-Year-Old Patient

by Florin Tripon, Alina Bogliș, Cristian Micheu, Ioana Streață and Claudia Bănescu

Genes 2020, 11(6), 596; https://doi.org/10.3390/genes11060596 - 28 May 2020

Cited by 5 | Viewed by 6083

Abstract

Pitt Hopkins syndrome (PTHS) is a very rare condition and until now, approximately 500 patients were reported worldwide, of which not all are genetically confirmed. Usually, individuals with variants affecting exons 1 to 5 in the TCF4 gene associate mild intellectual disability (ID), between exons 5 to 8, moderate to severe ID and sometimes have some of the characteristics of PTHS, and variants starting from exon 9 to exon 20 associate a typical PTHS phenotype. In this report, we describe the clinical and molecular findings of a Caucasian boy diagnosed with PTHS. PTHS phenotype is described including craniofacial dysmorphism with brachycephaly, biparietal narrowing, wide nasal bridge, thin and linear lateral eyebrows, palpebral edema, full cheeks, short philtrum, wide mouth with prominent and everted lips, prominent Cupid’s bow, downturned corners of the mouth, microdontia and also the clinical management of the patient. The previously and the current diagnosis scores are described in this report and also the challenges and their benefits for an accurate and early diagnosis. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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14 pages, 5447 KiB

Open AccessCase Report

Two Novel FAM20C Variants in a Family with Raine Syndrome

by Araceli Hernández-Zavala, Fernando Cortés-Camacho, Icela Palma-Lara, Ricardo Godínez-Aguilar, Ana María Espinosa, Javier Pérez-Durán, Patricia Villanueva-Ocampo, Carlos Ugarte-Briones, Carlos Alberto Serrano-Bello, Paula Jesús Sánchez-Santiago, José Bonilla-Delgado, Marco Antonio Yáñez-López, Georgina Victoria-Acosta, Adolfo López-Ornelas, Patricia García Alonso-Themann, José Moreno and Carmen Palacios-Reyes

Genes 2020, 11(2), 222; https://doi.org/10.3390/genes11020222 - 20 Feb 2020

Cited by 10 | Viewed by 6872

Abstract

Two siblings from a Mexican family who carried lethal Raine syndrome are presented. A newborn term male (case 1) and his 21 gestational week brother (case 2), with a similar osteosclerotic pattern: generalized osteosclerosis, which is more evident in facial bones and cranial base. Prenatal findings at 21 weeks and histopathological features for case 2 are described. A novel combination of biallelic FAM20C pathogenic variants were detected, a maternal cytosine duplication at position 456 and a paternal deletion of a cytosine in position 474 in exon 1, which change the reading frame with a premature termination at codon 207 and 185 respectively. These changes are in concordance with a negative detection of the protein in liver and kidney as shown in case 2. Necropsy showed absence of pancreatic Langerhans Islets, which are reported here for the first time. Corpus callosum absence is added to the few reported cases of brain defects in Raine syndrome. This report shows two new FAM20C variants not described previously, and negative protein detection in the liver and the kidney. We highlight that lethal Raine syndrome is well defined as early as 21 weeks, including mineralization defects and craniofacial features. Pancreas and brain defects found here in FAM20C deficiency extend the functional spectrum of this protein to previously unknown organs. Full article

(This article belongs to the Special Issue Molecular Genetics of Facial Traits and Malformations)

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