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7 The Biological Basis ofChromosomal andSingle Gene Disorders
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91
Fig. 7.8 Mitochondrial inheritance. (a) Possible progeny
of unaffected father and affected mother would be affected
children whose degree of penetrance depends upon the
amount of mitochondria affected. (b) Possible progeny of
affected father and unaffected mother would be unaffected children
5. Mitochondrial inheritance
Both genders are equally affected with
females being the only carriers. The expression of the disease occurs in every generation.
E.g., Leber’s hereditary optic neuropathy [10,
12, 14, 21] (Fig.7.8)
7.2.5 Mutations inSingle Gene
Disorders
As we are already aware that the genes are
responsible for the coding of proteins necessary
for determining the structure and function of
each cell in the body, their disruption due to various factors manifests signicantly. Mutations are
the essential element in single gene disorders.
The form and the place in which they occur are
diverse. The consequences of such a mutation
results in a protein product that may be unable to
perform its function or may perform its function
but in a reduced capacity or even a new protein
may be synthesized with damaging function or
ultimately a protein may be entirely disabled due
to mutation.
The above brieng strengthens that the prime
etiology of the single gene disorders is mutations.
Owing to the DNA chemical instability of the
bases and replication errors are the factors
responsible for the emergence of mutations.
These mutations can either involve change in a
single base pair or deletions of a few base pairs
resulting in the disturbance in the function of the
affected single gene. Molecular studies on abnormal hemoglobin and different forms of thalassemia were crucial in amassing our knowledge
on different types of mutations.
Fig. 7.9 Schematic representation of point mutation.
Upper schematics represent normal sequence of base
pairs, while the below represents mutated sequence of
base pairs. Highlighted represents point mutation of the
base pair
Point mutations are changes involving a single
base pair of a gene (Fig.7.9). They result in either
of the following mutations. If an amino acid is
replaced for another in a protein, it is termed as
missense mutation. If an amino acid codon is
replaced with a stop codon resulting in premature
termination of the translation, it is termed as nonsense mutation. The specic sequence of codons
that run from the start codon to the stop codon in
mRNA is called a reading frame. Changes in the
reading frame resulting in unrelated amino acid
introduction into the protein are termed as frame
shift mutations. Structural variation due to point
mutations can be seen in alpha 1 antitrypsin deciency, while nonsense and frame shift mutations
are evident in factor VIII and IX deciency.
Deletions of genes either partial or complete
will subsequently lead to change in the gene
number which is manifested in thalassemia and
Lesch Nyhan syndrome. Inversions seen in δβ
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S. Patil et al.
thalassemia, initiation and termination codon
mutations in α thalassemia, and RNA processing
mutations are some examples of mutations that
take part in the etiopathogenesis of single gene
disorders [10, 12, 13, 15].
Accumulation of information on the molecular level of these disorders is essential to understand the variation in the penetrance and clinical
phenotypic expression of them. Also, the reection of the expression of these disorders may or
may not be constricted to a particular organ/system of the body but may involve a group of
organs or affect different systems of our body.
Hence, we have tried to list some of the single
gene disorders affecting the various systems of
our body though their expression may be evident
in other systems too (Table7.1). The register of
single gene disorders http://www.ncbi.nlm.nih.
gov/omim continues given the number of genes
and the sequences recorded [22]. However, some
of the disorders with signicant oral manifestations are listed in Table7.2.
7.3 Chromosomal Disorders
Chromosomal disorders are those disorders where
the chromosomes exhibit signicant and evident
changes in them. Each of the 46 chromosomes
houses thousands of genes accommodating information required for the overall growth and development of our body. Any disturbance during the
developmental stages of either the egg or the sperm
formation or even during the fetus formation and
development may lead to chromosomal abnormalities. However, the presentation of the different
effects is dependent on the type of abnormalities.
Therefore, any changes either affecting the number
or structure of the chromosomes may hamper the
normal functioning of the individual [3–7].
7.3.1 Numerical Abnormalities
inChromosomal Disorders
In humans, the somatic nucleated cells are diploid or 2N signifying the presence of 46 chromosomes, in contrast to the haploid/1N nature of the
germ cells with 23 chromosomes. Therefore, any
changes in the number either addition or deletion
manifest as numerical abnormalities in chromosomal disorders. They are listed below:
1. Aneuploidy
When the total number of chromosomes
present is not an exact multiple of the haploid
number, then it is termed as aneuploidy. E.g.,
2N-1(45 chromosomes), 2N+1 (47 chromosomes). Nondisjunction, i.e., failure of normal
separation of the chromosomes during cell
division either during meiosis or mitosis, is
considered as the most common mechanism
responsible for aneuploidy. During mitosis,
nondisjunction leads to two or more cell lines
derived from the same zygote, termed as
mosaicism, commonly observed in cancers.
Anaphase lag is another form of nondisjunction resulting in one normal daughter cell,
while the other is monosomic due to the missing chromosome (Table
2. Polyploidy
When the total number of chromosomes
present is a multiple of the haploid number,
then it is termed as polyploidy. E.g., 3N (69
chromosomes), 4N (92 chromosomes). It is
commonly manifested in dividing cells and
therefore may be the reason for spontaneous
abortions [23].
7.3).
7.3.2 Structural Abnormalities
inChromosomal Disorders
Structural abnormalities are those abnormalities
within the structure of the chromosome as a result
of breakage and incorrect rejoining of its segments. These abnormalities can be either balanced or unbalanced in nature. The presence of
complete chromosomal set despite of rearrangement is termed as balanced while any additions
or missing information is termed as unbalanced
structural rearrangements. These abnormalities
occur during gametogenesis and get transmitted
to all the somatic cells leading to hereditary
transmissible disorders or mutation of somatic
cells (Fig.7.10).
7 The Biological Basis ofChromosomal andSingle Gene Disorders
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Table 7.1 Single gene disorders affecting the various systems of our body
Single gene disorders
System affected Disorder Gene/locus affected
Blood and lymphatic system Sickle cell anemia HBB AR
Hemophilia B F9 XLR
Gaucher disease GBA AR
Hemophilia A F8 XLR
Niemann-Pick disease SPMD1 (type A and
Porphyria HMBS AD
Alpha-thalassemia ATRX XLD
Digestive system Cystic brosis CFTR AR
Diabetes, type II PAX4
Glucose galactose malabsorption SLC5A1 AR
Zellweger syndrome PEX AR
Wilson’s disease ATP7B AR
ENT Deafness POU3F4 XLR
Neurobromatosis NF2 AD
Pendred syndrome SLC26A4 AR
Eye Macular dystrophy, vitelliform 2 BEST 1 AD
Glaucoma MYOC
Retinoblastoma RB1 AD
Gyrate atrophy of the choroid and
retina
Gland and hormones Congenital adrenal hyperplasia CYP21A2 AR
Adrenoleukodystrophy PEX1 AR
Autoimmune polyglandular syndrome AIRE AD, AR
Cockayne syndrome ERCC AR
Diastrophic dysplasia SLC26A2 AR
Multiple endocrine neoplasia MEN1
Heart and blood vessels Ataxia telangiectasia ATM AR
Long QT syndrome KCNQ1
Von Hippel-Lindau syndrome VHL AD
Immune system DiGeorge syndrome TBX1 AD
Familial Mediterranean fever MEFV AR
Immunodeciency with hyper-IgM TNFSF5
Muscle and bone Charcot-Marie-Tooth syndrome PMP22
Myotonic dystrophy DMPK
Marfan syndrome FBN1 AD
Fibrodysplasia ossicans progressiva ACVR1 AD
Achondroplasia FGFR3 AD
Duchenne muscular dystrophy DMD XLR
Amyotrophic lateral sclerosis1 SOD1 AD, AR
B)
NPC1(C1 and D)
AKT
CYP1B1
OAT AR
RET
KCNH2
SCN5A
AICDA
MPZ
CNBP
Pattern of
inheritance
AR
AD
AD
AR
AD
AD
XLR
AR
AD
AD
93
(continued)
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Table 7.1 (continued)
Single gene disorders
System affected Disorder Gene/locus affected
Neonatal disease Angelman syndrome UBE3A AD
Fragile X syndrome FMR1 XLD
Prader-Willi syndrome NDN
Werner syndrome RECQL2 AR
Skin and connective tissue Menkes disease ATP7A XLR
Ellis-van Creveld syndrome EVC AR
Respiratory system Alpha-1-antitrypsin deciency SERPINA1 AR
Nutritional and metabolic
system
Nervous system Alzheimer disease PSEN1 AD
Others Rett syndrome MECP2 XLD
Tay-Sachs disease HEXA AR
Tangier disease ABCA1 AR
Refsum disease PHYH AR
Phenylketonuria PAH AR
Maple syrup urine disease BCKDHA
Hereditary hemochromatosis HFE AR
Lesch Nyhan syndrome HPRT1 XLR
Huntington disease HIT AD
Parkinson disease SNCA
Friedreich’s ataxia FXN AR
Spinal muscular atrophy DYNC1H1 AD
Spinocerebellar ataxia ATXN2 AD
Alport syndrome COL4A4 AR
SNRPN
BCKDHB
DBT
PRKN
Pattern of
inheritance
AD
AR
AD
AR
7.3.2.1 Balanced Rearrangements
Balanced rearrangements may go undetected as
full complement of DNA is still retained and fails
to manifest as a disease. Complete absence or
synthesis of nonfunctional protein due to breakage of chromosome or formation of a hybrid due
to chromosomal segment fusion of two genes
resulting in a new detrimental protein is the possible consequences required for the manifestation
of the disease. Inversion and translocation of
chromosomal regions are the two types of balanced rearrangements. Inversion involves the
breakage of a single chromosome at two points
and usually does not manifest as an abnormality.
On the other hand, translocation literally means
cross-over or exchange of chromosome fragments and is of two types, reciprocal and
Robertsonian translocation. Exchange of genetic
material due to single chromosomal breakage
without the involvement of the centromere is
termed as reciprocal translocation which can
either be balanced or unbalanced in nature.
Philadelphia chromosome, commonly seen in
chronic myeloid leukemia, is a typical example
for balanced type of reciprocal translocation.
Robertsonian translocation occurs due to fusion
manifesting as one large chromosome and other
small one. They express normal phenotype but
are usually accompanied with infertility.
7.3.2.2 Unbalanced Rearrangements
These include deletions, inversions, ring, and iso
chromosome. Loss of genetic material either
from the middle or terminal part of a chromosome is termed as deletion which is commonly
seen in cri du chat syndrome. Rearrangement of a
single chromosome due to breakage at two points
is termed as inversion. Breakage of the terminal
7 The Biological Basis ofChromosomal andSingle Gene Disorders
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Table 7.2 Single gene disorders with oral manifestations
Disorder Gene/locus affected Pattern of inheritance
Amelogenesis imperfecta LAMB3
ENAM
AMELX
Apert syndrome FGFR2 AD
Basal cell nevus syndrome PTCH2 AD
Beckwith Wiedemann syndrome CDKN1C
ICR1
Cleidocranial dysplasia RUNX2 AD
Cowden syndrome PTEN AD
Crouzon syndrome FGFR2 AD
Dentinogenesis imperfecta DSPP AD
Clouston syndrome (ED II) GJB6 AD
Ectodermal dysplasia I EDA XLR
Ehlers-Danlos syndrome COL5A1
COL3A1
Epidermolysis bullosa KRT5
LAMB3
COL7A1
Noonan syndrome PTPN11 AD
Odontohypophosphatasia ALPL AD, AR
Osteogenesis imperfecta COL1A1 AD
Pachyonychia congenita KRT16 AD
Rubinstein-Taybi syndrome CREBBP AD
Stickler syndrome COL2A1 AD
Treacher Collins syndrome TCOF1 AD
Tooth agenesis MSX1 AD
Tuberous sclerosis TSC1 AD
Van der Woude syndrome IRF6 AD
AD
AD
XLD
AD
AD
AD
AD
AD
AR
AD
95
Table 7.3 Aneuploidy numerical abnormalities in chro-
mosomal disorders
Chromosomal
disorders
Downs syndrome Trisomy 21
Mosaic variegated
aneuploidy
Pallister- Killian
syndrome
Klinefelter syndrome Sex chromosome trisomy, 47
Turner’s syndrome Monosomy (45, X0)
Aneuploidy numerical
abnormalities
Predominantly monosomies and
trisomies
Mosaicism for tetrasomy of
chromosome 12p
XXY karyotype
ends of a chromosome with deletion of the fragments that are broken followed by fusion of the
ends is termed as ring chromosome, whose outcome is determined by the amount of genetic
material lost. Transverse division of the centromere along the long axis of the chromosome
results in iso chromosome, seen in few cases of
Turner’s syndrome [23–25].
7.4 Cancer: AGenetic Disease
Cancer, as we all are aware, is a pernicious epidemic and a leading cause of death worldwide.
Irrespective of the vast research in this eld, survival rates remain stunted and unaltered. We can
speculate its complex behavior to be a reason for
the same. Cancer is considered to be a multifactorial disease with combined genetic, metabolic,
and environmental inuences.
7.4.1 Genetic Factors inCancer
Cancer may be due to inherited, somatic, or even
a combination of these mutations. Mankind has
strived to analyze the genetic basis of cancer as it
forms the core for its emergence. To date, nearly
1000 known cancer-associated genes are identied composing of both oncogenes and tumor
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abc
d
S. Patil et al.
Fig. 7.10 Schematic representation of different types of mutations. (a) Duplication, (b) deletion, (c) inversion, (d)
translocation
suppressor genes. Carcinogenesis is thought to be
attained with two or more mutations in the above
genes, which makes us realize that there may be
7.4.2 Other Contributing Factors
inCancer
more than a million cancer genotypes.
Deciphering the cancer genetics, researchers
have identied nearly more than million coding
point mutations and non-coding mutations, more
than ten thousand gene fusions and genome rearrangements, lakhs and millions of abnormal copy
number segments, and varied expressions.
What’s further more interesting is that in a
study by Lee etal., they revealed that nearly 10–50
thousand of different single nucleotide variants in
cancer cells were observed when compared to normal counterparts on whole genome sequencing
[26, 27]. We have tried to list some of the cancers
and their mode of inheritance in Table7.4.
Apart from inheritance of mutated genes, several other factors inuence the microenvironment for the development of cancer. Our
environment and lifestyle contribute tremendously in our well- being. Inuence of habits
such as tobacco, both smokeless and smoking
forms, and alcohol is the major culprits in cancer. Tobacco is known to be associated with carcinoma of lung, mouth, esophagus, and larynx.
It is observed that cytochrome P450 (CYP) gene
polymorphism either alone or in combination of
certain deciencies may predispose a smoker to
cancer [28]. It is an established fact that most of
7 The Biological Basis ofChromosomal andSingle Gene Disorders
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97
Table 7.4 List of cancers with genes affected
Cancer
Lung cancer CYP2A6
MEN IIB RET AD
Thyroid cancer NKX2-1 AD
Colorectal cancer TLR2
Leiomyomatosis and
renal cell cancer
Gardner syndrome APC AD
Basal cell nevus
syndrome
Breast cancer RAD54L
Adrenocortical
carcinoma
Prostate cancer CDH1
Muir-Torre syndrome MSH2
Head and neck
squamous cell
carcinoma
Gastrointestinal stromal
tumor
Cutaneous
telangiectasia and
cancer syndrome,
familial
Palmoplantar
carcinoma, multiple
self-healing
Basal cell carcinoma TP53 AD
Nasopharyngeal
carcinoma
Wilms tumor POU6F2
Pheochromocytoma SDHD
Peutz-Jeghers syndrome STK11 AD
Gene/locus
affected
EGFR
CASP8
PLA2G2A
ODC1
MSH6
CyclinD1
FH AD
PTCH1
PTCH2
CASP8
BARD1
BRCA2
CDH1
TP53 AD
BRCA2
MLH1
TNFRSF10B AR
SDHB
SDHC
KIT
ATR AD
NLRP1 AD
MST1R AD
WT1
BRCA2
KIF1B
SDHB
Pattern of
inheritance
AD
AD
AD
AD
AD
AD
AD
AD
AD
the HPV-associated oral cancer patients with a
habit of chewing tobacco present with p53 alterations such as point mutations, overexpression,
or even degradation [27]. Thence, exposure to
tobacco leads to DNA single-strand breaks,
polymorphisms, genetic mutations, chromosome aberrations, micronuclei, reactive oxygen
species-induced oxidative stress, etc. Further,
literature supports the role of alcohol consumption combined with polymorphism of ADH1B
(alcohol dehydrogenase) and ALDH2 (aldehyde
dehydrogenase) in cancer. Therefore, cancer is
an amalgamation of genetic changes either
inherited or acquired due to the environmental
inuences or a combination of both [29–33].
7.5 Conclusion
The repertoire of chromosomal and single gene
disorders strives upon the importance of assimilation of the biological basis as it is the core for
the recognition and diagnosis and forms the basis
for counselling in these disorders. Having a thorough knowledge of the facts and gures at the
molecular level aids in correlation of the clinical
presentation with that of identication of the disorders; otherwise we might end up looking for a
needle in a haystack.
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Fundamental Mechanisms
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ofOrofacial Clefts
MichaelA.Garland, KurtReynolds,
ShuwenZhang, BoSun, RebeccaDe Frates,
andChengjiJ.Zhou
8
8.1 Introduction
Orofacial cleft (OFC) is a congenital disorder
referring to any cleft involving the mouth and
possibly the nose, face, or combined. It is among
the most common birth defects worldwide,
occurring at an average incidence of 1:700 births
globally with signicant geographical and ethnic
M. A. Garland · S. Zhang · B. Sun
Department of Biochemistry and Molecular
Medicine, University of California at Davis, School
of Medicine, Sacramento, CA, USA
Institute for Pediatric Regenerative Medicine of
Shriners Hospitals for Children, University of
California at Davis, School of Medicine,
Sacramento, CA, USA
magarland@ucdavis.edu
e-mail:
K. Reynolds
Department of Biochemistry and Molecular
Medicine, University of California at Davis, School
of Medicine, Sacramento, CA, USA
Institute for Pediatric Regenerative Medicine of
Shriners Hospitals for Children, University of
California at Davis, School of Medicine,
Sacramento, CA, USA
Biochemistry, Molecular, Cellular, and
Developmental Biology (BMCDB) Graduate Group,
University of California, Davis, CA, USA
e-mail:
ksreynolds@ucdavis.edu
R. De Frates
Department of Biochemistry and Molecular
Medicine, University of California at Davis, School
of Medicine, Sacramento, CA, USA
variance [1]. The high incidence is reective of
the complex and sensitive nature of human craniofacial development through the rst
10–12 weeks of gestation [2]. While OFCs are
associated with several congenital syndromes,
nonsyndromic patients account for approximately 70% of all cases [1]. OFCs may be further
classied into various subtypes including cleft lip
Institute for Pediatric Regenerative
Medicine of Shriners Hospitals for Children,
University of California at Davis,
School of Medicine,
Sacramento, CA, USA
Neuroscience Graduate Program,
University of California,
Davis, CA, USA
C. J. Zhou (*)
Department of Biochemistry and Molecular
Medicine, University of California
at Davis, School of Medicine,
Sacramento, CA, USA
Institute for Pediatric Regenerative
Medicine of Shriners Hospitals for Children,
University of California at Davis,
School of Medicine,
Sacramento, CA, USA
Biochemistry, Molecular, Cellular, and
Developmental Biology (BMCDB)
Graduate Group, University of California,
Davis, CA, USA
Neuroscience Graduate Program,
University of California, Davis, CA, USA
e-mail: cjzhou@ucdavis.edu
© Springer Nature Switzerland AG 2021
U. Meyer (ed.), Fundamentals of Craniofacial Malformations,
https://doi.org/10.1007/978-3-030-46024-2_8
99
100
cd
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a b
M. A. Garland et al.
Fig. 8.1 Pediatric patients with various OFC subtypes.
(a) Cleft lip only (it can be left or right or both sides). (b)
Unilateral cleft lip with cleft palate (it can be left or right).
only (CLO, Fig.8.1a), cleft lip with or without
cleft palate (CL/P, shown with cleft palate,
Fig. 8.1b), bilateral cleft lip and palate (BCLP,
Fig.8.1c), and cleft palate only (CPO, Fig.8.1d).
Some studies may also differentiate between
CL/P and cleft lip with cleft palate (CLP). Others
describe submucous cleft palate (SMCP), a condition where the palatal cleft is obscured by an
intact mucous membrane [4]. Oro-orbital cleft
has been described in the context of parasitic
infection [5]. At present, it is generally accepted
that OFCs can be etiologically stratied into one
of two major subtypes: CL/P or CPO.However,
there is increasing evidence that CLO may have
etiologies that are distinct from CL/P [6].
Orofacial morphogenesis involves tightly regulated cellular processes including cell migration, proliferation, differentiation, transition, and
apoptosis. These processes are reviewed in
(c) Bilateral cleft lip and cleft palate. (d) Cleft palate only.
(From Stoll et al. [3], BMC Medical Genetics.
Copyright@2004, Springer Nature)
greater by Ji etal. [7]. Craniofacial development
begins with the epithelial-mesenchymal transition (EMT) of cranial neural crest cells (CNCCs)
that stream from the cephalic end of the neural
tube into the frontonasal process (FNP) and rst
branchial arch (BA1) [8–10]. CNCCs differentiate into structural craniofacial tissues including
the bone, cartilage, and connective tissues [7,
11]. While the mandibular structures are derived
from the posterior portion of BA1, the maxillary
structures develop from the anterior portion of
BA1. The two major developmental processes
implicated in OFCs include midfacial morphogenesis, involving upper lip and primary palate
development, and palatogenesis, which involves
development of the secondary palate [7].
Despite some differences between species, the
cellular and molecular mechanisms underlying
these processes are generally conserved between
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