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18 Early Clinical Investigations and Management of Syndromes Aecting Craniofacial and Dental Structures
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dimensional
Genomic Aspects fortheDiagnosis
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ofCraniofacial Disorders
ValentinKerkfeld, UlrichMeyer, ArnoldRaem,
andNadjaEhmke
19
19.1 Introduction
A deeper understanding of craniofacial diseases is
based on the increased knowledge in disease biology and genetics. Advanced technologies in chromosomal and genetic analysis as well as the recent
possibilities in bioinformatics and multi- omics
data help to get a deeper insight in genotypephenotype relation. In the past decade, efforts to
classify diseases were based on molecular insights
increased with studies related to molecular-based
disease subtyping in different disease conditions
[1]. The sheer volume of data collected in analysing genetics and in documentation of phenotypes
from 3D scans and omics data generates massive
and complex data sets. The size and heterogeneity
of such data sets do not only pose new challenges
V. Kerkfeld (*)
Clinic for Skull-, Face and Jaw Surgery,
Münster, Germany
U. Meyer
Craniofacial Center, Kieferklinik Münster,
Münster, Germany
University of Düsseldorf, Westdeutsche Kieferklinik,
Moorenstrasse, Düsseldorf, Germany
e-mail: info@kieferklinik-muenster.de
A. Raem
Arrows Biomedical, Gene Analysis Institute, Center
of Nanotechnology, Münster, Germany
N. Ehmke
Institut für Medizinische Genetik und Humangenetik,
Charité- Universitätsmedizin Berlin,
Berlin, Germany
© Springer Nature Switzerland AG 2021
U. Meyer (ed.), Fundamentals of Craniofacial Malformations,
https://doi.org/10.1007/978-3-030-46024-2_19
to efciently and effectively store data but are also
challenging to develop new algorithms to gain
insight into the cause-and-effect correlations
between genetics, embryological pathogenetics
and disease extent (phenotypic outcome).
19.1.1 Technical Approaches
Today, genetics play an important role in medical
practice. With the knowledge of genetics, it is possible to provide the nal precise diagnosis to many
different diseases. Understanding the reason of the
disease helps to make it tangible, generate a better
treatment plan, and maybe even a cure. Technically,
the human genome can be determined on various
levels, starting at a chromosomal level up to
changes in the base sequence. Many genetic diseases appear phenotypically different and dening
the underlying cause in the DNA for each disease
was often complicated in the past. However,
genetic measures were profoundly inspired by
Paul Berg [2], Frederick Sanger [3], and Walter
Gilbert [4] as they introduced DNA sequencing.
Further studies led to Sanger’s “chain-termination” sequencing technology [5] and later to
detecting the human genome [6]. In the last two
decades, two new techniques of measurement
were introduced, that are important in today’s
genetics. DNA microarrays can genotype millions
of specic positions in each human genome, while
“next-generation sequencing” (NGS) can even
generate billions of sequences in a few hours.
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lopment
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Approximately half the cases with suspected
syndromic diagnosis no underlying cause can be
detected despite the use of exome sequence and
genome sequence.Both techniques present limitations: structural modications, methylation
processes, repeats and mosaics may be partly or
fully detectable. In addition, non-coding sections can hardly be interpreted.
The knowledge of clinically driven genetics
and their inherent limitations in paediatrics is
therefore important for the evaluation of craniofacial disorders. This rapid development of
molecular diagnostics helps practitioners and
patients nowadays to get a deeper insight into the
diagnostic approach towards craniofacial disorders. In order to gain insight into the geneticdisorder relationship, it is on one hand important
to know the denition of subsets of craniofacial
anomalies and on the other hand to be aware of
technical approaches in genetic testing.
19.1.2 Denition
19.1.2.1 Syndromes andSequences
A syndrome is dened by a set of symptoms and
is correlated independently. It etymologically
means ‘concurrence’ and consequently means
medical signs that appear together. A clinical
example might be Treacher Collins syndrome.
Infants with Treacher Collins present with hypoplasia of the viscerocranium, cleft palate, malformation of the ears, pharyngeal hypoplasia and
several other symptoms [7].
A sequence needs to be differentiated from
this as it shows a set of symptoms that depend on
one primary defect affecting other structures
consecutively. A clinical example might be Pierre
Robin sequence (PRS). Patients with PRS present with the triad of micrognathia, glossoptosis
and resulting airway obstruction. Pierre Robin
himself declared the drop of the base of the
tongue as a disturbance of the nasopharyngeal
airway [8]. The sequence is also often accompanied by cleft palates. It is commonly assumed
that the micrognathia causes a dislocation of the
tongue to an upper and posterior direction medially between the two parts of the developing pal-
ates during pregnancy. This irregular development
results in a U-shaped cleft [9].
19.1.2.2 Pathogenesis ofAnomalies
In general, anomalies mean the departure of a
common phenotype. There are four underlying
mechanisms of pathogenesis that lead to structural craniofacial anomalies (Fig.19.1) [10]:
(i). Deformations.
(ii). Malformations.
(iii). Disruptions.
(iv). Dysplasias.
Deformations
Deformation means that a part of the head or face
has a different shape or position because of distorting mechanical inuence (e.g. turricephaly).
This may cause a loss of symmetry or abnormal
position [11].
Malformations
Malformation is dened as an alteration of the
primary developmental program (e.g. pharyngeal
arch) that leads to a congenital morphological
anomaly. This may cause further structural or
physiological failures [12].
Healthy
Deformation
Malformation
Dysruptions
Dysplasia
normal genome
abnormal developmental gene
abnormal gene
Fig. 19.1 Pathogenesis of anomalies. Based on the
graphic by Hennekam et al. [10]
mechanical influence
destructive influence
normal development
abnormal organ deve
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Disruptions
Disruption is a breakdown of a normal, healthy
body structure that leads to a congenital morphological anomaly.
Dysplasias
Dysplasia means abnormal tissue architecture
(e.g. skeletal dysplasias) [13].
19.2 Genomic Testing
Prenatal tests like the early preimplantation
genetic diagnosis or amniocentesis give information about the presence of genetic diseases in an
early state of pregnancy [14]. However, many
pregnant women decide to non-invasive prenatal
testing (NIPT) that analyses small pieces of
embryonic genome to detect chromosomal aberrations including trisomy 21, 13 and 18 [15].
Furthermore, it is postnatally also possible to
screen for germ line mutations by tests based on
blood or saliva samples. Nowadays, many differ-
ent biological materials can be used to test for
genetically caused anomalies. Examination
material, more precisely genomic DNA, can be
extracted from lymphocytes or broblasts postnatally and from chorionic villi prenatally.
There are many different kinds of genomic
testing. However, new genomic testing techniques have not replaced older ones but have
expanded traditional diagnostic possibilities.
Figure 19.2 provides an overview chart on
genomic testing methods.
19.2.1 Cytogenetics
Cytogenetics mean the science of chromosomes,
their number and structure.
19.2.1.1 Chromosomal Analysis
The chromosomal analysis evaluates chromosomes by light microscopy. Karyotype gives
information about the number and structure of
chromosomes. A karyogram shows the size,
Genomic testing
Cytogenetics
Chromosomal analysis
Fluorescence-in-situ-
hybridization (FISH)
DNA-Array
Fig. 19.2 Overview chart on genomic testing methods
Moleculare genetics
Southern-blot-
analysis
Classical-DNA-
sequencing
Next-generation-
sequencing
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Fig. 19.3 Human karyotype
shape and banding of an individual by the use of
cytogenetic technique. This analysis with limited
resolution was the rst technique to reveal the
genome (Fig.19.3).
The classical cytogenetic technique is able to
detect chromosomal aberrations, including
numerical and structural changes. Nondisjunctions,
incorrect distributions and structural aberrations
can be displayed. Numerical changes can be due
to nondisjunction, which means the missing separation of homologous chromosomes during meiosis I and of the sister chromatids during meiosis II
or mitosis. Risk factors include increased mater-
nal age as well as ionizing radiation. Incorrect distribution might affect gonosomes (e.g. Turner
syndrome, monosomy 45,X0; Fig.19.4) or autosomes (e.g. Down syndrome, trisomy 21;
Fig.19.5).
0.5% of all infants show chromosomal aberrations, and more than half of spontaneous aborts
are caused by numerical chromosomal aberrations [16]. Somatic chromosomal aberrations
also play an important role in tumorigenesis as it
is in detail investigated in translocation t(9;22),
also known as the Philadelphia chromosome,
that leads to chronic myeloid leukaemia [17].
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Fig. 19.4 Karyotype with monosomy 45,X0 (Turner syndrome)
19.2.1.2 Fluorescence inSitu
Hybridization (FISH)
Further developments lead to uorescence in situ
hybridization (FISH) in the late 1980 that pro-
high resolution but is limited to single chromosomal sections and therefore cannot provide
genome-wide examination.
vides deeper insights and more detailed examination of the individual chromosome. FISH
combines cytogenetic and molecular genetic
approaches and offers the opportunity to display
chromosomes and chromosomal sections in
colour by uorescence microscopy. Fluorescently
labelled DNA probes join single-stranded DNA
(hybridization) directly on the patient’s sample
(in situ). With this technique, diagnosticians are
able to detect specic chromosomal sections and
reveal microdeletions that could not be recognized by classical chromosomal analysis [18].
19.2.1.3 DNA Microarray
Today, DNA microarrays combine the advan-
tages of both the chromosomal analysis and
FISH.DNA microarrays are able to examine the
whole genome on many areas of the genome at
once with a resolution of a few thousand nucleo-
tides. Hereby, unbalanced chromosomal changes,
including small copy number variants, can be
detected. This reveals all numerous and unbal-
anced structural chromosomal aberrations, such
as microdeletion syndromes (Fig.19.6).
Locus-specic FISH analysis can detect with
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Fig. 19.5 Karyotype with trisomy 21 (Down syndrome)
Fig. 19.6 DNA microarray
Modern SNP arrays are also able to give quantitative information about copy numbers [19].
Copy number variation means structural differences of the genome due to a gain (duplication)
or loss (deletion) of chromosomal material. In
conclusion, the number of gene copies in a sample differs to the number in a reference genome.
Duplications and deletions can affect the phenotype of a patient in a highly wide range depending, among others, on the length of the DNA
section and its gene content [20]. Modern SNP
arrays are also able to detect uniparental disomy,
which means that both homologous chromosomes originate from the same parent. DNA
microarrays are not able to detect balanced chromosomal aberrations, including balanced
translocations.
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The diagnostic yield of a karyotype or DNA
microarray analysis used to screen individuals
with craniofacial malformations varies by type
and category. For example, in some studies, the
diagnostic yield for isolated nonsyndromic
single- suture craniosynostosis cases is very low
or near zero. Yet in syndromic craniosynostosis,
the yield ranges from 6.7% to 28%. The vast
majority (85%) of craniosynostosis due to chromosomal aberrations affects the midline (metopic
and sagittal) sutures. Karyotype and DNA microarray studies in individuals with oral clefts also
have varying degrees of diagnostic yield depending on whether the clefts were detected prenatally or postnatally. Maarse etal. summarized a
comprehensive review of prenatal and postnatal
chromosomal and microarray studies [21]. Of
407 foetuses with oral clefts, cleft lip and palate
had the highest prevalence of associated anomalies (54%, range 39.1–66%). There were 23 cases
of cleft lip without cleft palate, and three of these
had associated anomalies, while only one had a
chromosomal defect. Studies that grouped both
cleft lip and cleft palate had a lower prevalence of
associated anomalies (29.9%, range 17.2–
57.1%). The prevalence of chromosomal defects
in cleft cases with associated anomalies was 50%
(74/146), while it was 0.9% in cases with clefts
that were formerly presumed to be isolated. Of
28,953 postnatally assessed infants, almost all
chromosomal abnormalities were found in association with additional anomalies. Cleft palate
was the category most frequently associated with
other anomalies (45.9%, range 22.2–78.3%). The
prevalence of associated anomalies in cleft lip
cases was approximately 10%. One study of isolated cleft lip cases found a chromosomal defect
in 1.8% (2/110) of cases (both having a 22q11.2
deletion). Overall, the diagnostic yield of screening for chromosomal defects in cases of cleft lip
with or without cleft palate was 9.5% (range 0.5–
12.6%) [21].
information in extracted RNA or DNA.Molecular
genetics made giant leaps due to the development
of polymerase chain reaction (PCR) and is
increasingly expanding classical analyses.
19.2.2.1 Southern Blot Analysis
Southern blot analysis provides information
about the length of a specic DNA section.
Specic restriction enzymes cut the genomic
DNA into pieces that will be separated electrophoretically afterwards. After transferring onto a
nylon membrane (blotting), the technique is able
to detect restriction fragment length polymorphism (RFLP) (Fig.19.7).
The approach used to be very effective in
detection of point mutations before PCR was
established but is still the method of choice in
detection of massive repeat expansions occurring
in trinucleotide diseases.
19.2.2.2 Sanger Sequencing
Sanger sequencing is the gold standard and
detects mutations reliably. Polymerase chain
reaction (PCR) is able to amplify small DNA sections that can then be sequenced. The technique
determines the sequence of nucleic acids (order
of nucleotides in DNA) (Fig.19.8).
Most recognizable craniofacial syndromes are
monogenic Mendelian disorders, but even within
the same condition, there is often allelic heterogeneity with most individuals having different
mutations in the same gene. One exception to this
are the recognizable craniosynostosis syndromes
involving the FGFR genes (FGFR1, FGFR2,
19.2.2 Molecular Genetics
Molecular genetics contains all diagnostic
approaches that examine alterations of genetic
Fig. 19.7 A DNA Southern blot chart
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Fig. 19.8 Sanger sequencing. In this case determining a point mutation
FGFR3). In craniofacial medicine, there are a
growing number of clinically indistinguishable
or overlapping phenotypes that may be caused by
mutations in different genes (locus heterogeneity). Examples include rasopathies, cohesinopathies, mandibulofacial dysostoses and Stickler
syndrome [19]. When using a major malformation as the only search criterion, the number of
genes involved can range from just a few to more
than a hundred. For many genetically heterogeneous craniofacial disorders, the full complement
of causal genes is yet to be established.
A craniofacial condition such as Treacher
Collins syndrome, which had initially been
ping phenotype with autosomal dominant
(COL2A1, COL11A1, COL11A2, VCAN) and
autosomal recessive inheritance (COL9A1,
COL9A2, COL9A3, LOXL3) [25].
As of today, Sanger sequencing remains the
gold standard molecular diagnostic tool used to
screen DNA for unknown point mutations in
dened genes; this may change as the condence
and quality of newer technologies improve. Up
until recently, some larger genes had remained
inaccessible to clinical testing because the older
methods were too burdensome on laboratory
staff, or the condition was too rare for a test to be
commercially viable.
reported to be monogenic and autosomal dominant, has subsequently been found to be multi-
19.2.2.3 Next-Generation
genic with autosomal dominant (TCOF1,
POLR1D) and recessive forms (POLR1C).
Stickler syndrome is another rare condition with
a growing number of genes related to an overlap-
Next-generation sequencing (NGS) contains all
new approaches of high-throughput sequencing.
The underlying idea is the massive parallel
Sequencing
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sequencing of millions of DNA sections in a single sequencing run. This results in the theoretical
opportunity to detect nearly all genetic alterations (like minor insertions or major translocations and even aneuploidy) by a single test. The
use of this next-generation sequencing (NGS)
technologies to interrogate the exome sequence
(ES) or genome sequence (GS) may circumvent
some of the difculties of older technologies.
Today, this technique is work and cost intensive. Since the importance of introns is still not
claried, the sole sequencing of exomes as the
protein coding area of the genome represents a
good alternative. However, in 2010, nextgeneration sequencing was used to reveal the
underlying gene for the Miller syndrome, a
pathology with micrognathia, cleft lip and palate
and other anomalies [22].
19.3 Management
Determining genetic causality for a particular
disease and establishing a molecular diagnosis in
clinical practice can be challenging. In recent
years, exome and genome sequencing have
increased the rate of gene discovery for singlegene disorders among patients with suspected,
but previously undiagnosed, genetic disorders.
Although exome and genome sequencing are
becoming more readily available, the value of
molecular diagnosis should be viewed from a
clinical perspective as similar to other diagnostic
tests. The decision to proceed with molecular
testing must integrate many factors specic to
clinical status of the affected individual, such as
probability of diagnostic yield and the patient’s/
family’s personal preference.
19.3.1 Clinical Evaluation
To evaluate craniofacial disorders, it is obligatory
to get detailed information about risk factors.
First of all, potential prenatal exposures have to
be retrieved and checked on their teratogenic
potential [23]. Among other things, this is important to calm parents who are afraid of exposures
of drugs that are not teratogenic. Other common
risk factors for malformations are maternal diseases like diabetes or alcoholism. Furthermore, a
pedigree analysis can reveal genetic diseases due
to its penetrance, anticipation and expressivity.
Besides the genetic diagnosis, standard paediatric assessments like growth measurements should
be mentioned. The results of this analysis lead to
differential diagnoses.
Besides this standard examination, experienced practitioners are able to detect common
syndromes or sequences based on typical patterns of morphological anomalies [
orphan diseases or minor variants of certain disorders might remain unrecognized. In these
cases, molecular diagnostics offer a powerful
instrument to detect the underlying cause of craniofacial disorders.
24]. However,
19.3.1.1 Genetic Test
Molecular genetic tests are of increasing importance in all medical professions. However, there
is a great discrepancy between technical abilities and sensible use of these instruments. The
practitioner has to evaluate the right diagnostic
methods in order to gain the best information
and to cause least costs. Detection of an underlying pathogenic DNA variant is only one aspect
in the diagnosis of craniofacial disorders. The
clinical question arises which information will
be gathered after testing, how this information
will help the patient and how will it affect the
patient.
19.3.1.2 Future Directions
Large- scale studies are needed and are recently
on the way to identify the complex correlations
between genetic inuences, embryological development and the resulting phenotype. This is especially important for seldom diseases like
craniofacial malformations. One way to improve
in future the approach to gain a deeper insight
into disease biology of rare diseases is to integrate genetic and molecular data as well as phenotypic appearances into a broad network of
craniofacial data. A specic ontology—the
Ontology of Craniofacial Development and
Malformation (OCDM)—was developed years
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