Transcript Complication to AR inheritance

PATTERNS OF INHERITANCE
dr. R. Sutomo, Sp.A, Ph.D
Pattern of inheritance
Why concerns?
• Genetic counseling
• Impact of genetic counseling
– Not for reducing the incidence
– Option for therapy frequently unavailable
Why genetic counseling?
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Recurrence risk assessment
Well-informed-based decision
Psychological impacts
Adjustment
Predicting prognosis
Studying pattern of inheritance
How to investigate?
• Family studies
• Drawing a pedigree
Family studies
• A particular trait or disorder  genetic and
hereditary?
– observation of the way in which it is transmitted
from one generation to another, or
– on study of its frequency among relatives
• Taking a family history can, in itself, provide a
diagnosis
Family tree
• A family tree is a shorthand system of
recording the pertinent information about a
family
• Begins with the person through whom the
family came to the attention of the
investigator index case, proband or
propositus, or proposita (for female)
Mendelian character
• Its presence and absence depends on the
genotype at a single locus
• A certain genotype at one locus is necessary
and sufficient for the character to be
expressed
• Does not mean that the character is
programmed by only one pair of genes
• ±10.000 mendelian characters
Mendelian inheritance
• Remind: dominance and recessiveness are
properties of characters, not genes
• Character:
– Dominant  manifest in heterozygote
– Recessive  not manifest in heterozygote
Symbols in pedigree
Individuals
Symbols in pedigree
Individuals
Symbols in pedigree
Relationships
Symbols in pedigree
Assisted reproductive scenarios
Mendelian inheritance
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Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Y-linked
Autosomal dominant
Autosomal
recessive
Basic
Mendelian
inheritance
X-linked recessive
X-linked dominant
Y-linked
Autosomal dominant
inheritance
Pedigree of autosomal dominant
inheritance
Features of AD inheritance
• An affected person usually has at least one
affected parent
 No skipping of generation
• Affects either sex
• Transmitted by either sex
• Affected x unaffected mating  child: 50%
chance of being affected (assuming that the
affected parent is heterozygous)
RISK CALCULATION
Dd x Dd
Dd x dd
d
d
D
Dd
Dd
d
dd
dd
Affected : unaffected
1
:
1
D
d
D
DD
Dd
d
Dd
dd
??????
Autosomal dominant disorders
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Achondroplasia
Myotonic dystrophy
Neurofibromatosis
Osteogenesis
imperfecta
• Tuberous sclerosis
• Facioscapulohumeral
dystrophy
• Acute intermittent
porphyria
• Acute intermittent
porphyria
• Familial breast cancer
(BRCA 1, BRCA 2
• Familial
hypercholesterolemia
• Familial adenomatous
polyposis
• Charcot-Marie-Tooth
disease
• Huntington disease
Unusual autosomal dominant inheritance
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Non-penetrance
Variable expression
Anticipation
De novo mutation
Genetic imprinting
Non-penetrance
• Penetrance: the probability that a person with a certain
genotype will manifest the character
• Non-penetrance  failure of a dominant character to
manifest
• Theoretically, dominant character 100% penetrance
• In fact  continuum characters:
– Fully penetrant mendelian   multifactorials
• Complicating the genetic counseling
Variable expression
• Different family members  different features of the
disease/syndrome
• Waardenberg syndrome
– Hearing loss
– Different color eyes
– White forelock
– Premature graying of hair
Genetic anticipation
• The phenotype is more severe in successive
generation
• Unclear mechanism
• Examples:
– Myotonic dystrophy
– Huntington disease
Genetic imprinting
• Normally, genes are equally express either
from paternal or maternal copies
• Genetic imprinting: expression depends on
the origin of the gene/genes paternal or
maternal
• Paternal imprinting Prader-Willi syndrome
• Maternal imprinting  Angelman syndrome
Genetic imprinting
• The disorder manifests only when the gene is
inherited from the mother
Genetic imprinting
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The disorder manifests only when the gene is
inherited from the father
Prader Willy Syndrome
Angelman Syndrome
• Prevalence: 1/10.000-15.000
• Chromosome 15q11-q13
• Genotipe
paternal  (-)  PWS
maternal  (-) AS
• Paternal/maternal deletion of 5q11-q13 (70%)
• Uniparental disomy (UPD) (25-30%)
– Maternal UPD (PWS)
– Paternal UPD (AS)
• Defect of imprinting center in 15q11-q13
PRADER-WILLI Obesity
SYNDROME
Short stature
Peeled skin
Almond-shaped eyes
Hypotonicity
Small hands and feet
Mental reterd
Dysartria
Sticky saliva
Narrowed nasal bridge
Down-turned mouth
Narrowed bitemporal
Hypogonadism
ANGELMAN SYNDROME
(Happy puppet syndrome)
Happy face
Hyperactivity
Flat occiput
Prominent mandible
Microcephaly(~2 yo)
Hypopigmentation
Strabismus
Contracture
Ataxic gait
Hand flapping
Puppet-like movement
Severe MR
Epilepsy
Severe speech imp
Wide mouth
Spaced teeth
Chewing/
mouthing >>
De novo mutation
• Newly occured
mutation
Autosomal recessive?
X-linked recessive?
Complicated AD pattern
What’s the shortcut...?
Be familiar with common AD disorders
Autosomal recessive inheritance
Pedigree of AR inheritance
Features of AR inheritance
• Affected people are usually born to unaffected parents 
WHY?
• Parent of affected people are usually asymptomatic carrier
• Increased incidence of parental consanguinity  WHY?
• Affect either sex
• After the birth of an affected child, each subsequent child
has a 25% chance of being affected
Segregation of AR alleles
AR inheritance
affected
carrier
Effect of consanguinity on AR inheritance
Autosomal recessive disorders
Complication to AR inheritance
Pseudo-dominant
• Common recessive conditions can give a pseudo
dominant pedigree pattern
• Blood group O may be seen in successive generation
because of repeated marriages of group O people
with heterozygotes
Complication to AR inheritance
Pseudo-dominant
• A individual who is homozygous for an
autosomal recessive disorder marries a carrier
of the same disorder, their children have a 1 in
2 (50%) chance of being affected
Complication to AR inheritance
Complementation
• Two affected parents may give unaffected child
• The disorder is associated with defect in several genes
• The children will be normal whenever the parents carry
mutation in different genes
• AR congenital profound hearing loss
• Usher syndrome: hearing loss + retinitis pigmentosa
– Associated with defects in 8 different genes
Complementation
• Locus heterogeneity
• Mutational heterogeneity
• Genocopy
– Disorders with the same phenotype due to
different genetic loci
• Phenocopy
– Disorders with the same phenotype being the
result of environmental causes
For life we learn, not for school