Inheritance of Complex

Disorders

Session ID: complex

Karen Weissbecker, Ph.D.

Tulane University Health Science Center
Department of Psychiatry and Neurology
and The Hayward Genetics Center
 LEARNING OBJECTIVES
 Explain the principles of multifactorial inheritance in
normal human traits and the multifactorial nature of
complex disorders
 Define non-Mendelian mechanisms such as: reduced
penetrance, variable expressivity, anticipation, delayed
age of onset, uniparental disomy, mosaicism, genomic
imprinting and unstable repeat expansion.
 Explain how these mechanisms of non-Mendelian
inheritance affect phenotypic expression and
recurrence risk of genetic disorders.
 Define heritability and explain its usefulness in
understanding the genetic role in a given trait or
disorder
What is the most likely mode
of inheritance?

A. Autosomal Dominant
B. Autosomal Recessive
C. X-Linked Dominant
D. X—Linked recessive
E. I don’t know
What is the most likely mode
of inheritance?

A. Autosomal Dominant
B. Autosomal Recessive
C. X-Linked Dominant
D. X—Linked recessive
E. I don’t know
What is the mode of
inheritance?
 What complicates things?
What factors do you already know – that
affect “simple Mendelian disorders” ?
• Reduced penetrance
• Variabile expresiviity
• Heterogeneity
• Mosaicism
• New mutations
 Achondroplasia: Molecular
findings
 Autosomal dominant, >50% represent new
mutations
 Responsible gene:
 FGFR3 - Fibroblast growth factor receptor 3
 98 % - G1138A substitution in FGFR3
 1 % - G1138C substitution in FGFR3
Molecular testing has shown the mutation in
people with achondroplasia to be due to
mutations in the FGFR3 gene:
98 % - G1138A substitution in FGFR3
1 % - G1138C substitution in FGFR3
This is an example of ….

A. Allelic – this one

heterogeneity
B. Locus
heterogeneity
C. Phenotypic
heterogeneity
D. Variable expressivity
E. Anticipation
 Heterogeneity
Different genetic loci produced
phenotypes that are clinically
indistinguishable
For example: There are at least 4 known
genes causing susceptibility to
Alzheimer’s
Locus=gene
 Interlocus or “locus” heterogeneity: more
than one loci (gene) causes the disease

 Intralocus or Allelic heterogeneity: more than

one allele at a single locus can cause the
disease
A 30-year-old healthy man has 2 children with
retinoblastoma, one had bilateral age 2 ½ and the
other had unilateral at 18 months. In addition, his
mother had retinoblastoma as a young child, and his
brother had bilateral retinoblastoma at age 3. What is
the most likely explanation for the absence of
retinoblastoma in this man?

Heteroplasmy is the presence of more than one

A. Highly variable type of organellar genome (mitochondrial DNA
expressivity or plastid DNA) within a cell or individual. It is
an important factor in considering the severity
B. Incomplete of mitochondrial diseases.
Penetrance
There is variable expressivity in the family-
C. New mutations different ages of onset with different severities
D. Pleiotropy But the man shows incomplete penetrance
because he doesn’t have it at all
 Penetrance – all or none
Frequency of expression of a genotype or the
proportion of individuals who have the
disease allele(s) who do not express clinical
symptoms
for example: a penetrance of 80% means 20% of the individuals who carry the
gene do not have clinical symptoms.

Variable Expressivity –
mild to severe
The degree of variation in the expression of a
phenotype among individuals with the same
genetic disorder
 Phenocopies

Mimic of a phenotype that is

usually determined by a specific
genotype but is produced instead
by an environmental cause or the
interaction of an environmental
factor with a different genotype.
(e.g.: Retinoic acid embryopathy looks like
DiGeorge sequence)
Environmental cause for something
than can be genetic
 Inheritance of Complex Disorders

• Coronary artery • Bipolar disorder

disease
• Schizophrenia
• Type I and II diabetes
• Alcoholism
• Most cancers
• Kidney stones
• Rheumatic heart
disease • Gallstones
• Autoimmune • Peptic ulcer disease
disorders • Gout
• Asthma, allergies
• Multiple sclerosis
• Obesity
Pretty much every common disease
 Complex Disorders/Traits

• More common than single

gene disorders
• Often the genes involved
disrupt hemostasis over time
or cumulatively
• Risk prediction is problematic
Other factors making Complex
Disorders “complex”
 Age of onset: the expression of the trait does not
appear in an individual until later in life

 Modifying genes - Many genes of small effect can

modify the phenotype of a single major gene (i.e.
cause of disease). E.g. intelligence in down modified
not only by down but by general variation due to
genes

 Pleiotropy: if a single locus produces an effect on

several traits, that locus is said to be pleiotropic

 Gene x environment interaction

 Polygenic Inheritance

 A large number of genetic loci are postulated to

contribute an equal and additive in the
expression of a trait

For example:
3 locus system with loci A, B, C with alleles Aa, Bb,
Cc respectively
 the phenotype is determined by the number of capital
letter alleles
Polygenic diagram

aabbcc Aabbcc AaBbcc AaBbCc AABbCc AABBCc AABBCC

Distribution of quantitative
polygenic trait
 Variations in Eye Color

 The number of human eye color genes is

unknown (at least 16)
 Mice have more than 60 eye color genes
 Multifactorial Inheritance

Threshold Model:
distribution of liability
for a trait or disease
determined by both
genes and
environment at a
certain threshold, the
person is affected.
Multifactorial Inheritance
What we expect to see: (Criteria)
• Correlation between relatives is
proportional to the genes in common
• Recurrence risk is higher when more
than one family member is affected or
the disorder is more severe in expression
• Occurrence may differ based on sex
• Consanguinity increases recurrence risk
Cleft lip and palate

• More common in
males and Asians
• recurrence risk
drops off from 1st
degree to 2nd
degree relatives
Empiric Relative Risks
Cleft lip and palate
Pyloric Stenosis
 Severe feeding
problems, with projectile
vomiting in infancy due to
narrowing of pyloric
opening

 more common in males

 birth order effects
 greatest at risk to sons of
affected women
Sex differences in relative risk

Occrerence differs based on sex

Recurrence risk is higher when the
affected relative is of the lower risk sex
 Multifactorial
Inheritance
Example: Type 2 diabetes:
• At least 6 genes
identified for familial
forms of T2D (1 -2% of
cases)
• At least 18
“susceptibility” genes
identified for non-
Mendelian case
• Multiple environmental
factors: BMI, age, sex, With the possible exception of some
smoking etc. highly familial cases, genotyping of
susceptibility genes only slightly
improves the prediction of risk over
conventional clinical criteria (which
includes family history)
Idea is can add up all genes that give
susceptibility to predict someone’s risk –
problem is we don’t fully understand
how different genes interact with each
Gene-Environment
Interaction
• Differences between genotypes with
respect to risk factors variability (e.g.
one genotype does not respond to
dietary treatments)
• Genotype/phenotype relationship is
dependent on presence or absence of
environment factors (fauvism, smoking
and lung cancer, NTD and folic acid)
 Qualitative v Quantitative
Traits
 Discrete phenotypic expression
 Presence or absence of disease
 Red cell antigens
 Continuous variation in phenotype
 Traits that must be measured
 Is it continuous or dichotomous
character?
Dichotomous – have it or don’t have it
Continuous –quantitative– falls along a
spectrum – but we can create a Clinical
threshold for this cut-off level
of diabetes
Those people could be
chronically hypoglycemic

Insulin resistance in a general population

 Distribution of Quantitative Traits
Can still be largely influenced by a
single major gene such that the mean
is primarily determined by the
underlying genotype at a single locus,
with the variation around the mean
being determined by environmental
factors (including measurement error)
and/or other genes of small effect
 • Heritability

How do • Familial aggregation studies

we know • Twin studies
it is • Segregation analyses
Genetic? • Linkage Studies
• Association studies
 Heritability (H)
Estimates the proportion of the phenotypic variation in a population
due to genetic differences
Easiest way to measure it is through twin
studies: compare concordance of MZ
twins versus DZ twins.
Heritability
This is a population
statistic so we can
not infer, for
example, that if
heritability for a trait
h2 = 0.5 that 50% of
an individual’s
personality or IQ, or
phenotype, is
genetically acquired
In one person genetics
may play a larger
role than in another
person
Heritability is a population
statistic
What is the best
interpretation of
this data?
A. There are more cases of
autism in Finland than Israel
B. Genetics plays a larger role
in determining the risk of
autism in Finland than Israel-
--this
C. A child from Israel has a
51% chance of being
autistic
D. If an Israeli family has a
child with autism the
chance they will have
another child with it is 51%
and for a Finish family it is
87%
E. For an Israeli child with
autism, 51% of the cause is
attributable to genetics
Familial Aggregation
• The tendency of disease to “cluster”
in families
• Basic question: Are relatives of an
affected person at a higher risk than
someone in the general population?
• Look at correlations or concordance
rates Can have shared environment and
shared genes
• What factors can cause familial
aggregation?
 Correlation Among Relatives for
Systolic Blood Pressure*
Relatives Compared Correlation (r)
Monozygotic twins 0.55
Dizygotic twins 0.25
Siblings 0.18
Parents and offspring 0.34
Spouses 0.07
Age or interuterine effect may explain
difference between dizygotic twins
and siblings
* Feinlieb M et al as cited in Gordis,
2007
New Mechanisms and
Nontraditional Modes of
Inheritance
 Nontraditional modes of
inheritance
 Mitochondrial inheritance
 Mosaicism
 Uniparental Disomy
 Genetic Imprinting
 Anticipation
 Heritable unstable elements (Trinucleotide
repeats)
 Copy Number Variants (CVN)
 Epigenetic effects
xxxMitochondrial
inheritance

 Also known as
maternal inheritance,
applies to genes in
mitochondrial DNA.
 only females can pass
on mitochondrial
conditions to their
children.
Mosaicism

Two cell lines of different

genotype or karyotype,
derived from a single
zygote.
This can result from a
new mutation in a
precursor cell, or during
tissue differentiation so
you can either have
mosaicism within a cell
type or between cell
type
Mosaicism

• Chromosomal mosaicism
• Mosaicism in females due
to X inactivation
• Mosaicism arising from a
(single gene) mutation in a
single cell either prenatally
or postnatally (mitotic cell
division)
 BOTH: (before or after separation of
Mosaicism germline cells from somatic cells)
Gametic mosaicism – don’t have
genetic disorder but have a high risk of
Somatic mosaicism: A passing it on
mutation in some cells, but
not all, in different parts of
the body, or mixed cells
throughout. (mutation
during mitotic cell division).
Gametic Mosaicism: Don’t see
clinical symptoms because
the mutation is only in the
gametes, but this can have
significant effect on
recurrence risks
Both: depending on when the
mutation occurred in
development
Segmental NF

Maybe mosaicism – half body shows

signs of NF half doesnt
When the mutation matters

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 Germline Mosaicism or
reduced penetrance?

Will be on test
OI is autosomal dominant with 100%
penetrance but dad doesn’t have it –
germline mosaicism

What if I told you this pedigree both

kids had AD Osteogenesis Imperfecta?
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 xxxUniparental Disomy

Both chromosomes of a pair come

from one parent and none from
the other parent
isodisomy: both chromosomes from
one parent are identical
heterodisomy: both chromosomes
from one parent are different
 xxxGenetic Imprinting

• Modification (methylation) of
genetic material that takes place
depending on whether the genetic
information is derived from the
mother or the father

• Classic Example: Prader Willie and

Angelman Syndrome
 xxxPrader Willie and
Angelman
 A deletion in the paternally derived gene – Prader Willie
 A deletion in the maternally derived gene – Angelman’s
OR
 Uniparental disomy of maternal genes – Prader Willie
 Uniparental disomy of paternal genes – Angelman’s
 xxxImprinting in sheep

 Callipyge gene in
sheep: “beautiful
buttocks
 Lambs with a copy of
this gene have more
meat on their
hindquarters but only
if paternally inherited
 Overdominance: 2
copies of the gene
and you are back to
a normal sized rear
end
Anticipation

 Increase in severity
or decrease in age
of onset of a
disorder in
successive
generations.
 Often found to be
due to increases in
the number of
trinucleotide
repeats
 Heritable unstable elements and
trinucleotide repeat disorders

 Trinucleotide repeat regions:

become unstable and during
reproduction tend to
increase the number of
trinucleotide repeats,
resulting in gene abnormality
and disease expression.
Example: Huntington’s disease
 Examples: Huntington's,
Fragile X, myotonic dystrophy,
Kennedys disease, SCA
Anticipation + Genomic Imprinting

Huntington's Disease:
the trinucleotide repeats become
greatly increased if transmitted
through a male and results in the
earlier age of onset.
Myotonic Dystrophy – if it is
transmitted through the mom, you
are more likely to get expansion
xxxCopy Number Variants
de novo changes
 Segments of DNA that are 1 kilobase or
larger and present at a variable copy
number in comparison with a reference
genome
 Copy number variants are mutations and
can include deletions, insertions, and
duplications
 Implicated in Developmental delay,
autism, schizophrenia, etc.
(Feuk et al., 2006)