9/18/14

X-LINKED INHERITANCE
X-LINKED RECESSIVE INHERITANCE
X-LINKED DOMINANT INHERITANCE
dr. R. Sutomo, SpA(K), PhD
Developmental & Behavioral Pediatrics
Human Molecular Genetics
rsutomo.id@gmail.com

a good learner
is
a good listener

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X-link inheritance

§  The  responsible  gene  located  in  X-­‐sex  

chromosome  
§  The  trait  is  either  recessive  or  dominant  
§  X-­‐linked  recessive  inheritance  
§  X-­‐linked  dominant  inheritance  

X-LINKED RECESSIVE INHERITANCE

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X-linked recessive inheritance:

Features

A  Affects  mainly  males  

A  Affected  males  usually  born  to  unaffected  parents  
A  Transmission  through  carrier  females  
A  No  male-­‐to-­‐male  transmission  
A  All  daughters  of  affected  males  are  carriers  

3 possible clinical situation

§   Normal  father    +    carrier  mother  

§   Affected  father      +    normal  mother  
§   Affected  father      +    carrier  mother  

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carrier mother normal father

Segregation of X-linked recessive allele

1 Carrier mother
Xm X
Normal father

X XmX XX

Y XmY XY

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2
Affected father

Segregation of X-linked recessive allele

2
Normal mother
X X
Affected father

Xm XmX XmX

Y XY XY

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3
Carrier mother
Xm X
Affected father

Xm XmXm XmX

Y XmY XY

Pedigree of X-linked recessive inheritance

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X-linked recessive disorders

•  Hemophilia  A,  B   •  Ocular  albinism  

•  Color  blindness   •  Duchenne  muscular  
•  G6PD  deficiency   dystrophy  (DMD)  
•  Fragile  X  syndrome   •  Becker  muscular  
dystrophy  (BMD)  

Complication to X linked pedigree

De novo mutation
Mutated X

De novo mutation in DMD

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X-linked recessive disease in female

1.  Mating of affected father + carrier mother

2.  Non-random X inactivation
3.  Female with single X chromosome
4.  Translocation of X chromosome
5.  Androgen insensitivity syndrome (AIS)

X-linked recessive disorder in female

Affected male + carrier female

Mother’s gametes
Xm X
Father’s gametes

Xm Xm Xm XmX

Y XmY XY

Usually lethal

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X-linked recessive disorder in female

Female with single X chromosome

A 45, X0
" Turner’s syndrome

X-linked recessive disorder in female

Non-random X inactivation

§  Only one X chromosome active in each cell, other/others inactivated

§  Normally, inactivation of X chromosome occurs randomly (by chance) ž
random (balanced) X inactivation
§  Chance for each X chromosome being inactivated in each cell is 50%
§  In normal female (46, XX), mutation in one X chromosome will be
compensated by another active X chromosome
§  In certain condition, most cells activate the defective X chromosome and
only few cells activate the normal one ž non-random (imbalanced, skewed)
X inactivation

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X-linked recessive disorder in female

Translocation of X chromosome

§  TranslocaWon  of  X  chromosome  segments  to  

autosomes  
§  The  translocated  X  chromosome  ’defecWve/non-­‐
funcWonal  
§  Mimics  individual  with  single  X  chromosome  for  the  
associated  gene  

X-linked recessive disorder in female

Androgen insensitivity syndrome

—  Phenotypically  female  but  genotypically  male  (pseudo  

female)  
—  Non-­‐responsiveness  of  androgen  receptor  to  androgen  
sWmulaWon  
—  No  development  of  male  sex  characters  
—  DMD  in  Vietnamese  “girl”  
—  KaryoWpe:  46,  XY  ’  boy  
—  Carries  mutaWon  in  androgen  receptor  gene  

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X-LINKED DOMINANT
INHERITANCE
dr.  R.  Sutomo,  Sp.A(K),  PhD                                rsutomo.id@gmail.com  

X-linked dominant inheritance

Characteristics

§  Affects  either  sex,  F  >  M  

§  Females  are  o]en  less  severely  affected  than  males  
§  Child  of  an  affected  female  has  a  50%  chance  of  being  affected,  
regardless  the  sex  
§  Affected  male  à  all  his  daughters  affected,  but  none  of  his  sons  
§  The  pedigree  resembles  AD  inheritance,  except    
§  no  male  to  male  transmission  
§  excess  of  affected  females  

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X-linked dominant pedigree

Which one is X-inked dominant inheritance?

X-linked dominant autosomal dominant

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X-linked dominant inheritance

Characteristics

§  In some disorders the condition appears to be lethal in affected

males
§  Ex: focal dermal hypoplasia (Goltz syndrome), incontinentia pigmenti
§  There will be fewer males than expected, half of the females will be
affected and all surviving males will be unaffected
§  Some XLD disorders affects girls almost exclusively and usually
occurs sporadically, since affected females do not reproduce
§  Ex: Rett syndrome " gene mapped to Xq24

X-linked dominant pedigree " lethality in male

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POLIFACTORIAL INHERITANCE

Patterns of inheritance
— Mendelian  inheritance  
 →  monogenic  inheritance  
— Non-­‐Mendelian  inheritance  
— Poligenic  inheritance  
— Polifactorial  inheritance  
— Chromosomal  disorder  

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Non-mendelian inheritance

—  Poligenic  inheritance  

—  Involves  >  1  gene  

—  Polifactorial  inheritance  

—  Poligenic  +  environmental  factors  

Monogenic vs poligenic characters

§  Monogenic character

§ Qualitative discontinuous à present/absent
§  Poligenic character
§ Quantitative/continuous à gradation

§  Do not confuse: poligenic versus poli-allelle

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Limitation of Mendelian inheritance

§  Oversimplification of the real

phenomenon
§  Fails to explain the inheritance of
many traits in real life

Galtonians
Regression to mean

§  Extremely  tall  fathers  tend  to  have  sons  shorter  than  
themselves,  extremely  short  fathers  tend  to  have  sons  taller  
than  themselves  
§  "Tallness"  or  "shortness"  is  not  similar  to  Mendel's  pea  
experiments  
§  The  height  of  the  father  and  the  average  height  of  the  son  
are  related,  but  the  average  height  of  the  son  always  
regresses  toward  the  mean  

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Polifactorial inheritance
Characteristics

§  Several loci are involved in the expression of the trait

§  No dominance or recessivity at each locus
§  The loci act in concert in an additive fashion, each adding
or detracting a small amount from the phenotype
§  Environment interacts with the genotype to produce the
final phenotype

Polifactorial inheritance
Characteristics

§  Most affected children have normal parents

o Most geniuses come from normal parents,
most mentally challenged come from normal
parents
§  Recurrence risk ↑ with the number of affected
children in a family

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Polifactorial inheritance
Characteristics

§  Recurrence risk increases with severity of the

defect
o More severely affected parent is more likely to
produce an affected child
§  Consanguinity slightly increases the risk for an
affected child

Polifactorial characters

•  Body  height   •  Dyslipidemia  

•  Intelligence   •  Obesity  
•  Diabetes  mellitus   •  Neural  tube  defect  
•  etc.  
•  Hypertension  

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Polifactorial determination of disease

The balance between angels and devils

INBREEDING / CONSANGUINITY

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Inbreeding

§ Mating between related individuals

§ Consanguinity g "mixing of the
blood“

Inbreeding in human

§  Relatively rare

§  Many customs and laws prevent human
inbreeding
§  The chance to have offspring with a
disease or birth defect >> baseline risk in
the general population.

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Inbreeding in human

§  Many genetic diseases are recessive

§ only people inherit two disease alleles
develop the disease
§  All individuals carry several single
recessive alleles for genetic diseases

Inbreeding in human

§  Close relatives have more genes in

common than unrelated individuals
g Parents → higher chance of having
the same disease alleles
g Child → higher risk for inheriting
homozygous for a recessive disease

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Case study
§  Shared gene = 1/8
§  If each parent has 1 copy of the allele → chance of the
child to inherit the allele from both parents = 1/4
§  Risk of the child inherit 2 copies of the same allele = 1/8
× 1/4, or 1/32, about 3 percent
§  The risk of having a child affected with a recessive
disease approximately 3 percent, in addition to a
baseline risk

Any benefit of inbreeding?

q  Improve specific characteristics

q  Facilitate genetic study g gene mapping

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Any benefit of inbreeding?

Improve specific characteristics

q  Inbreeding commonly practiced in animal breeding to

enhance specific characteristics (e.g. milk production)
q  But, if genes controlling unselected traits are also
influenced g deleterious effects
q  Moreover, inbreeding results in decreased genetic
diversity

Any benefit of inbreeding?

Valuable resource for genetic study

•  Inbred  populaWons  g  relaWvely  homogeneous  in  both  

geneWcs  and  environment  g  rich  resource  for  geneWc  
studies  
•  Homozygosity  mapping  g  idenWfy  several  recessive  
mutaWons  in  inbred  groups  

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Finally…….
Human inbreeding

Just don’t do it!

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