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U. Meyer
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6.8 Proposed New Classication
System
Important in craniofacial malformation classication is the underlying genetic state, the embryologic disease pattern, and the clinical outcome
in respect to the resulting phenotype.
The proposed classication system is based on
a comprehensive three-axis genetic, pathogenetic,
and phenotype stratication approach (Fig.6.13).
It is elaborated (1) on the developmental steps
during embryogenesis and (2) the underlying
genetic disturbance and (3) the resulting phenotype. This primary classication (x-axis) system
used in this book (Fig. 6.14) is based on the
embryologic pathogenesis graduation as a leading
and iterative arrangement. Figure 6.15 displays
examples of the recently known genetic-clinical
correlation of the diseases entities. As the book
series Fundamentals of Craniofacial
Malformations is conceptualized for basic
researchers as well as for surgeons, all medical
disciplines are incorporated in the stratication.
approach as used in this book is often used in
medicine. The phrase “axis of classication”
means a way of classifying and studying diseases. When utilizing an axis of classication for
morbid conditions, diseases are assigned to a system of categories based on established criteria.
Such criteria may be based on the affected part of
the body (anatomy/phenotype), the nature of a
disease process (pathophysiology, embryology),
or genetic etiology. The ICD 10-CM is a typical
example of an axis-related system of classication (Fig.6.16). Anatomy, for example, is the primary axis of classication of ICD-10-CM, as it
was in ICD-9-CM.This is evident by the fact that
most of the ICD-10-CM chapter titles reect diseases of a particular body system, such as
“Diseases of the Respiratory System,” “Diseases
of the Nervous System,” etc. ICD-10-CM
employs many other axes as well, such as etiology, as found in Chap. 1 (“Certain Infectious and
Parasitic Diseases”). A combination of multiple
and diverse axes are used in classifying some dis-
A stratied (axis related) classication
z - phenotype
severe
moderate
mild
A facial duplication
fferentiation
formation/migration
B craniosynostosis
C branchial arch diseases
D cleft lip palate
E environmental diseases
x –clinicalpathology
Fig. 6.13 Proposed three-axis classication scheme
F various
III GWAS
II definedgenes
I chromosomes
VI epigenetics
V WES
IV GWLS
y- genetics
VII environmental/comple
chromosomal disorder
9 MONTHS8 MONTHS7 MONTHS6 MONTHS5 MONTHS4 MONTHS3 MONTHS2 MONTHS1 MONTHS
Catel-Manzke syn.
COF1 (AD, AR possible)
6 Classication ofCraniofacial Malformations
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81
facial duplication
craniosynostosis
branchial arch diseases
clefts
postural head deformations
others
I TRIMESTER II TRIMESTER III TRIMESTER
Fig. 6.14 Embryonic-pathogenetic classication model, used as a primary axis in this book. Source: Reprinted from
Shanvood/Shutterstock.com with permission
Pathology
A conjoined tissues
B craniosynostosis
D branchial arch dis.
E clefts
G various/complex
Fig. 6.15 Examples of chromosome and gene alteration-based craniofacial malformation The displayed list represents
only a part of known genetic-disease relationships. AD autosomal dominant, AR autosomal recessive
eases within the same chapter. When designing a
disease classication system, the primary axis
reects the most important statistical and clinical
aspects of the disease. For example, for a diagnosis of heart failure, the rst axis of classication
is “type,” and the second is “acuity.” It is the vari-
Disease
Facial duplication
Conjoined twins
ERF, TCF-12, ZIC-1 related craniosynostosis
Apert Syndrome
Crouzon syndrome
Pfeiffer Syndrome
Treacher-Collins-syndr.
MFD with alopecia
AFD Cincinatti type
RCPS
Burn- MC Keown syn.
Cerebrocostmandibular syn.
MFD Guion Almeida
Nager
Miller
van der Woude 2
Acromelic frontonasal dysostosis
OpitzG/BBB
Trisomie 21
Cri-du-chat
ACS;IQME
ation and combination of these axes of classication that contribute to the tremendous increase in
the number of codes available for assignment in
ICD-10-CM as compared to ICD-9-CM.
Large-scale studies are now needed to iden-
tify the 3D correlations between genetic
Chromo
somes
Chr.21
Chr. 5
Genetics
ERF, TCF12, ZIC1 (AD)
FGFR2
FGFR2
T
EDNRA (AD) alopecia
POLR1A (AD) cincinatti
EIF4A3 (AR) rcps
TXNL4A (AR) bmc
SNRPB (AD) cerebo
EFTUD2
SF3B4 (AD, AR, spor.)
DHODH (AR)
GRHL3 (AD)
ZSWIM6 (AD)
SPECC1L (AD)
defined genes
82
• Etiology
•
•
•
•
•
•
•
, depending
•
• Number of fetus (i.e. 1-5, other.)
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U. Meyer
Manifestation or complication
Specificity of anatomical site
Chronicity (i.e. acute, subacute, chronic, unspecified
vs.acute/subacute, chronic, unspecified, etc.)
Degree (i.e., mild, moderate, severe, unspecified vs
total/complete, partial/incomplete, etc.)
Type (i.e., primary, secondary, unspecified, etc.)
Laterality (i.e., R/L/unspecified or R/L/bilateral/
unspecified)
Episode of care (3-16 "extension" options
on code category)
Tr imester (i.e., 1, 2, 3,unspecified, etc.)
Fig. 6.16 Axis (parameter) system of classication in the
ICD10 stratication
inuences, embryologic development, and the
resulting phenotype. This is an inherent problem
in seldom diseases like craniofacial malformations. One way to improve in future the approach
to develop a modern classication system and to
integrate such systems into a broader framework
of craniofacial data, a specic ontology—the
Ontology of Craniofacial Development and
Malformation (OCDM)—was developed as part
of a NIDCR- funded research network, FaceBase
(https://www.facebase.org). The purpose of
FaceBase is to provide diverse but standardized
data to the craniofacial community and to facilitate collaboration among investigators to
advance craniofacial research. The goal of the
OCDM is to provide a unifying framework to
represent and standardize the set of terms and
relationships used to capture different forms of
craniofacial data, including clinical data, within
FaceBase and integrate data types to maximize
their utility and accessibility [34]. This way of
information technology has a great promise for
future classication systems. The sheer volume
of data collected in analyzing genetics, in documentation of phenotypes from 3D scans and
omics data sets, generates massive and complex
data sets. The size and heterogeneity of such
data sets do not only pose new challenges to efciently and effectively store data, but it is challenging to develop new algorithms to gain insight
into the cause-and-effect correlations between
genetics, embryological pathogenetics, and disease extent (phenotypic outcome).
It still remains in the future to develop an allencompassing classication that will clarify (and
include a correlation strength determination)
the complex genetically driven morphopathogenesis of the resulting craniofacial malformation phenotype. By incorporation of limitations
and challenges associated with using disparate
classications systems, it is hoped that future
approaches will promote more discussion and
cooperation in standardizing the classication of
craniofacial malformations.
References
1. Wang K, Gaitsch H, Poon H, Cox NJ, Rzhetsky
A.Classication of common human diseases derived
from shared genetic and environmental determinants.
Nat Genet. 2017;49(9):1319–25.
2. Kendler KS. The nature of psychiatric disorders.
World Psychiatry. 2016;15:5–12.
3. Endlicher S. In: Beck F, editor. Genera plantarum
secundum ordines naturales disposita. 1836.
4. Jussieu ALD, Staeu FA.In: Cramer J, editor. Genera
plantarum. Stechert-Hafner Service Agency; 1964.
5. Linne CV, etal. The families of plants: with their nat-
ural characters, according to the number, gure, situation, and proportion of all of the parts of fructication.
1787. Printed by John Jackson, sold by J.Johnson …
T.Byrne … and J.Balfour.
6. Thunberg KP, et al. Nova genera plantarum. apud
J.Edman etc; 1781.
7. Council National Research Committee Framework
Developing New Taxonomy and Disease, editor.
Toward precision medicine: building a knowledge
network for biomedical research and a new taxonomy
of disease. Washington, DC: The National Academies
Press; 2011.
8. Felsenstein J. Inferring phylogenies. Sunderland:
Sinauer Associates; 2004.
9. Bianchini G, Balko JM, Mayer IA, Sanders ME,
Gianni L. Triple-negative breast cancer: challenges
and opportunities of a heterogeneous disease. Nat Rev
Clin Oncol. 2016;13:674–90.
10. McClellan J, King MC. Genetic heterogeneity in
human disease. Cell. 2010;141:210–7.
11. Arostegui I, Esteban C, Garcia-Gutierrez S, Bare
M, Fernandez-de-Larrea N, Briones E, Quintana
JM.Subtypes of patients experiencing exacerbations
of COPD and associations with outcomes. PLoS One.
2014;9:e98580.
12. Jeste S, Geschwind DH. Disentangling the hetero-
geneity of autism spectrum disorder through genetic
ndings. Nat Rev Neurol. 2014;10:74–81.
13. Mannino DM. COPD: epidemiology, prevalence,
morbidity and mortality, and disease heterogeneity.
Chest. 2002;121:121S–6S.
6 Classication ofCraniofacial Malformations
https://t.me/medicina_free
83
14. Mirnezami R, Nicholson J, Darzi A. Preparing for
precision medicine. N Engl J Med. 2012;366:489–91.
15. Barabasi AL, Gulbahce N, Loscalzo J.Network medicine: a network-based approach to human disease.
Nat Rev Genet. 2011;12:56–68.
16. Zanzoni A, Soler-Lopez M, Aloy PA. Network
medicine approach to human disease. FEBS Lett.
2009;583:1759–65.
17. Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller
JW.Pleiotropy in complex traits: challenges and strategies. Nat Rev Genet. 2013;14:483–95.
18. Zhou Y, Jun Liu LL, Halu A, Zhang Y, Li B, Guo
Z, Liu G, Sun C, Loscalzo J, Sharma A, Wang Z.A
systems approach to rene disease taxonomy by
integrating phenotypic and molecular networks.
EBioMedicine. 2018;31:79–91.
19. Menche J, Sharma A, Kitsak M, Ghiassian SD, Vidal
M, Loscalzo J, Barabasi AL. Disease networks.
Uncovering disease-disease relationships through the
incomplete interactome. Science. 2015;347:1257601.
20. Hofmann-Apitius M, Alarcon-Riquelme ME,
Chamberlain C, McHale D.Towards the taxonomy of
human disease. Nat Rev Drug Discov. 2015;14:75–6.
21. Jameson JL, Longo DL.Precision medicine—personalized, problematic, and promising. N Engl J Med.
2015;372:2229–34.
22. Richmond S, Howe LJ, Lewis S, Stergiakouli E,
Zhurov A. Facial genetics: a brief overview. Front
Genet. 2018;9:462.
23. Marcucio R, Hallgrimsson B, Young NM. Facial
morphogenesis: physical and molecular interactions
between the brain and the face. Curr Top Dev Biol.
2015;115:299–320.
24. O’Rahilly R.Guide to the staging of human embryos.
Anat Anz. 1972;130:556–9.
25. Danescu A, Mattson M, Dool C, Diewert VM,
Richman JM.Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion.
J Anat. 2015;227:474–86.
26. Barlow AJ, Bogardi JP, Ladher R, Francis-West
PH. Expression of chick Barx-1 and its differential
regulation by FGF-8 and BMP signaling in the maxillary primordia. Dev Dyn. 1999;214:291–302.
27. Hu D, Helms JA. The role of sonic hedgehog in
normal and abnormal craniofacial morphogenesis.
Development. 1999;126:4873–84.
28. Lee SH, Fu KK, Hui JN, Richman JM.Noggin and
retinoic acid transform the identity of avian facial
prominences. Nature. 2001;414:909–12. https://doi.
org/10.1038/414909a.
29. Everson JL, Fink DM, Chung HM, Sun MR, Lipinski
RJ.Identication of sonic hedgehog-regulated genes
and biological processes in the cranial neural crest
mesenchyme by comparative transcriptomics. BMC
Genomics. 2018;19(1):497.
30. Mossey PA, Little J, Munger RG, Dixon MJ, Shaw
WC.Cleft lip and palate. Lancet. 2009;374:1773–85.
31. Parsons TE, Downey CM, Jirik FR, Hallgrimsson B,
Jamniczky HA.Mind the gap: genetic manipulation
of basicranial growth within synchondroses modu-
lates calvarial and facial shape in mice through epigenetic interactions. PLoS One. 2015;10:e0118355.
32. Ashique AM, Fu K, Richman JM.Endogenous bone
morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion. Development.
2002;129:4647–60.
33. Boehringer S, Van Der Lijn F, Liu F, Günther M,
Sinigerova S, Nowak S, et al. Genetic determination of human facial morphology: links between
cleft-lips and normal variation. Eur J Hum Genet.
2011;19:1192.
34. Brinkley JF, Fisher S, Harris MP, Holmes G, Hooper
JE, Jabs EW, etal. The FaceBase consortium: a comprehensive resource for craniofacial researchers.
Development. 2016;143:2677–88.
35. Visscher PM, Hill WG, Wray NR.Heritability in the
genomics era–concepts and misconceptions. Nat Rev
Genet. 2008;9:255–66.
36. Jelenkovic A, Ortega-Alonso A, Rose RJ, Kaprio
J, Rebato E, Silventoinen K. Genetic and environmental inuences on growth from late childhood to
adulthood: a longitudinal study of two Finnish twin
cohorts. Am J Hum Biol. 2011;23:764–73.
37. Twigg SR, Wilkie AO. New insights into craniofacial malformations. Hum Mol Genet.
2015;24(R1):R50–9.
38. Som PM, Naidich TP.Illustrated review of the embryology and development of the facial region, part 1:
early face and lateral nasal cavities. AJNR Am J
Neuroradiol. 2013;34:2233–40.
39. Som PM, Naidich TP.Illustrated review of the embryology and development of the facial region, part 2:
late development of the fetal face and changes in the
face from the newborn to adulthood. AJNR Am J
Neuroradiol. 2014;35:10–8.
40. Ahmed MK, Ye X, Taub PJ. Review of the genetic
basis of jaw malformations. J Pediatr Genet.
2016;5(4):209–19.
41. Dixon J, Jones NC, Sandell LL, etal. Tcof1/Treacle is
required for neural crest cell formation and proliferation deciencies that cause craniofacial abnormalities.
Proc Natl Acad Sci U S A. 2006;103(36):13403–8.
42. Morriss-Kay GM, Wilkie AO. Growth of the normal skull vault and its alteration in craniosynostosis:
insights from human genetics and experimental studies. J Anat. 2005;207(5):637–53.
43. Stephan C, Norris R, Henneberg M. Does sexual
dimorphism in facial soft tissue depths justify sex distinction in craniofacial identication? J Forensic Sci.
2005;50:513–08.
44. Wilkinson C, Rynn C, Peters H, Taister M, Kau
CH, Richmond S. A blind accuracy assessment of
computer-modeled forensic facial reconstruction
using computed tomography data from live subjects.
Forensic Sci Med Pathol. 2006;2:179–87.
45. Shrimpton S, Daniels K, de Greef S, Tilotta F, Willems
G, Vandermeulen D, etal. A spatially-dense regression study of facial form and tissue depth: towards
an interactive tool for craniofacial reconstruction.
Forensic Sci Int. 2014;234:103–10.
84
https://t.me/medicina_free
U. Meyer
46. De Greef S, Claes P, Vandermeulen D, Mollemans W,
Suetens P, Willems G.Large-scale in-vivo Caucasian
facial soft tissue thickness database for craniofacial
reconstruction. Forensic Sci Int. 2006;159(Suppl.
1):S126–46.
47. Al Ali A, Richmond S, Popat H, Toma AM, Playle
R, Pickles T, et al. A three-dimensional analysis
of the effect of atopy on face shape. Eur J Orthod.
2014;36:506–11.
48. Kovacs L, Eder M, Hollweck R, Zimmermann
A, Settles M, Schneider A, et al. Comparison
between breast volume measurement using 3D
surface imaging and classical techniques. Breast.
2007;16:137–45.
49. Kuijpers MA, Chiu YT, Nada RM, Carels CE, Fudalej
PS.Three-dimensional imaging methods for quantitative analysis of facial soft tissues and skeletal morphology in patients with orofacial clefts: a systematic
review. PLoS One. 2014;9:e93442. 10.1371
50. Tzou CH, Artner NM, Pona I, Hold A, Placheta
E, Kropatsch WG, et al. Comparison of threedimensional surface-imaging systems. J Plast
Reconstr Aesthet Surg. 2014;67:489–97.
51. Kerkfeld V, Meyer U.Higher resolution in cone beam
computed tomography is accompanied by improved
bone detection in peri-implant bone despite metal
artifact presence. Int J Oral Maxillofac Implants.
2018;33(6):1331–8.
52. Liu F, Van Der Lijn F, Schurmann C, Zhu G,
Chakravarty MM, Hysi PG, et al. A genome-wide
association study identies ve loci inuencing facial morphology in Europeans. PLoS Genet.
2012;8:e1002932. 10.1371.
53. Kau CH, Richmond S, Zhurov AI, Knox J, Chestnutt
I, Hartles F, etal. Reliability of measuring facial morphology with a 3-dimensional laser scanning system.
Am J Orthod Dentofacial Orthop. 2005;128:424–30.
54. Leslie EJ, Marazita ML. Genetics of cleft lip and
cleft palate. Am J Med Genet C Semin Med Genet.
2013;163:246–58.
55. Craig R, Dufresne MD. Classication of craniofacial malformations chapter. 2012. https://doi.
org/10.1007/978- 1- 4614- 0971- 7_65. https://www.
researchgate.net/publication/300508100
56. Ornoy A.Craniofacial malformations and their association with brain development: the importance of a
multidisciplinary approach for treatment. Odontology.
2020;108(1):1–15.
57. Bartzela TN, Carels C, Maltha JC.Update on 13 syndromes affecting craniofacial and dental structures.
Front Physiol. 2017;8:1038. https://doi.org/10.3389.
58. Sanvenero-Rosselli G. Developmental pathology of
the face and the dysraphia syndromes—an essay of
interpretation based on experimentally produced congenital defects. Plast Reconstr Surg. 1953;11:36.
59. Burian F.Median clefts of the nose. Acta Chir Plast.
1960;2:180.
60. Tessier P, et al. A new anatomical classication of
facial clefts craniofacial and latero-lateral clefts and
their distribution around the orbit. In: Plastic surgery
of the orbit and eyelids. NewYork: Masson; 1981.
61. Tessier P. Anatomical classication of facial, craniofacial and laterofacial clefts. J Maxillofac Surg.
1976;4:69.
62. Van der Meulen JC, etal. A morphogenetic classication of craniofacial malformations. Plast Reconstr
Surg. 1983;71:560.
63. Allanson JE, Biesecker LG, Carey JC, Hennekam
RC. Elements of morphology: introduction. Am J
Med Genet A. 2009;149A:2–5.
64. Carey JC, Allanson JE, Hennekam RC, Biesecker
LG. Standard terminology for phenotypic variations: the elements of morphology project, its current progress, and future directions. Hum Mutat.
2012;33:781–6.
65. Cox TC, Luquetti DV, Cunningham ML.Perspectives
and challenges in advancing research into craniofacial
anomalies. Am J Med Genet C Semin Med Genet.
2013;163:213–7.
66. Koul R. Describing cleft lip and palate using a
new expression system. Cleft Palate Craniofac J.
2007;44:585–9.
67. Long RE Jr, Hathaway R, Daskalogiannakis J,
Mercado A, Russell K, Cohen M, etal. The Americleft
study: an inter-center study of treatment outcomes
for patients with unilateral cleft lip and palate part 1.
Principles and study design. Cleft Palate Craniofac J.
2011;48:239–43.
Part II
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Biological Basis of Disease
Highlighted by an extraordinary and complex review on the biology of
orofacial clefts by Dr. Chengji Zhou and colleagues.
The Biological Basis
https://t.me/medicina_free
ofChromosomal andSingle Gene
Disorders
ShankargoudaPatil, G.S.Vidya,
andKhaledM.Alqahtani
7
7.1 DNA
DNA is a hereditary component of living organisms including humans. It is primarily located in
the nucleus of a cell called the nuclear DNA,
while a small portion of it may be present within
the mitochondria referred to as the mitochondrial
DNA.DNA stores its information in the form of
a code comprising of four chemical bases,
namely, adenine “A,” cytosine “C,” guanine “G,”
and thymine “T.” The order or the sequence in
which these bases pair up with each other forms
the crux for the formation, development, and
functioning of an organism. In humans, roughly
about 3 billion bases take part in the creation of
the double helix DNA structure [1–3] (Fig.7.1).
S. Patil (*)
Division Of Oral Pathology, Department of
Maxillofacial Surgery and Diagnostic Sciences,
College of Dentistry, Jazan University,
Jizan, Saudi Arabia
e-mail: spatil@jazanu.edu.sa
G. S. Vidya
Chief Consulting Surgeon, Sreee NRJV Specialists
Dental Clinic, Bangalore, India
K. M. Alqahtani
Department of Mathematics, College of Sciences and
Humanities Slayel-Prince Sattam Bin Abdulaziz
University, Riyadh, Saudi Arabia
e-mail: K.alqahtani@psau.edu.sa
7.1.1 What Are Chromosomes?
Chromosomes are thread-like structures present
within the nucleus of a cell. The tightly coiled
DNA around the histone proteins forms the
framework of a chromosome and stores the
genetic information or code. In total, 23 pairs,
i.e., 46 chromosomes, comprise the total DNA
framework of a cell. Out of these, 22 pairs are
autosomes, while 1 pair, i.e., X and Y, is the allosomes or sex chromosomes [4–6] (Fig.7.2).
7.1.2 Then What Are Genes? Where
Are They Located?
The basic physical and functional unit of hereditary is a gene. It is a DNA segment where the
nucleotides are arranged in a specic sequence.
Depending on the number of bases, a gene may
vary in size. Their main functions are (1) to code
protein and (2) to control the transmission and
Fig. 7.1 Schematic representation of double helix struc-
ture of DNA
© Springer Nature Switzerland AG 2021
U. Meyer (ed.), Fundamentals of Craniofacial Malformations,
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S. Patil et al.
expression of the trait also depends on other factors such as the penetrance (frequency of expression of the trait in an individual) and expressivity
(amount large enough of the trait to be expressed
in an individual) [
3, 6].
7.2.1 Derivation ofFundamental
Laws ofInheritance
Fig. 7.2 Schematic representation of a chromosome
present with the nucleus of a cell
Gene
Fig. 7.3 Schematic representation of a gene
expression of the traits procured through hereditary [6, 7] (Fig.7.3).
7.2 Alleles
Variant form of a gene is called an allele. Diploid
organisms, like humans, have two alleles, each
inherited from both the parents individually.
These alleles are responsible for the phenotype
(outward appearance) of an organism. The genotype of a particular gene is represented by each
pair of alleles. If the two alleles are identical at
a specic locus, then the genotype is homozygous, and if they differ, then they are heterozygous in nature. Further, alleles can be either
dominant or recessive in expression of the trait.
In heterozygous genotype with one allele dominant and another recessive, the dominant phenotype is expressed. However, the phenotypic
Based on the general information acquired, it can
be summarized that the specic sequence of
arrangement of the nucleotides forms our genetic
makeup which is unique to each and every individual. This is the reason why we appear different from each other. Such observations and
curiosity drive the quest for better perception of
oneself and our surroundings.
This was what drew Gregor Johann Mendel,
a scientist and an abbot, to conduct a series of
experiments on pea plants and put forth the rules
of inheritance which not only gained him recognition but also earned him the title of “Father of
Modern Genetics.” Mendel’s laws of inheritance
have not only answered the questions on expression and transmission of the inherited traits but
also aided in the recognition of genetic disorders and the emergence and ourishment of
geneticists [8, 9].
Inference drawn through his experiments provided answers to most of the abstract content
around us. The very actuality of genes, presence
of genes in pairs, existence of alleles, and gametic
content are some of the observations protracted
from his experiments. Further, he was able to
deduce that the expression of the trait depends on
the presence of an allele of either recessive/dominant phenotype.
The fundamental laws of inheritance can be
broadly encapsulated as:
1. Law of segregation
2. Law of independent assortment
3. Law of dominance
These laws laid the very foundation of fulledged research in the eld of genetics in mankind. Sequencing of human genome has not only
7 The Biological Basis ofChromosomal andSingle Gene Disorders
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89
provided us information on our genetic heritage
but also helped us to understand the pattern of
inheritance accompanied by unraveling the complex network of genetic events that contributes to
a disease [3, 8, 9].
7.2.2 What Are Genetic Disorders?
In general, diseases which are a result of change
in part or whole of the normal sequence of DNA
are referred to as genetic disorders. Therefore,
the mutations of a gene, i.e., any permanent alteration of the normal sequence of the DNA, e.g.,
thalassemia, either through inherited or environmental factors and even a combination of both
are considered to be the prime culprits of genetic
disorders [8, 9].
The ideology of classifying the genetic disorders is primarily dependent on the parameters
such as the genes and the genetic-environmental
interactions. Therefore, it is more of a genecentric and factor-centric classication. These
genetic disorders can be broadly classied into:
1. Single gene disorders
2. Chromosomal disorders
3. Multifactorial genetic disorders
Mitochondrial DNA present within the mitochondria of a cell can undergo mutations too,
hence termed as mitochondrial disorders which
also can be included under genetic disorders.
The estimated frequency of the genetic disorders in humans is 670 per 1000 which is quite a
signicant number of cases. Hence, the biological basis of these disorders forms the crucial link
to understand their modes of inheritance, their
penetrance, and expressivity of the inherited
traits [10–13].
ciples. Therefore, they are also referred to as
Mendelian disorders/diseases [
In general, we do come across numerous cases
of complex disorders, for example, type II diabetes,
which are more common and lifestyle oriented and
their onset is manifested later in life. On the other
hand, these single gene disorders are denitely not
rare and are far more numerous than we generally
assume. In contrast to the complex disorders, they
manifest early in life, may present with severe conditions, and require support and care throughout
life. Moreover, recent molecular studies have also
provided evidence suggesting that these single gene
disorders may also play a vital role in the etiopathogenesis of several complex/multifactorial disorders.
Responsibility lies with us to have a thorough
knowledge on the biological assembly of genes and
their mutations to delineate its recognition and
molecular makeup to aid in the early diagnosis,
screening, and necessary counselling for the wellbeing of mankind [
14–20].
3, 8].
7.2.4 Mode ofInheritance inSingle
Gene Disorder
Determining the probabilities of trait recurrence in
the successive generation establishes the pattern of
inheritance. In these disorders it is based on the
Mendel’s principles. More than one version of
genes exists either due to mutations or polymorphism which are termed as alleles. The inheritance
of the single gene disorders is either based on the
location of the gene or depends on the number of
copies of the genes required to express the phenotypic features of the disorder. Having said that,
mutated allele expression in relation to the normal
allele may either be dominant, recessive, or even
co-dominant in nature [3, 10, 15]. Based on these
features, the pattern of inheritance for the single
gene disorders can be broadly listed as:
7.2.3 Single Gene Disorders
Single gene disorders are those disorders where
the change in the sequence of the DNA is known
to occur in a single gene. The inheritance pattern
of these disorders is based on the Mendel’s prin-
1. Autosomal dominant inheritance
Dominant genotypic inheritance is present
in a heterozygous individual where a single
copy of mutant allele sufces for the manifestation of the disease. Presents with vertical
mode of transmission, affecting both the gen-
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S. Patil et al.
ders equally. 50% risk of transmitting the
mutant allele lies with the affected individual.
E.g., achondroplasia (Fig.7.4)
2. Autosomal recessive inheritance
Recessive genotypic inheritance is seen in
homozygous individual requiring two copies of
mutant allele for the expression of the disease.
Only one mutant allele leads to the failure of
expression of the disease with the individual
being a carrier. In case both the individuals are
carries, the resultant offspring will have a 25%
chance of inheritance and expression of the disease. E.g., cystic brosis (Fig.7.5)
3. X-linked dominant inheritance
In this mode of inheritance, the sex chro-
mosome/allosomes are involved. X chromo-
some houses the mutant allele where even a
single copy is responsible for the expression
of the disease. The features are similar to the
autosomal pattern of inheritance. However,
the mutant allele will be transmitted to
female offspring but not to the male offspring
of the affected male. E.g., α-thalassemia
(Fig.7.6)
4. X-linked recessive inheritance
Males are predominantly affected due to
their hemizygyous state for most of the genes
on X chromosome. In this mode of inheritance, the resultant male offspring will have
50% chance of inheritance of the disease,
while female progeny will become a carrier.
E.g., hemophilia (Fig.7.7)
XY
XY
xX
Xx
xY
XX
Fig. 7.4 Autosomal dominant mode of inheritance.
Possible progeny of affected father with a dominant
mutant gene and unaffected mother would either be an
affected male or female offspring possessing one dominant mutant gene and normal gene or unaffected male and
female offspring with normal genes. (Purple indicates
dominant mutant gene; green indicates normal gene)
Fig. 7.5 Autosomal recessive mode of inheritance.
Possible progeny of carrier father and carrier mother each
with one recessive mutant gene and a normal gene would
either be an affected female offspring possessing both the
recessive mutant gene or unaffected male with normal
genes or carrier female/male possessing one recessive and
one normal gene. (Purple indicates recessive mutant gene;
green indicates normal gene)
Fig. 7.6 X-linked dominant mode of inheritance.
Possible progeny of unaffected father and affected mother
with a dominant mutant gene would either be an affected
female or male offspring possessing dominant mutant
gene and normal gene or unaffected male or female possessing normal gene. (Purple indicates dominant mutant
gene; green indicates normal gene)
XY
XY
Fig. 7.7 X-linked recessive mode of inheritance. Possible
progeny of unaffected father and carrier mother with a
recessive mutant gene would either be an affected male
offspring possessing recessive mutant gene and normal
gene or unaffected male or female with normal genes or
carrier female with one recessive mutant gene and a normal gene. (Purple indicates recessive mutant gene; green
indicates normal gene)
XX
Xx
xY
Xx
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