1

MENDELIAN INHERITANCE2002

• Genotype• Phenotype• Locus• Allele• Homozygote/ Heterozygote• Compound heterozygote• Proband

A. ADB. ARC. XLRD. XLDE. Not genetic

2

Mozart’s Piano Concerto in A-major is Köchel number

• A K365

• B K450

• C K482

• D K488

• E 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

3

Laboratory analysis

• Skin fibroblasts: abnormal type III collagen

• COL3A1 DNA analysis: Gly25Val

• Diagnosis: Ehlers-Danlos Syndrome,

Type IV

Pedigree symbols

4

Autosomal dominant inheritance

• Vertical

• Males and females affected

• Males and females transmit

• Each affected has one affected parent…

5

NF1

Café-au-lait

Neurofibroma

6

Lisch Nodules

Neurofibromatosis 1variable expressivity

• Café-au-lait spots

• Axillary freckling

• Lisch nodules

• Cutaneous neurofibromas

• Plexiform neurofibromas

• Scoliosis

• CNS tumors

7

Marfan syndrome

Marfan ectopia lentis

8

Marfan life expectancy

Marfan Syndromevariable

expressivity

9

Incomplete penetrance

AD Erythermalgia

Achondroplasia

10

What is the risk that this couple’schild will have achondroplasia ?

• A _

• B _

• C _

• D 1

• E 0

11

Achondroplasiamutations in FGFR3

Allelic Heterogeneity

COL3A1 (EDS IV)

12

Autosomal Recessive

Autosomal Recessive

• Horizontal

• Males and females affected

• Parents of affected are normal

13

14

Autosomal recessive

A. ADB. ARC. XLRD. XLDE. Not genetic

15

Locus Heterogeneity

IV-1,2,3,4,5,6 are all double heterozygotes

congenital deafness

16

X-linked recessive

X-linked recessive inheritance

• “Diagonal”

• Males affected…

• Transmitted by carrier females

• NO male-to-male transmission

• Daughters of affected males are obligate carriers

17

X-linkedrecessive

inheritance

X-linked dominant

18

X-linked NOT sex-linked

Mitochondrial inheritance

• Mitochondrial DNA– 2 to 100 mitochondria/cell– 5 to 10 chromosomes/mitochondrium– 16.5 kb mt DNA– 37 genes

• Mitochondrial inheritance– Maternal– Heteroplasmy

19

MERRF

MERRF Pedigree

20

Heteroplasmy

Myotonic Muscular Dystrophy

• Most common inherited muscular dystrophy ofadults

• Muscle wasting—face, neck, distal muscles• Myotonia• Cardiac and smooth muscle affected• Cataracts• Immunoglobulin abnormalities• Insulin resistance• Occ. Mild MR

21

22

23

Autosomal dominant

ANTICIPATION

DENIAL AIN’T JUST ARIVER IN EGYPT

-Rap song

24

The absence of evidence is NOTequivalent to evidence of absence

Triplet (CTG) Repeats

25

RepeatExpansion

Triplet Repeat Diseases

26

Pathogenesis of MyotonicDystrophy

• Loss of Function– Haploinsufficiency of DMPK

– Cis-chromatin effects

Cis-chromatin effects

27

Pathogenesis of MyotonicDystrophy

• Loss of Function– Haploinsufficiency of DMPK

– Cis-chromatin effects

• Gain of Function

Gain of Function

28

Ypsilanti

Demetrius Ypsilanti

29

Alexander Ypsilanti

30

31