9/18/14

AUTOSOMAL
INHERITANCE
dr. R. Sutomo, Sp.A(K), Ph.D
Developmental & Behavioral Pediatrics
Human Molecular Genetics

rsutomo.id@gmail.com,  rsutomo@ugm.ac.id  

Mendelian trait

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Mendelian trait / character

§  The   presence/absence   depends   on   the   genotype   at  
a  single  locus  
§  Does  not  mean  that  the  character  is  programmed  by  
only  one  pair  of  genes  
§  A   certain   genotype   at   one   locus   is   necessary   and  
sufficient  for  the  character  to  be  expressed  
§  ±  10.000  Mendelian  characters  
§  OMIM  (Online  Mendelian  Inheritance  in  Men)  

Mendelian inheritance

§  Remind:  dominance  and  recessiveness  are  

properGes  of  characters,  NOT  genes  
§  Character:  
§   Dominant  ž  manifest  in  heterozygote  
§   Recessive  ž  not  manifest  in  heterozygote  

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Symbols
in
pedigree

Symbols
in
pedigree

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Basic Mendelian
Autosomal dominant inheritance

Autosomal
X-linked recessive
recessive

X-linked dominant

Y-linked

Clinical concern...?

§  GeneGc  counseling  

§  Recurrence  risk  
§  Informed  decision  
§  Adjustment  

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Autosomal dominant
inheritance

Pedigree of AD inheritance

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Features of AD inheritance
§  An affected person usually has at least one affected parent
A  No skipping of generation
§  Affects either sex
§  Transmitted by either sex
§  Affected x unaffected mating g child: 50% chance of being
affected (assuming that the affected parent is
heterozygous)

RISK CALCULATION
Dd x dd Dd x Dd
d d D d

D Dd Dd D DD Dd

d dd dd d Dd dd

Affected : unaffected ??????

1 : 1

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Autosomal dominant disorders

§  Achondroplasia   §  Familial  adenomatous  

§  Tuberous  sclerosis   polyposis  
§  Neurofibromatosis   §  Myotonic  dystrophy  
§  Familial  breast  cancer   §  Osteogenesis  imperfecta  
(BRCA  1,  BRCA2)   §  Familial  hypercholesterolemia  

Unusual AD inheritance

§  Non-­‐penetrance  
§  Variable  expression  
§  AnGcipaGon  
§  De  novo  mutaGon  
§  GeneGc  imprinGng  

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Non-penetrance
§  Penetrance:  probability  that  a  person  with  a  certain  
genotype  will  manifest  the  character  
§  Non-­‐penetrance  
§  Failure  of  a  dominant  character  to  manifest  
§  Dominant  character  à  100%  penetrance  ž  in  fact??  
§  ConGnuum  characters:  
§  Fully  penetrant  Mendelian  ž  ž  mulGfactorials  
§  Complicates  the  geneGc  counseling  

Variable expression
§  Different  family  members  show  
different  features  of  the  disease/
syndrome  
§  Waardenberg  syndrome  
§  Hearing  loss  
§  Different  color  eyes  
§  White  forelock  
§  Premature  graying  of  hair  

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Genetic anticipation

u  More  severe  phenotype  in  successive  generaGon  

u  Unclear  mechanism  

u  Examples  à  myotonic  dystrophy  

Genetic imprinting

§  Normally,  genes  are  equally  express  either  from  

paternal  or  maternal  copies  
§  GeneGc  imprinGng:  expression  depends  on  the  
origin  of  the  gene/genes  žpaternal  or  maternal  
§  Paternal  imprinGng  ž  Prader-­‐Willi  syndrome  
§  Maternal  imprinGng  ž  Angelman  syndrome  

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Genetic imprinting

l  The disorder manifests only when the gene is

inherited from the father

Genetic imprinting

¨  The disorder manifests only when the gene is inherited

from the mother

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Prader Willy Syndrome

Angelman Syndrome
¨  Prevalence: 1/10.000-15.000 paternalž (-) ž PWS
¨  Chromosome 15q11-q13 maternalž (-) ž AS
¨  Genotipe

n  Paternal/maternal deletion of 5q11-q13 (70%)

n  Uniparental disomy (UPD) (25-30%)
n  Maternal UPD (PWS)
n  Paternal UPD (AS)
n  Defect of imprinting center in 15q11-q13

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Obesity
PRADER-WILLI Short stature
SYNDROME Peeled skin
Almond-shaped eyes

Hypotonicity
Small hands and feet Narrowed nasal bridge
Mental reterd Down-turned mouth
Dysartria Narrowed bitemporal
Sticky saliva Hypogonadism

ANGELMAN SYNDROME
(Happy puppet syndrome)
Happy face Flat occiput
Hyperactivity Prominent mandible
Microcephaly(~2 yo)
Hypopigmentation
Strabismus
Contracture

Ataxic gait
Hand flapping
Puppet-like movement
Wide mouth
Severe MR Spaced teeth
Epilepsy Chewing/
Severe speech imp mouthing >>

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De novo mutation

Newly  occured  mutaGon  

Autosomal recessive?
X-linked recessive?

Complicated AD pattern

What’s the shortcut...?

Be familiar with common AD disorders

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Autosomal recessive inheritance

Pedigree  of  AR  inheritance  

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Features of AR inheritance
§  Affected  people  are  usually  born  to  unaffected  parents  ž  
WHY?  
§  Parent  of  affected  people  are  usually  asymptomaGc  carrier  
§  Increased  incidence  of  parental  consanguinity  ž  WHY?  
§  Affect  either  sex  
§  A_er  the  birth  of  an  affected  child,  each  subsequent  child  
has  a  25%  chance  of  being  affected  

Segregation of AR alleles

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AR inheritance

affected
carrier

Effect of consanguinity on AR inheritance

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Autosomal recessive disorders

Complication to AR inheritance
A Pseudo-­‐dominant  

§  Common  recessive  condiGons  can  give  a  pseudo  

dominant  pedigree  paaern  
§  Blood  group  O  may  be  seen  in  successive  generaGon  
because  of  repeated  marriages  of  group  O  people  
with  heterozygotes  

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Complication to AR inheritance
AComplementa;on  

§  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  
mutaGon  in  different  genes  
§  AR  congenital  profound  hearing  loss  
§  Usher  syndrome:  hearing  loss  +  reGniGs  pigmentosa  
§  Associated  with  defects  in  8  different  genes  

THE END

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