RESEARCH REVIEW

Summarizing Craniofacial Genetics and Developmental Biology (SCGDB) Brian K. Hall* Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada Manuscript Received: 4 December 2011; Manuscript Accepted: 29 December 2011

This overview article highlights active areas of research in craniofacial genetics and developmental biology as reflected in presentations given at the 34th annual meeting of the Society of Craniofacial Genetics and Developmental Biology (SCGDB) in Montreal, Quebec on October 11, 2011. This 1-day meeting provided a stimulating occasion that demonstrated the present status of research in craniofacial genetics and developmental biology and where the field is heading. To accompany the abstracts published in this issue I have selected several themes that emerged from the meeting. After discussing the basis on which craniofacial defects/syndromes are classified and investigated, I address the multi-gene basis of craniofacial syndromes with an examination of the roles of Sox9 and FGF receptors in normal and abnormal craniofacial development. I then turn to the knowledge being gained from population-wide and longitudinal cohort studies and from the discovery of new signaling centers that regulate craniofacial development. Ó 2014 Wiley Periodicals, Inc.

Key words: craniofacial development; neural crest cells; Sox9; FGFR; dysmorphology; knockout mice; zebrafish; chondrogenesis; cartilage development In the closest union there is still some separate existence of component parts; in the most complete separation there is still a reminiscence of union. Butler [1986] (Samuel Butler, 1835–1902).

INTRODUCTION This overview article on active areas of research in craniofacial genetics and developmental biology accompanies the publication in this issue of the abstracts of talks and poster presentations given at the 34th annual meeting of the Society of Craniofacial Genetics and Developmental Biology (SCGDB) in Montreal, Quebec in October 2011. A major theme underlying the invited talks was clinical craniofacial dysmorphologies. The objectives of the Society of Craniofacial Genetics and Developmental Biology are to promote understanding, teaching, research, and interdisciplinary communication concerning craniofacial genetics, and to apply the results of basic and clinical research to the care and management of individuals with craniofacial

Ó 2014 Wiley Periodicals, Inc.

How to Cite this Article: Hall BK. 2014. Summarizing craniofacial genetics and developmental biology (SCGDB). Am J Med Genet Part A 164A:884–891.

problems. (See http://craniofacialgenetics.org/index.php?section¼ ABOUTþUS for detailed objectives.) I say ‘‘problems’’ because deviations away from normal variation in the craniofacial region fall into four major categories as outlined in the next section. Although small, the society is enormously active in pursuit of its objectives. Thanks in large part to the work of Geoffrey Sperber, abstracts of presentations at past general meetings are posted on the society’s web site. Sperber is also the lead author on a definitive text on craniofacial genetics and development, the 2nd edition of which was published in 2010 [Sperber et al., 2010]. As befits a discipline in which genetics plays a large role, Geoff’s son is one of the three authors of the 2nd edition. As befits Geoff’s status in the field and role in the society, the ‘‘Geoffrey Sperber Award for Excellence in Craniofacial Research’’ was established at the Montreal meeting. Zohreh Khavandgar of the Faculty of Dentistry at McGill University (the host institution for the meeting) received this award for her research on mechanisms of bone mineralization [Khavandgar et al., 2012a, 2012b]. A second award, the Genesis award for excellence in craniofacial research, generously funded by the journal genesis was won by Christopher Percival for his research on bone mineral density in a mouse model for Beare-Stevenson Cutis Gyrata Syndrome [Percival et al., 2012]. The custom of the Society is to meet in conjunction with a larger meeting devoted to human genetics, usually the American Society of Human Genetics (ASHG), which was established in 1948. The abstracts of presentations at the 2010 meeting of what was then Grant sponsor: NSERC of Canada; Grant number: A5056. *Correspondence to: Brian K. Hall, Ph.D., D.Sc., Department of Biology, Dalhousie University, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 30 January 2014 DOI 10.1002/ajmg.a.35288

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HALL called the Society of Craniofacial Genetics (established 1975) are published in the American Journal of Medical Genetics [Sperber, 2011], as are the abstracts from the 2011 meeting of the Society (this issue). Reflecting the tight yet hierarchical integration between genetics and development/embryogenesis, the name of the Society has been expanded to include developmental biology. This year (2012) SCFDB will again meet with ASHG, which will convene in San Francisco from November 6 to 10 (http://www.ashg.org/ 2012meeting/). Mark your calendar and monitor the SCGDB and ASHG web sites for details of the day on which SCGDB will meet. For the remainder of this brief overview of the 2011 SCGDB meeting I have selected several themes that both made the meeting an exciting one in which to participate and demonstrate where research in craniofacial genetics and developmental biology is now, and where it is heading. After discussing the basis on which craniofacial defects/syndromes are classified and investigated, I explore the multi-gene basis of craniofacial syndromes with an examination of Sox9 and FRF receptors, before turning to the knowledge being gained from population-wide and longitudinal cohort studies and from the discovery of new signaling centers involved in craniofacial development. I apologize in advance to those whose presentation topics could not be included because of space limitations.

CLASSIFICATION The classification of defects and syndromes that affect human embryos follows a set of recommendations from an international working group [Spranger et al., 1982]. These four classes of birth defects—malformations, deformations, disruptions, dysplasias—are used by clinical geneticists [Cassidy and Allanson, 2010], anatomists/embryologists [Sperber et al., 2010] and basic scientists [Hall, 2009]. The definitions below are from the presentation by Marilyn Jones at the 2011 annual meeting [Jones, 2012; see also Jones and Jones, 2009]: (1) Malformation: a structural defect arising from a primary localized error in morphogenesis (e.g., cleft lip). (2) Deformation: an alteration in the shape or structure of a part, which has differentiated normally caused by non-disruptive mechanical forces (e.g., clubbed foot). (3) Disruption: a structural defect resulting from destruction of a part that has differentiated normally (e.g., amputation). (4) Dysplasia: an abnormal organization of cells into tissue(s) and its morphologic result(s) as a consequence of a dyshistogenetic process (e.g., hemangioma). Clearly, this classification takes as its basis, the embryological process(es) that has been disrupted—morphogenesis, abnormal mechanical forces, differentiation/histogenesis. Dufresne and Richtsmeier [1995] correlated the severity of these defects with whether embryonic growth was disrupted locally or more regionally, and whether surgical intervention gave poor or optimal results. Dysplasias, which often affect individual regions (modules), are generally poorly resolved surgically. Deformations, which are usually local (an amniotic band constricting a finger, for

885 example), usually respond well to surgical intervention. So, too do malformations such as cleft lip, especially when unilateral. Bilateral clefts, which extend over a greater region, and non-syndromic cleft lip/palate, respond less well [Precious and Hall, 1992; Hall and Precious, 2012; Leslie et al., 2012]. More recently, and as summarized in Figure 1, Sperber et al. [2010] related the four categories of abnormalities to the nature of the factors initiating the abnormality (genetic, cytoplasmic, environmental), the developmental processes affected (induction, yto-, histo-, or morphodifferentiation), and the regulatory mechanisms involved (transcription, receptor signaling, cell–cell interactions, hyper- and hypoplasia, cell death).

Clinical Diagnosis and Microarrays Jones [2012] and Krakow [2012] both addressed the issue of classifying craniofacial anomalies on the basis of clinical diagnosis, accompanied by 2D or 3D ultrasound imaging; Krakow et al., 2003, chromosomal abnormalities of DNA microarrays. As accessibility to microarray becomes more and more routine, discussions on whether clinical diagnosis or DNA microarrays provide the most optimal first-line of diagnosis are an important part of the current debate over optimizing diagnosis (and training). (Four major papers and two commentaries in the September 30, 2011 issue of the journal Cell provide up-to-date analysis of genomics in the clinic.) Krakow makes the strong cases for the insights gained from clinical diagnosis based on ultrasound: ‘‘Determining the constellation of abnormal facial findings can help direct the prenatal geneticists towards differential diagnoses, including recognition of novel disorders.’’ Molecular diagnostics can then be used ‘‘to help identity the causative mechanisms’’ [Krakow, 2012], as amply demonstrated at the meeting in studies from Scott Lozanoff’s group on cleft lip/palate and frontonasal dysplasia in mice (see Abstracts in this issue). Undertaking microarray analysis as a matter of routine when assessing an individual has the important advantage that, when unexpected clinical situations present later in life in individuals diagnosed early in life with a craniofacial anomaly, the microarray is available to pinpoint the genetic changes associated with that late onset feature. Comparison between individuals then provides a strong basis for integrating the clinical and microarray data and determining whether the similar features share a common genetic basis. The knowledge to be gained from such an approach, both of normal variation, and of deviation associated with anomalies, is amply illustrated in a recent study of single nucleotide polymorphisms (SNPs) in Dutch and German cohorts with or without nonsyndromic cleft lip with or without cleft palate [Boehringer et al., 2011]. Bizygomatic distance and nose width were determined from 2D digital portraits. Genotyping and identification of SNPs revealed that two percent of variation in nose width in the German cohort and 0.5% of the variation in bizygomatic distance in the Dutch cohort were explained by a single SNP in each case. The study is presented as ‘‘a first link between genetic loci involved in a pathological facial trait such as non-syndromic cleft lip/palate and variation of normal facial morphology.’’ [Boehringer et al., 2011,

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FIG. 1. The four classes of developmental abnormalities—malformations, disruptions, dysplasias, deformations—in relation to the nature of the factors initiating the abnormalities, developmental processes affected, and the regulatory mechanisms involved. Reproduced from Craniofacial embryogenetics and development. Second edition, with the permission of Dr. Geoffrey H. Sperber.

p. 1192]; the studies by Young et al. [2010], Marcucio et al. [2011], and Parsons et al. [2011] discussed below in the context of signaling centers provide another means of detecting normal variation in the context of craniofacial anomalies. Of course, genetic analyses are not infallible. Although error in the data obtained in microarray analyses is small our current interpretation of causality can lead us astray, as illustrated in a recent analysis of de novo copy number variation as the mechanism ‘‘explaining’’ some anomalies. As outlined by Vermeesch et al., Vermeesch et al., 2011[2011, p. 112] ‘‘a rule of thumb is that de novo CNVs [copy number variations], not occurring in normal individuals, are considered causal for the abnormal phenotype’’ (my italics).

Using a combination of clinical screening, identification of a de novo 86.5 kb deletion in an individual with an eye malformation and mental retardation, identification of the deletion as the single gene autophagy/beclin-1 regulator 1 (AMBRA1, which is expressed in the neural retina and brain) and that knock-out of the homologous gene in mice results in exencephaly and in zebrafish in eye colobomas, the deletion was considered as the likely cause of the altered phenotype. However, a more detailed clinical examination of the individual revealed a CHARGE-like phenotype, and mutation analysis of the gene chromodomain helicase DNA binding protein 7 (CHD7) revealed a de novo mutation, causing a splice site mutation that disrupted CHD7 function.

HALL A second individual with different clinical features revealed the same situation; a de novo mutation rather than a de novo CNV provides a better explanation for both phenotypes. Molecular diagnoses ‘‘can only be as good as clinical diagnosis;’’ importantly, ‘‘completeness of the clinical information directed the genetic testing;’’ and ‘‘a genomic analysis of all variants will only enable the causative variants to be identified in relation to a well-defined clinical question’’ [Vermeesch et al., 2011, p. 1113].

MORE THAN ONE GENE–ONE SYNDROME As just discussed, independent genetic changes occur in individuals with craniofacial anomalies. It takes a combination of clinical and genetic diagnoses both to classify the anomaly and to determine its underlying genetic basis. Although we now realize that ‘‘onegene-one syndrome’’ is an unrealistic summary of how genes function (or of how syndromes arise), analysis of individual genes has greatly expanded our understanding of how genes contribute to craniofacial development, both normal and abnormal. Sox9 is an excellent example.

Sox9 Studies in the zebrafish Danio rerio, the frog Xenopus laevis and in various inbred strains of mice (Mus musculus) have revealed both the modes of action of Sox9 and whether those modes are conserved across this broad range of vertebrates; for reviews see Hall [2009] and Lee and Saint-Jeannet [2011]. Sox9 is active from the earliest stages when neural crest cells emigrate from the neural tube, through the processes of the condensation of prechondrogenic cells [Hall, 2003, 2012] and the differentiation of these cells into chondroblasts and chondrocytes [Hall, 2005]. Sox9 is especially required in the pharyngeal arches where it is co-expressed in prechondrogenic mesenchyme with Col2a1 [Chiang et al., 2001; Kerney et al., 2007]; Sox9 binds to chondrocyte-specific enhancer elements in Col2a1. (Alterations in enhancers are increasingly being shown to be involved in craniofacial dysmorphologies and syndromes as discussed by Fakhouri [2012] at the 2011 SCGDB meeting.) Morpholino-based knockout of Sox9 in Xenopus results in complete loss of Meckel’s cartilage and defective development of more posterior arch cartilages. Zebrafish have two copies of Sox9—Sox9a, Sox9b—each with a distinct function but each complementing the role of the other. Knocking out Sox9a results in embryos lacking all cranial cartilages, although chondrogenic condensations form normally. In contrast, knocking out Sox9b results in reduction in all cartilages derived from the first and second pharyngeal arches. Mouse mutants that are heterozygous for Sox9 die soon after birth (homozygotes die during gestation). All cartilages are reduced in size and the mice have cleft palates. Inactivation of Sox9 in the neural crest using a Wnt1-Cre transgenic approach eliminates all cranial cartilages but spares intramembranous bones. Individuals die at birth because of respiratory complications resulting from a widely cleft palate [Mori-Akiyama et al., 2003].

887 These studies on non-human species of vertebrates inform our approach to the role of Sox9 in human craniofacial development to the extent that SOX9 is a candidate gene for campomelic dysplasia (OMIM # 114290), in which failure of the development of cranial cartilages (and the bones that would normally replace them) results in facial dysmorphia and micrognathia accompanied by cleft palate. As in mice, respiratory distress usually results in the death of affected humans in the first year. Most cases of campomelic dysplasia are the result of haploinsufficiency of SOX9, although deletions, translocations and upstream inversions also have been identified. In humans, long-range tissue-specific enhancers that regulate SOX9 [Gordon et al., 2009] are currently thought to relate to the spectrum of defects seen in this dysplasia.

FGF Receptors A second class of gene products that featured in several presentations at the Montreal meeting is the fibroblast growth factor receptors (FGFRs) and their involvement in craniosynostosis. Discussion went in both directions: (i) can individual craniosynostosis phenotypes be assigned to individual FGF receptors? And (ii) can syndromes involving craniosynostosis be distinguished with sufficient precision to assign to defects in specific FGFRs? As presented by Heuze et al. [2012], with a prevalence of one in 10,000 live births, craniosynostosis has been described in association with 180 syndromes, most but not all of which are the result of mutations in FGFRs. All show premature fusion of one or more cranial sutures and all are associated with other anomalies, affecting the limbs, lungs, brain, face, and/or skin. Using a morphometric approach of medical CT scans of the skulls of 37 individuals with Apert, Crouzon, Pfeiffer or Muenke syndromes and CT scans of 20 unaffected individuals, Hueze and colleagues showed that clinical diagnosis of a specific syndrome is less certain when only altered skull shape is considered. There is considerable overlap in skull shape between individuals with different syndromes (as assessed by genetic analysis), especially those with syndromic bicoronal craniosynostosis, although morphometric analysis did separate individuals with syndromic from individuals with non-syndromic bicoronal craniosynostosis. A morphometric analysis of skull and brain growth of FGFr2þ/ P253R Apert syndrome mice by Hill et al. [2012] showed that while both brain and skull show divergent patterns of postnatal growth when compared with wild-type littermates, correlated growth in the ‘‘Apert mice’’ points to coordinated interactions between brain and skull in mutant mice, as is seen in wild types (see the following section). Determination of bone mineral density and volume from CT scans in the Fgfr2Y394C/þ mouse model of Beare–Stevenson cutis gyrata syndrome enabled Percival et al. [2012] to demonstrate that bone development was affected throughout the skull, not only near prematurely fused sutures. Here, morphometrics revealed previously unexpected effects on bone development distant from the sutures, thereby opening up new avenues to explore the mechanism(s) of action of the mutation. In a further FRGF study presented at the meeting, Ye et al. [2012] reported ongoing analysis of a population-based study of candidate gene analysis of 96 individuals with non-syndromic sagittal

888 craniosynostosis, illustrating how knowledge of mutational bases of syndromes can accrue from such studies. One of three novel genetic variants revealed was a frameshift variant in FGFR1 isoform 6 (c.732_733insG) with a predicted effect of abolishing the entire extracellular immunoglobulin III domain responsible for binding of FGF.

POPULATION-WIDE AND LONGITUDINAL COHORT STUDIES The insights to be obtained from population-wide and from longitudinal studies of a single cohort were evident from studies in addition to the study by Ye and colleagues noted above. Results from one longitudinal cohort study were reported at the meeting. Its basis was analysis of 3D high-resolution facial images of 4,745 individuals in the Avon Longitudinal Study of Parents and Children, established when 14,000 mothers enrolled during their pregnancies in 1991–1992. This genome-wide association study (GWAS) has the long-term goal of documenting normal variation in 3D-morphology and its genetic basis. These are long-term studies; the individuals in this report were all 15-years old. Analysis of genome-wide data on a subset of 2,185 individuals revealed four associations with genome-wide significance. The association reported was between an intron of PAX3 (rs7559271) and the 3D distance between the nasion and the mid-endocanthion, which is the most stable landmark around the eyes and orbits [Paternoster et al., 2012]. Thus, PAX3, previously associated with the flattened nasal bridge and widely spaced eyes seen in individuals with Waardenberg syndrome, has been shown to contribute to facial morphology in non-syndromic individuals. Such regional (focused, local, modular) expression of genes affecting craniofacial development was explored at the cellular level at the meeting [Hall, 2012]. Here the populations are the condensations of prechondrogenic and preosteogenic cells that form the basic modules from which the elements of the craniofacial region are built and evolve, modularity now being a central concept in evolutionary-developmental approaches to the origin, maintenance and variation associated with morphology [Bolker, 2000; Gass and Bolker, 2003; Hall, 2003; Schlosser and Wagner, 2004; Franz-Odendaal and Hall, 2006]. Other results from GWAS reported at the meeting (see the individual Abstracts in this issue) included identification of a gene encoding a Rho GTPase activating protein as a novel candidate gene in non-syndromic cleft lip/palate by Elizabeth Leslie and colleagues; six genetic susceptibility loci for non-syndromic cleft lip with or without cleft palate in central Europeans reported by Kerstin Ludwig and colleagues; and identification of common and rare variants of PAX7 and VAX1 for non-syndromic cleft lip in individuals from Iowa, Japan the Philippines and magnolia by Azeez Butali and colleagues. Results of population-based studies reported at the meeting include identification of the frameshift variant in FGFR1 isoform 6 (c.732_733insG) and its association with non-syndromic sagittal craniosynostosis discussed above, and variation in proteins that regulate the structure of carbonated hydroxyapatite crystals in enamel in human teeth reported by Hazim Eimar and colleagues. Painstaking as such research is, the accumulated knowledge obtained from GWASs in large cohorts is

AMERICAN JOURNAL OF MEDICAL GENETICS PART A incrementally building our knowledge base of the genetic basis of normal variation in craniofacial form.

RECENTLY DISCOVERED SIGNALING CENTERS In the past few years, several new signaling centers have been added to our knowledge of how development, morphogenesis, and growth of the brain, face, and head are controlled. Some of these are previously undiscovered loci of gene activity, analogous to the enamel knot shown almost 20 years ago to control the morphogenesis of mammalian teeth [Jernvall et al., 1994]. The potential for a gene cascade initiated by endogenous Wnt signaling to activate stem cells within pulp to repair toot defects is another cascade that was discussed at the meeting [Hunter, 2012]. One recently discovered signaling center, the frontonasal ectodermal zone (FEZ), found first in chick embryos and named by Hu et al. [2003] is localized between boundaries of Shh and Fgf8. Transplanting a FEZ within the developing upper or lower jaws of early chick embryos induces a duplication of the upper or lower jaws. A FEZ also is present in mouse embryos [Hu and Marcucio, 2009; Marcucio et al., 2011], regulated by Pax6 [Compagnucci et al., 2011]. Other centers are anatomical regions with unsuspected (epigenetic) influences on adjacent developing regions [Hallgr^ımsson and Hall, 2011]. Thus, the brain, long known to affect morphogenesis and growth of the face and skull because of mechanical forces generated by its growth [Hall, 2005; Richtsmeier et al., 2006; Aldridge et al., 2010; Hallgr^ımsson and Hall, 2011; Parsons et al., 2012], is now know also to be a signaling center; Foxg1 and the downstream gene Dicer1, which produces the key enzyme in a cascade requires to form active miRNAs, are required for forebrain development. Without Foxg1 and Dicer1, substantial craniofacial malformations affecting the eyes, ears, and cerebellum arise [Kersigo et al., 2011]. Sonic hedgehog, which plays a central role in the frontonasal ectodermal zone, also functions in the developing brain to regulate facial growth and shape. Reducing brain-derived SHH results in narrow frontonasal processes, subsequent hypotelorism and rotation of the medial maxillary processes. Enhancing SHH in the developing brain results in a widened midface, hypoplasia, or bifurcation of the midface, and laterally diverging maxillary processes [Young et al., 2010]. Whether SHH is enhanced or reduced, the size of the FEZ correlates with Shh levels. Alteration in SHH signaling in human embryos result in phenotypes that can be interpreted as responses to variation along a SHH gradient (Fig. 2), seen in holoprosencephaly consequent to reduced SHH signaling (brain malformations, hypotelorism, and midfacial changes ranging from hypoplasia to cyclopia [Muenke and Beachy, 2000; Muenke and Cohen, 2000], and in phenotypes ranging from hypertelorism to medial facial clefts in Greig cephalopolysyndactly and Gorlin syndrome consequent to increased SHH signaling. As you can see from Figure 2, and as discussed further in Marcucio et al. [2011], a gradient in SHH signaling activity also has been implicated in the evolution of midfacial features in hominoid apes. These are exciting times to be involved in craniofacial research, which as this snippet shows, is forging ahead because

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FIG. 2. Hypothetical relationship of Shh-signaling activity in the brain and FEZ to both population and evolutionary level variation in midfacial shape. A. Normal levels of SHH-signaling activity in the brain regulate FEZ formation, which establishes growth zones that help to regulate the shape and size of midfacial structures such as the frontal, premaxilla and nasal septum. Extremes of signaling due to mutational effects, environmental factors, or combinations of both, can cause progressive loss of midline structures when signaling is abnormally low (e.g., in Holoprosencephaly), or expansion of midline structures when signaling is abnormally high (e.g., in Gorlin Syndrome). More subtle differences in signaling introduce variation in the midline facial structures of normal individuals that can serve as a target of natural selection. B: Species exhibit a range of normal and abnormal intraspecific variation in midfacial shape, as well as interspecific or evolutionary variation between species. In the case of hominoid apes, interorbital spacing varies from narrower in the orangutan to wider in gorillas (tree illustrates phylogenetic relationships of living and recent species as well as facial skeletons of potential ancestral species). Selection on variation in Shh-signaling is hypothesized to have contributed to the evolution of the midface in living apes and humans, as well as other vertebrate species, either through direct effects on the face or indirect effects on the brain.

of interdisciplinary and inter-institutional studies that range from analysis of single genes to screening of tens of thousands of individuals in cohorts and populations.

ACKNOWLEDGMENTS I thank Dwight Cordero and Joan Richtsmeier, President and Vicepresident, respectively, of the Society of Craniofacial Genetics and Developmental Biology (formerly the Society of Craniofacial Genetics) for the opportunity to prepare this overview of what was a stimulating meeting. My thanks to Geoff Sperber and to Joan Richtsmeier for their comments on the draft manuscript. Research in my laboratory is supported by NSERC discovery grant A5056.

types in two FGFR2 mouse models for Apert syndrome. Dev Dyn 239:987–997. Boehringer S, van der Lijn F, Liu F, Geunter M, Sinigerova S, NowaK S, Kerstin UL, Herbetz R, Klein S, Hofman S, et al. 2011. Genetic determination of human facial morphology: Links between cleft-lip and normal variation. Eur J Human Genet 19:1192–1197. Bolker JA. 2000. Modularity in development and why it matters to evodevo. Am Zool 40:770–776. Butler S. 1986. Mind and motion. In: Jones HF, editor. The notebooks of Samuel Butler. London: Chatto & Windus. Cassidy SB, Allanson JE. 2010. Management of genetic syndromes. New York: Wiley-Blackwell.

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Summarizing craniofacial genetics and developmental biology (SCGDB).

This overview article highlights active areas of research in craniofacial genetics and developmental biology as reflected in presentations given at th...
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