genetics in orthodontics

2. BY:
Kumar Adarsh

4. • In 1953 Watson & Crick
published a paper in
Nature which suggested
the structure of DNA.
This paper which first
put forth the correct
structure of DNA is a
milestone in modern era
of molecular genetics

5. Genome
Genes
Genotype
Phenotype
Trait
Monogenic/mandelian trait
Allele
Homozygous
Heterozygous
 Online Mendelian Inheritance in Man
(OMIM)
 McKusick-Nathans Institute for Genetic
Medicine
 Johns Hopkins University [Baltimore, MD]
 National Center for Biotechnology
Information
 National Library of Medicine [Bethesda])
 www.ncbi.nlm.nih.gov/sites/entrez?db=o
mim.

6. AUTOSOMAL DOMINANT
Dentinogenesis imperfecta,
neurofibromatosis type 1
•Expressed in heterozygote
•Half of offsprings affected
•Equal frequency n severity
in both sexes
•Variable expressivity
AUTOSOMAL INHERITANCE
Genes occupy specific locus
Autosomal genes are in pairs

7. • The trait occurs in successive generations; that is, it shows
vertical inheritance
• On the average, 50% of the offspring of each parent who has the
trait also will have the trait
• If an individual has the gene that results in the trait, each child
has a 50% chance of inheriting the gene that leads to the
expression of the trait
• Males and females are equally likely to have the trait
• Parents who do not have the trait have offspring who do not
have the trait.

8. • The trait is present or not (nonpenetrant) in an individual.
• If some of the individuals do not manifest the trait in a sample of
individuals with the trait-associated genotype, then the trait is
said to have a penetrance of whatever percentage of the trait-
associated genotype that the group actually manifests.
• This is a situation most commonly seen with dominant traits.
• Other exceptions are
(1) a new mutation occurred in the sperm or egg that formed the
offspring and
(2) germinal mosaicism occurred, in which case one of the parents
is mosaic in the germ cell line and the sperm or eggs are of two
types—one cell line with and one cell line without the mutation.

9. Variable
Expressivity
• Penetrance
• Pleiotropic effect
• Osteogenesis imperfecta involving type I collagen
abnormalities

10. AUTOSOMAL RECESSIVE
cystic fibrosis,
sickle cell anemia
Pigmented hypomaturation
of enamel
•Expressed in homozygote
(Schull and Neel )
•Equal frequency n severity
in both sexes
•Constant expressivity in the
family
•Importance of consanguinity
•Transmission of the phenotype
in a pedigree is horizontal
(typically present only in siblings)
and not vertical, as with a
dominant trait

11. SEX LINKED INHERITANCE
hemophilia,
Hypomaturation of enamel
• almost completely restricted
to males
• X-LINKED or Y-LINKED
•QUEEN VICTORIA

12. X-inactivation (also called lyonization)
• A process by which one of the copies of the X
chromosome present in female mammals is inactivated.
• The inactive X chromosome is silenced by its being packaged
in such a way that it has a transcriptionally inactive structure
called heterochromatin.
• As nearly all female mammals have two X chromosomes, X-
inactivation prevents them from having twice as many X
chromosome gene products as males, who only possess a
single copy of the X chromosome.
• The choice of which X chromosome will be inactivated is
random, but once an X chromosome is inactivated it will
remain inactive throughout the lifetime of the cell and its
descendants in the organism.

13. Barr bodies
• DNA packaged in heterochromatin, such as the Xi,
is more condensed than DNA packaged
in euchromatin, such as the Xa.
• The inactive X forms a discrete body within the
nucleus called a Barr body.
• The Barr body is generally located on the periphery
of the nucleus, is late replicating within the cell
cycle, and, as it contains the Xi, contains
heterochromatin modifications and the Xist RNA.

15. first suggested by Galton
form a unique tool to evaluate the interactions
between "nature" and nurture."
• Concordant twins:
• If both show a trait
• Discordant twins:
• If only one shows the trait

16. TwinStudyModels
Monozygotic Co-twin Design
Twins Reared Apart
Opposite Sexed Dizygotic Twins
The Twin Half Sib Model
Mirror Imaging

17. WILSON According to study conducted by Wilson 20-25% of congenital defects in man is genetics the known casual
factors.
-5-10% is attributed to environmental factors such as injuries, drugs, radiation.
- 65 - 70% of the cases can be classified as unknown cause.
Lauweryns et al summarizing a number of research investigations of this type, concluded that about 40% of dental and facial
variations that lead to malocclusion can be attributed to hereditary factors.
Corrucini and
coworkers
argue that with appropriate corrections for unsuspected environmental differences within twin pairs, the
heritability for some dental characteristics such as overjet is almost zero.
Harris and Johnson concluded that the heritability of craniofacial (skeletal) characteristics was relatively high, but that of dental
(occlusal) characteristics was low.
For skeletal characteristics, the heritability estimates increased with increasing age; for dental characteristics, the
heritability estimates decreased, indicating an increasing environmental contribution to the dental variation
TWAGAKI According to Twagaki (1938) mandibular prognathism is heredity related , he collected more
than 2,000 family histories councelling mandibular prognathism.
DOBZHANSKY Dobzhansky (1954) found that growth pattern possesses genetically determined plasticity
which makes it possible for environmental conditions to influence it therefore orthodontists
should not hesitate in their attempt to change or forstall abnormalities of genetic origin in the
dentofacial area.
MONTAGN Montagn (1963) calls attention to the fact that since the expression of heredity is the function
of the environment, it is to a certain extent subject to human control, we can influence the
development of hereditary characteristics by changing the environment of a person.
NEEL According to Neel , genetic factors are entirely or largely responsible for not more than 20%
of all malformation .
Chromosomal defects account for 10% and virus infection for another 10%.
This leaves 60% of the defects that can be attributed to environmental causes.
BACHRACH AND
YOUNG
Bachrach and Young noted that coincidence of type of occlusion was greater in identical than
in fraternal twins of the some sex.
BRODIE According to Brodie's concepts that the development of the dentition is based on a congenital
pattern. Growth patterns are considered to be hereditary.
CURTNER Curtner superimposed head films of related persons to show similarities and concluded that it
seemed possible to predetermine the adult face in most children by the superimposition of
their head films upon those of their parents.
JOHNSON
In crossing of different breeds of dogs Johnson claims that (malocclusion in these animals
definitely and probably in man is caused by differences in size or shape between the upper
and lower jaws due to the different genetic background of the parents.
DETLEFSEN Detlefsen from a study of 35 pairs of identical twins reported that tooth and arch shape and
size are inherited.
Twin study Conclusion
LUNDSTORM 100 identical and 102 fraternal (dizygotic) twins found greater dissimilarity in the latter both as
regards to malocclusion and in number of type of teeth lost.
WLLIAM K.
LOBB
study on 60 pairs of twins , 30 MZ and 30 DZ , finding a strong genetic component overlaid by
functional adaptation most prominent in the dental area.
Keeler produced a number of pedigrees of various conditions to show that heredity affects the teeth
SWAIN AND
LEBOW
Swain and Lebow published additional pedigrees indicating inheritance of human facial features.
Swain reported four cousins with a similar type of overbite.
MOORE AND
HUGHES
Moore and Hughes observed individuals of 56 families and 95 children and found that the incidence
of asymmetry in absolute size of the jaw parts in children with asymmetrical parents was 300 times as
great as in children with normal parents.
They conclude that in the form of the arches, the crowding and spacing of teeth, the number of
teeth, type of malocclusions and depth of bite children tended to follow the parenteral pattern.
They believe that single genes may operate in causing rotated teeth but suggest multiple factors for
crowding and spacing.

18. DEVELOPMENT OF CRANIOFACIAL SKELETON
BLASTOCYST
GASTRULATION NOTOCHORD FORMATIONC.S
T.S

19. • The r1 & 2 NC populate the 1st
pharyngeal arch
• The cells from r4 migrate into
the 2nd
• Cells from r6 & 7 migrate to 3rd
pharyngeal arch
• Cells from r8 move to 4th & 6th
arch

20. • The streams of neural crest cells exiting the dorsal
aspects of the hindbrain are sculpted through
apoptotic elimination of crest cells originating in Rh
3 and 5.
• This apoptotic removal of the neural crest cells is
mediated by BMP4-induced Msx2 expression only in
odd-numbered rhombomeres

21. HOW DO NEURAL CREST CELLS KNOW WHICH PATH TO TAKE?
• Some ECM molecules promote cell migration
(fibronectin, laminin, tenascin, certain collagens
and specific proteoglycans)
• Some ECM molecules that restrict migration
(Ephrin)
• Together, these ECM molecules provides
specificity for cell movement.

22. • Edward Lewis
• in the fly
• help in controlling the developmental response of a
group of cells along the body’s antero-posterior
axis.
• also found in vertebrates (McGinnis et al., 1984).

23. • The first vertebrate homeobox was rapidly cloned
in the frog Xenopus levis (Carrasco et al., 1984) and
this was soon followed by the mouse (McGinnis et
al., 1984).

24. • In the mouse and human genomes there are 39
Hox genes related to Drosophila homeotic genes.
• These Hox genes are arranged in four clusters
(instead of one in the fly) on four different
chromosomes; Hoxa-d in mice and HOXA-D in man
(Scott, 1992).
considerable duplication and divergence had occurred from the original ancestral
cluster (Duboule and Dollé, 1989; Graham et al., 1989).

25. • ‘Master Genes’ of head and face with a prominent
control over
 patterning ,
 induction,
 programmed cell death and
 epithelial-mesenchymal interaction during craniofacial
development.

26. • The subfamilies of Hox genes, which are of
particular interest in craniofacial patterning and
morphogenesis include-
 muscle segment(Msx),
 Distal less(Dlx),
 orthodenticle(Otx),
 Goosecoid(Gsc),
 Bar class(Barx),
 paired-related(Prx, SHOT) and
 LIM homeobox.

27. • The expression of these genes is mediated through
two main groups of regulatory proteins-
Growth factor family and
steroid/thyroid/retinoic acid super family.
• The vehicle through which Hox gene information is
expressed for the regulation of growth process
include
fibroblast growth factor(FGF),
Transforming growth factor α and β, and
bone morphogenetic proteins 4 (BMP4).

29. The Muscle Segment (Msx)
• These genes are primarily expressed in regions that
give rise to highly derived or vertebrate specific
structures like
 skull
 teeth
 limbs
 axial and appendicular skeleton
 tripartite brain
• Vertebrate have three Msx (only the first two are involved in craniofacial
patterning and morphogenesis)
 Msx1
 Msx2
 Msx3

30. • Coexpressed in dental mesenchyme
• E 16.5-downregulate
• MSX1-ant portion of dev palatal shelves (Zhang et al )
• MSX2- precursors of the orofacial skeleton (mandibular and maxillary bones,
Meckel's cartilage, and tooth germs, vestibular lamina, enamel knot, IEE, dental
papilla mesenchyme)
• Defect
 1-tooth agenesis
 cleft palate associated with loss of palatine shelves in both maxillary and
palatine bones (resulted from a defect in cell proliferation in the anterior palatal
mesenchyme rather than a failure in palatal fusion)
 maxillary and mandibular hypoplasia and
 highly penetrant arrest of tooth formation at the bud stage of development.
 2-cuspal morphogenesis
 Root formation
 Enamel organ differentiation
 Dominant craniosynostosis

31. Distal less (Dlx)
• Dlx1 and Dlx2 are expressed throughout first and second branchial
arches whereas
• expression of Dlx3, Dlx4, Dlx5 and Dlx6 are restricted more distally
• Coincide with expression of MSX1 & 2
• Role- ameloblast differentiation, appendage development
• Mutation
enamel hypoplasia,
severe craniofacial, axial, and appendicular skeletal
abnormalities,
leading to perinatal lethality.
split-hand/split-foot malformation (SHFM), a heterogeneous
limb disorder characterized by missing central digits and claw-
like distal extremities. (Dlx5 and Dlx6 homeobox genes-
autosomal dominant form)

32. Role of Msx-Dlx in tooth development
• The BMP4 induction of Msx1 expression and
subsequent Msx dependent activation and
maintenance of BMP4 expression in dental
mesenchyme are key steps in conferring the
odontogenic potential to these tissues.

33. Goosecoid (Gsc)
• expressed during gastrulation in regions of the
embryo with axial patterning activity.
• At late stages of embryogenesis, Gsc is expressed in
craniofacial regions, ventral body wall and limbs.
• Mutation
multiple craniofacial defects and rib cage malformations
(Rivera-Perez ,1995)
hypoplastic mandible with lack of coronoid and angular process
along with several defects of other bones like maxilla, palatine
bones and pterygoid plates.

34. Orthodenticle Otx gene (Otx1 and Otx2)
• From experiments in mice it is clear that prior to
gastrulation Otx2 is expressed in epiblast and
visceral endoderm and its expression becomes
restricted to anterior parts of all three germ layers,
as the primitive streak is formed.

35. • According to Matsuo et al
(1995), Otx homozygous
mutants fail to develop
structures anterior to
rhombomere .
• the Otx2 in cranial neural crest
cells was evidenced by
otocephaly due to defect in
these cells of Otx2
homozygous mutants.

36. The Bar Class
• The Bar class of homeobox genes consisting of
Barx1 and Barx2, contains protein meant for
protein-protein interaction to regulate the function
of homeodomain.
• CNS & PNS
telencephalon,
diencehalon,
mesencephalon,
hind brain
spinal cord
in cranial and dorsal root ganglia.

37. • Expression of Barx 2 is most prominent in mantle
layer, in which post mitotic neurons are located,
• The palatal floor and dorsal root ganglia,
• Mutations of which can produce clefts of secondary
palate.

38. The Paired related gene (Prx and SHOT)
• To stabilize and maintain cell fates in craniofacial
mesenchyme.
• Ten Berge et al found
defects in external, middle and inner ear,
reduction or loss of skull bones,
a reduced or sometimes cleft of the mandible and
limb abnormalities

39. • Another paired related homeobox gene-SHOT- with
two different isomers SHOTa and SHOTb are considered
homologous to human SHOX and mouse OG-12.
• The transcription factors encoded by this gene are
expressed in the
 developing aorta,
 female genitalia,
 diencephalons,
 nasal capsule,
 palate,
 eyelid and
 limb.

40. • SHOT was mapped to human chromosome 3q25-
q26.
• this chromosomal region is involved in
development of Cornelia-de- Hange syndrome,
characterized by
 mental retardation,
 microcephaly,
 cleft palate,
 abnormally situated eyelids,
 nose and ear deformities,
 heart and lung defects.
• idiopathic short stature in humans,and Leri-Weill
dyschondrosteosis

41. • anterior domain of the secondary palate in mice
and humans.
• Shox2-/- mice develop an incomplete cleft that is
confined to the anterior region of the palate, an
extremely rare type of clefting in humans.
• The Shox2-/- palatal shelves initiate, grow and
elevate normally, but the anterior region fails to
contact and fuse at the midline, owing to altered
cell proliferation and apoptosis, leading to
incomplete clefting within the presumptive hard
palate.

42. • signals from the anterior palatal epithelium are
responsible for the restricted mesenchymal Shox2
expression.
• BMP activity is necessary but not sufficient for the
induction of palatal Shox2 expression.
• Studies demonstrate an intrinsic requirement for
Shox2 in palatogenesis, and support the idea that
palatogenesis is differentially regulated along the
anteroposterior axis.
• Also, the fusion of the posterior palate can occur
independently of fusion in the anterior palate.

43. The LIM homeobox genes
• The Lhx8 transcripts are expressed in neural crest
derived ectomesenchyme of the first branchial
arch and also in developing tooth during the
postnatal period.
• the formation and elevation of palatal shelves
appeared to proceed normally but failed to make
contact and fuse.

44. • The cleft palate is a common finding in mice
carrying mutations of Lhx8 gene and can be
considered as a potential gene for human cleft
palate also.

45. Heritability
Defined as – proportion of the total variation of a character
which can be attributed to genetic factors.
In other words, it is an estimate of how much of the
etiology of a disorder can be ascribed to genetic
influences rather than environmental factors.
Greater the heritability, greater the genetic component.
Disorder Heritability
(%)
Asthma 80
CL/CP 76
Hyper-
tension
62
Peptic
Ulcer
37

46. • More than one gene involved + environment
• Familial tendency
• Incidence in family more than in general population
• Less common than unifactorial disorders
• Normal traits – intelligence, skin colour, blood
pressure, etc.
• Abnormal traits – schizophrenia, diabetes, peptic
ulcer, ischemic heart disease, ankylosing spondylitis
etc.
Inheritance – Multifactorial

47. • Relatives generally have higher incidence than
general population
Inheritance – Multifactorial

49. • The incidence is greater among relatives of
individuals with more severe form of the disease
• Pt. with bilateral cleft lip – 6%
• Pt. with unilateral cleft lip – 2.5%
• Similarly, subsequent children have more chance of
being affected.
Inheritance – Multifactorial

50. melting pot
• The is a metaphor for a heterogeneous society becoming
more homogeneous, the different elements "melting
together" into a harmonious whole with a common culture or
vice versa, for a homogeneous society becoming
more heterogeneous through the influx of foreign elements
with different cultural background with a potential creation
of disharmony with the previous culture. Historically, it is
often used to describe the assimilation of immigrants to the
United States. The melting-together metaphor was in use by
the 1780s.The exact term "melting pot" came into general
usage in the United States after it was used as a metaphor
describing a fusion of nationalities, cultures and ethnicities
in the 1908 play of the same name.

51. • Genetic variation-Arch length & wd > OJ,OB,Molar relation
• arch size and shape are associated more with environmental variation
• Because many occlusal variables reflect the combined variations of
tooth position and basal and alveolar bone development, these
variables (e.g., overjet, overbite, and molar relationship) cannot be less
variable than the supporting structures.
• They will vary because of their own variation in position and those of
the basilar structures.

52. • Greater heritability exists for total anterior face height and lower anterior face
height than for upper anterior face height and posterior face height.
• This implies that the greater estimate of heritability for the total anterior face
height is due to the greater estimate of lower anterior face height than upper
face height.
• Possibly a lower heritability for the upper anterior face height reflects the effect
of the airway, and a lower heritability for posterior face height reflects dietary
effects.
• allergic rhinitis and mouth breathing?

53. • Malocclusion is less frequent and less severe in populations not industrialized (urbanized)
and that tend to be isolated.
• This has been attributed to the interbreeding of populations with, to some degree,
different physical characteristics, presumably resulting in a synergistic disharmony of tooth
and jaw relationships.
• This idea was supported by the crossbreeding experiments of Stockard and Anderson in
inbred strains of dogs, increasing the incidence of malocclusion, typically caused by a
mismatch of the jaws.

54. • A study of disparate ethnic groups that have interbred in Hawaii found that
children of racial crosses are at no increased risk of malocclusion beyond what
would have been expected from the usual parental influence.
• In addition, the increase in malocclusion in populations that have moved
recently into an industrialized lifestyle is too quick to be the result of genetic
change caused by evolutionary fitness pressure.
• The most likely explanation for the increased malocclusion seen in “civilization”
is changed environment, such as food and airway effects.

55. 56% to 92% of phenotypic variation
Primary second molars and permanent first molars.
Hypodontia-familial, but may occur without familial history, with syndrome
Gene for dentition patterening:-
MSX1 & PAX9-Non Sx AD Hypodontia
LTBP3 Gene-short stature, inc bone density-AR Hypodontia
10q11.2 & KROX26-other candidate gene
Polygenic influence with a multifactorial threshold

56. The presence of a single primary and permanent maxillary incisor at first
may appear to be a product of fusion.
However, if the single tooth is in the midline and symmetric with normal
crown and root shape and size, then it can be an isolated finding or can be
part of the solitary median maxillary central incisor syndrome.
This heterogeneous condition may include other midline developmental
abnormalities of the brain and other structures that can be due to
mutation in the
sonic hedgehog (SHH) gene,
SIX3 gene, or
genetic abnormality.
Following a review of published family pedigrees involving Class II,
Division 2 malocclusion, Peck and colleagues noted the probability of
• autosomal dominant inheritance with incomplete penetrance,
• although polygenic inheritance was also a possibility.

57. Impacted canine
• Labial/ buccal-15% with crowding
• Palatal-85%  No crowding
 Small/peg/missing lateral
 Hypodontia of other teeth
 Spacing
 Dentition with delayed eruption

58. Directional asymmetry
occurs when development of one
side is different from that of the
other during normal development.
The human lung, having three lobes
on the right side and two lobes on
the left side, is an example of
directional asymmetry.
Because this may be predicted
before development occurs, it is
under significant genetic influence.
Antisymmetry occurs when one side is
larger than the other, but which side is
larger varies in normal development and
cannot be predicted before development.
Normal,much less common
Like directional asymmetry, antisymmetry
has a significant genetic component that
is not fully understood.
Unlike structures that have normal
directional asymmetry, facial and dental
structures lateral to the midline are
essentially mirror images of each other,
with the same genetic influences affecting
both sides.
One does not find one group of genes for
the permanent maxillary right first molar
and another group of genes for the
permanent maxillary left first molar.
fluctuating, occurs when a difference
exists between right and left sides, with
which side is larger being random. This
reflects the inability of the individual to
develop identical, bilaterally homologous
structures.
Fluctuating asymmetry has been observed
in the primary and permanent dentitions,
as well as in the craniofacies
The greater amount of fluctuating
asymmetry for the distance between
cusps on each tooth than for the overall
crown size of primary second molars and
permanent first molars indicates that the
occlusal morphology of these teeth is
influenced more by environmental factors
than the overall crown size.
an indirect measure of environmental
stress so that differences between
bilateral structures are due predominantly
to environmental factors.
An individual’s level of fluctuating
asymmetry is an indicator of how well the
genome can produce the ideal phenotype
under certain circumstances.

59. • Multifactorial, involving host and environmental
factors.
• An association of EARR exists, in those who have
 not received orthodontic treatment,
 with missing teeth,
 increased periodontal probing depths, and
 reduced crestal bone heights.
 Bruxism
 chronic nail biting
 anterior open bites with concomitant tongue thrust
 pathologic consequence of orthodontic mechanical loading
 Orthodontic tooth movement, 1/10th to 1/3rd of EARR.
 Individual variation >force magnitude; Owman-Moll

60. • Heritability estimates have shown that approximately half of EARR variation
concurrent with orthodontia, and almost two-thirds of maxillary central incisor
EARR specifically, can be attributed to genetic variation.
• A retrospective twin study on EARR found evidence for both genetic and
environmental factors influencing EARR.

61. • Variation in the interleukin-1β gene (IL-1B) in orthodontically treated individuals
accounts for 15% of the variation in EARR.
• Persons in the orthodontically treated sample who were homozygous for IL-1B
+3953 (previously designated as +3954) SNP rs1143634 allele “1” were
estimated to be 5.6 times (95% confidence interval, 1.89–21.20) more likely to
experience EARR of 2 mm or more than were those who were heterozygous or
homozygous for allele “2” (p = .004).

62. • Interestingly, Iwasaki et al. found individual differences in a ratio of IL-1β
to IL-1RA (receptor antagonist) cytokines in crevicular fluid that
correlated with individual differences in canine retraction using identical
force.
• Although the relation to genetic markers was not undertaken, this study
indicates a variable individual response to orthodontic force that may be
mediated at least in part by IL-1β and IL-1RA cytokines.
• This supports the hypothesis that bone modeling mediated, at least in
part, by IL-1β as an individual response to orthodontic force can be a
factor in EARR.

63. • Further testing of another candidate gene using nonparametric sibling pair
linkage analysis with the DNA microsatellite marker D18S64 (tightly linked to the
gene TNFRSF11A) identified evidence of linkage (LOD = 2.5; p = .02) of EARR
affecting the maxillary central incisor.
• This indicates that the TNFRSF11A locus, or another tightly linked gene, is
associated with EARR.
• The TNFRSF11A gene codes for the protein RANK, part of the osteoclast
activation pathway.

64. Pain perception and
temporomandibular dysfunction
• Genetic factors-variation in individual pain perception,
• In 2003, Zubietta et al. reported that a common variant
of the gene that codes for the enzyme catecholO-
methyl-transferase (COMT) was associated in humans
with diminished activity of pain regulatory mechanisms
in the central nervous system.
• TMD onset was 2.3-fold greater for subjects who had
only high pain sensitivity (HPS) and/or average pain
sensitivity (APS) haplotypes based on COMT genetic
variation, compared with subjects who had one or two
low pain sensitivity (LPS) haplotypes. (Slade et al )

65. Malocclusions
• ClassII div 1-smaller body & overall Mn length (Harris,1965,73)
• Class II div 2
 deepbite,retroclined incisor,class II skeletal pattern, high lip line, strap like activity of
lower lip,active mentalis
 Poorly dev cingulum,crown root angulation,↓ MD/LLwd
 Forwardly rot Mn-deepbite, chin prominence, ↓ lower face ht.
 Lower lip position, inc.masticatory m/s force (Quinn & Yoshikawa,1985)
• Class III
 Hapsburg pedigree-Strohmayer,1937.A.D
 Family (34.3%) vs normal (7.5%)-Suzuku,1961
 MZ-6X (Schulze & Weise,1965)
 Polygenic hypothesis-Litton et al,1970
 Distinctive cranial base morphology (Ellis &McNamara,1984;Singh et al,1997)
 More acute cranial base angle
 Smaller post cranial base
 More ant positioning of glenoid fossa
 Mn prognathism

67. • The main use human single nucleotide polymorphisms, SNP map will be to
determine the contributions of genes to diseases (or nondisease phenotypes)
that have a complex, multifactorial basis.
• Heritability estimates can indicate how much of the phenotypic variation is
associated with genetic variation, a consideration in the feasibility of a search
for identifying the genetic factors.

68. • This was the approach in a study of the association of the Pro561Thr (P56IT)
variant in the growth hormone receptor gene (GHR), which is considered to be
an important factor in craniofacial and skeletal growth.
• Of a normal Japanese sample of 50 men and 50 women, those who did not have
the GHR P56IT allele had a significantly greater mandibular ramus length
(condylion-gonion) than did those with the GHR P56IT allele.
• The average mandibular ramus height in those with the GHR P56IT allele was
4.65 mm shorter than the average for those without the GHR P56IT allele.
• the association was with the mandibular ramus height but not mandibular body
length, maxillary length, or anterior cranial base length.
• This suggests a site-, area-, or region-specific effect.

69. Conclusions
• The study of gene function continues to
demonstrate how an understanding of the basic
science behind development can lead to advances
of direct relevance to the clinician.
• Many human syndromes and genetic abnormalities
have now been attributed to defects in individual
genes.