MENDELIAN INHERITANCE
2002
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Genotype
Phenotype
Locus
Allele
Homozygote/ Heterozygote
Compound heterozygote
Proband
A.
B.
C.
D.
E.
AD
AR
XLR
XLD
Not genetic
Mozart’s Piano Concerto in Amajor is Köchel number
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A
B
C
D
E
K365
K450
K482
K488
K491
Clinical vignette
• S G: 20 yo college student
– Spontaneous rupture of the common iliac artery
– Friable tissues, extensive bleeding
– Past history:
• Easy bruising
• Lax joints (fingers, elbows, left shoulder)
• D G: 53 yo mother of SG
– Spontaneous perforation of the sigmoid colon
– Past history
• Easy bruising
• No joint laxity
• Two normal pregnancies
Laboratory analysis
• Skin fibroblasts: abnormal type III collagen
• COL3A1 DNA analysis: Gly25Val
• Diagnosis: Ehlers-Danlos Syndrome,
Type IV
Pedigree symbols
Autosomal dominant inheritance
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Vertical
Males and females affected
Males and females transmit
Each affected has one affected parent…
NF1
Neurofibroma
Café-au-lait
Lisch Nodules
Neurofibromatosis 1
variable expressivity
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Café-au-lait spots
Axillary freckling
Lisch nodules
Cutaneous neurofibromas
Plexiform neurofibromas
Scoliosis
CNS tumors
Marfan syndrome
Marfan ectopia lentis
Marfan life expectancy
Marfan Syndrome
variable
expressivity
Incomplete penetrance
AD Erythermalgia
Achondroplasia
What is the risk that this couple’s
child will have achondroplasia ?
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•
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A
B
C
D
E
¼
½
¾
1
0
Achondroplasia
mutations in FGFR3
Allelic Heterogeneity
COL3A1 (EDS IV)
Autosomal Recessive
Autosomal Recessive
• Horizontal
• Males and females affected
• Parents of affected are normal
Autosomal recessive
A.
B.
C.
D.
E.
AD
AR
XLR
XLD
Not genetic
Locus Heterogeneity
congenital deafness
IV-1,2,3,4,5,6 are all double heterozygotes
X-linked recessive
X-linked recessive inheritance
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“Diagonal”
Males affected…
Transmitted by carrier females
NO male-to-male transmission
Daughters of affected males are obligate
carriers
X-linked
recessive
inheritance
X-linked dominant
X-linked NOT sex-linked
Mitochondrial inheritance
• Mitochondrial DNA
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–
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2 to 100 mitochondria/cell
5 to 10 chromosomes/mitochondrium
16.5 kb mt DNA
37 genes
• Mitochondrial inheritance
– Maternal
– Heteroplasmy
MERRF
MERRF Pedigree
Heteroplasmy
Myotonic Muscular Dystrophy
• Most common inherited muscular dystrophy of
adults
• Muscle wasting—face, neck, distal muscles
• Myotonia
• Cardiac and smooth muscle affected
• Cataracts
• Immunoglobulin abnormalities
• Insulin resistance
• Occ. Mild MR
Autosomal dominant
ANTICIPATION
DENIAL AIN’T JUST A
RIVER IN EGYPT
-Rap song
The absence of evidence is NOT
equivalent to evidence of absence
Triplet (CTG) Repeats
Repeat
Expansion
Triplet Repeat Diseases
Pathogenesis of Myotonic
Dystrophy
• Loss of Function
– Haploinsufficiency of DMPK
– Cis-chromatin effects
Cis-chromatin effects
Pathogenesis of Myotonic
Dystrophy
• Loss of Function
– Haploinsufficiency of DMPK
– Cis-chromatin effects
• Gain of Function
Gain of Function
Ypsilanti
Demetrius Ypsilanti
Alexander Ypsilanti