Transcript Medical Genetics - New York University

Medical Genetics in 2006
Harry Ostrer, M.D.
Human Genetics Program
NYU School of Medicine
A Conceptual History of Medical Genetics
1900
1901
1902
1918
1931
1937
1955
1970
1970
1976
1987
1991
2001
Mendel’s Laws rediscovered
Dominant inheritance of brachydactyly
Inborn errors of metabolism
Anticipation described
Cytoplasmic inheritance of mitochondrial DNA
Linkage of color blindness and hemophilia
Human diploid chromosome number is 46
Amniocentesis for chromosomal disorders
Tay-Sachs screening
Human globin genes cloned
Predictive genetic testing for Huntington disease
Medical genetics became an ABMS specialty
Draft sequence for the human genome
What Do Medical Geneticists Do in 2006?
Diagnosis and treatment of genetic disease
Presymptomatic testing for genetic disease
Carrier testing, especially for high risk people
Genetic counseling during pregnancy
1178 board-certified medical geneticists
Case Report
A man with cataracts, temporal balding, wasting
of his facial muscles and a myotonic grip
presents along with his young adult daughter,
who had similar features. What would you do
for the patient?
Genetic Evaluation
Data gathering
History, especially family history
Physical examination - major and subtle findings
Pattern recognition
Laboratory testing – EMG, DNA
A Family with Multiple Cases of
Myotonic Dystrophy
cataracts
Temporal balding
Cataracts
Hoarseness
Myotonia
Daytime somnolence
Weakness
Balding
Cardiac arrhythmia
Physical Diagnosis of Myotonic Dystrophy
Grip release test
Facial features
EMG Testing for Myotonic Dystrophy
Myotonic Dystrophy Results from Expansion of
a Trinucleotide Repeat
Correlation of Phenotype and CTG Repeat
Length in Myotonic Dystrophy
Phenotype
Clinical Signs
Premutation
Mild
CTG Repeat
Size
Age of Onset
(Years)
Average Age of Death
(Years)
None
38 to ~49
Normal
Normal
•Cataracts
•Mild myotonia
50 to ~150
20-70
60 - normal
Classical
•Weakness
•Myotonia
•Cataracts
•Balding
•Cardiac arrhythmia
~100 to ~10001500
10-30
48-55
Congenital
•Infantile hypotonia
•Respiratory deficits
•Mental retardation
~1000 to
>2000
Birth to 10
45
Genetic Evaluation/Counseling Issues
Patient education and treatment
Natural history
Risk of occurrence/re-occurrence
Possibilities for diagnosis and treatment
of symptoms
Impact on the individual and family
Results of Genetic Testing in a Family with
Multiple Cases of Myotonic Dystrophy
Ethical Issues
Protection of the individual’s right to privacy and
fair treatment (Autonomy and privacy)
Competing demands of family members or mothers
and fetuses (Privacy, equity and justice)
Justification of exposure to increased risks
(Beneficence)
What Do Medical Geneticists Do in 2006?
Diagnosis and treatment of genetic disease
Presymptomatic testing for genetic disease
Carrier testing, especially for high risk people
Genetic counseling during pregnancy
Case Report
A woman whose 63 year old father was
diagnosed with breast cancer makes an
appointment for genetic testing. Her family
history indicates that two paternal aunts died
from ovarian cancer. She is planning in vitro
fertilization because her husband has a low
sperm count. She comes for her appointment
with her younger, unmarried sister.
Family with Multiple Cases of Breast
and Ovarian Cancer
Br CA 63
Ov CA 50
Ov CA36
Genes Conferring High Risk for Breast and
Ovarian Cancer
Locus
Risk range
Associated syndrome
BRCA1
56-87% (by age 70)
Familial breast/ovarian cancer
BRCA2
37-84% (by age 70)
Familial breast/ovarian cancer
p53
50-89% (by age 50)
Li-Fraumeni syndrome
PTEN
30-40% (by age 50)
Cowden syndrome
MSH2, MLH1
12% (lifetime)
Muir-Torre syndrome
STK11
high
Peutz-Jeughers syndrome
Presumed Effects of Heritable BRCA1 and BRCA2 Mutations
DNA damage
BRCA1or
BRCA2-
BRCA1+
or
BRCA2+
BRCA1 BRCA2
BRCA1 BRCA2
P
RAD51
RAD51
failed DNA repair
p53+
DNA repair
p53-
checkpoint activation
p53
cell cycle arrest
p21
no checkpoint activation
p53
p21
unregulated growth
Event-Free Survival By Mutation Status
Proportion Event-Free
1.2
Mutation +
Mutation -
1
0.8
0.6
0.4
0.2
0
0
24
48
72
96
120
144
168
Months
from Robson, et al. J Clin Oncol 16:1642-1649, 1998
192
216
Second Malignancies in BRCA1/2 Carriers
Mutation carriers
No Mutation
12 contralateral BC
5 contralateral BC
3 ovarian neoplasia
0 ovarian neoplasia
1 AML
1 endometrial carcinoma
Benefit of Risk-Reducing Surgery
Breast
cancer
Ovarian
cancer
No
Hazards
Oophrectomy oophorectomy
ratio
21/99
60/142
0.47
(21.2%)
(41.3%)
(0.42-0.77)
8/259
58/282
0.04
(3.1%)
(19.9%)
(0.01-0.06)
Rebbeck, New Engl J Med. 346:1616-22, 2002
Case Report
A baby died from SIDS (sudden infant death
syndrome). Genetic testing in the medical
examiner’s office revealed that the baby
was homozygous for common mutations for
MCAD deficiency. Both parents were
found to be heterozygous for the mutation.
In a subsequent pregnancy, the fetus was
found to be homozygous normal.
Fatty Acid Oxidation is Required for Gluconeogenesis
glucose
fatty acid
oxidation
protein
New York Newborn Screening Program
More common among AfricanEndocrine disorders
Americans, Latino Americans,
Congenital hypothyroidism
Asian Americans
Congenital adrenal hyperplasia
Metabolic disorders
Hemoglobin disorders
Galactosemia
Hb S
Fatty acid oxidation disorders
Hb SC
Organic acidemias
HB S thal
Amino acid acidemias
Infectious disease
Genetic disorders
HIV
Biotinidase deficiency
Cystic fibrosis
Deafness
More common among
Caucasian-Americans
Criteria for Newborn Screening
Measurable burden of disease
High-quality screening test available
Confirmation available with gold standard test
Intervention available that makes a difference
System in place for providing confirmation,
treatment and counseling
Variation in Newborn Screening Practices
Among the States
as of May, 2005
What Do Medical Geneticists Do in 2006?
Diagnosis and treatment of genetic disease
Presymptomatic testing for genetic disease
Carrier testing, especially for high risk people
Genetic counseling during pregnancy
Genetic Risks: What Conditions
to Screen for to Identify Heterozygotes?
Ashkenazi Jews
Tay-Sachs
Canavan
Cystic fibrosis
Gaucher
Bloom
Other Caucasians
Fanconi
Cystic fibrosis
Niemann-Pick
Fragile X
Familial dysautonomia
Mucolipidosis IV
Greeks, Italians
Africans, Asians
Hemoglobinopathies
Thalassemias
MSUD
GSD1A
Fragile X
Tay-Sachs Disease Is Prevalent Among Ashkenazi
Jews Because of Founder Mutations
ACGT
Progressive neurological
disease
G-C
Exon 11 4bp ins
90%
IVS12 splice site
8%
Prototype for carrier testing
G-A
Exon 5 Gly269Ser
1%
50
40
30
Jewish
Non-Jewish
20
10
92
19
91
19
90
19
89
19
87
19
85
19
84
19
83
19
82
19
80
0
19
Number of Affected Children
Impact of Carrier Testing for Tay-Sachs
Disease
Years
Kaback, Int J Technol Assess Health Care. 10:592-603, 1994
Frequency of Carriers for Autosomal
Recessive Diseases Among Ashkenazi Jews
Tay-Sachs
Cystic Fibrosis
Canavan disease
Gaucher disease
Bloom syndrome
Fanconi anemia
Niemann-Pick disease
ML4
Familial dysautonomia
Fragile X
MSUD
GSD1A
1:11
1:9
1:5
1:4
1:3
Dor Yesharim Committee for Prevention of Jewish Genetic
Diseases is a Program for the Orthodox Jewish Population
Confidential genetic screening program for Jewish genetic disorders
Participants are tested at around the age of 18
Designed for couples contemplating marriage
The couple is notified later whether there is compatible (not both
carriers)
An incompatible couple is strongly
discouraged from marrying each other
Couples are not faced with difficult
reproductive decisions
What Do Medical Geneticists Do in 2006?
Diagnosis and treatment of genetic disease
Presymptomatic testing for genetic disease
Carrier testing, especially for high risk people
Genetic counseling during pregnancy
Case Report
A young woman with insulin-dependent diabetes
mellitus presents along with her fiance for genetic
counseling. During the course of the interview,
we discovered that the fiance had
neurofibomatosis I, a condition that was diagnosed
during his physical diagnosis course in medical
school. In addition, it became apparent that the
young woman had hypohydrotic ectodermal
dysplasia, a condition that she shared with her
mother and two sisters.
Case report (continued)
We counseled the couple that the likelihood of their
having a normal fetus was 21%.
w/o NF1 - 50%
w/o HED - 50%
w/o diabetic embryopathy - 85%.
Some weeks later we learned that the couple split up.
Fetal Nuchal Translucency Measurement
Improves Detection Rate for Chromosomal
Abnormalities
GA: 11 wks, 3 days to 13 wks, 6 days
Crown-rump length: 45 to 84mm
Increased in
chromosomal disorders,
congenital heart disease
congenital infection
fetal hydrops
rare genetic disease
(Noonan syndrome,
lethal multiple pterigium,
AR cystic hygroma)
FTS Studies Using free-Beta HCG / PAPP-A / NT
Author
Orlandi (1997)
Biagiotti (1998)
De Biasio (1999)
De Graaf (1999)
Spencer (1999)
Krantz (2000)
Niemimaa (2001)
Wapner (BUN) (2002)
Schucter (2002)
Von Kaisenberg (2002)
Bindra (2002)
Spencer (2003)
Sheffield (2003)
Borrell (2004)
CUBS (2004)
Nicolaides (2005)
Total
N
744
232
1,467
300
1,156
5,718
1,602
8,514
4,939
3,864
15,030
10,458
18,140
2,780
5,084
75,821
155,849
FPR
5.0
5.0
3.3
5.0
5.0
5.0
5.4
5.0
5.0
6.6
5.0
5.0
5.0
3.3
5.9
5.2
5.0
Sensitivity
6 of 7
24 of 32
11 of 13
31 of 37
187 of 210
30 of 33
4 of 5
48 of 61
12 of 14
16 of 19
74 of 82
23 of 25
60 of 64
7 of 8
14 of 15
301 of 325
848 of 950
(87%)
(76%)
(85%)
(85%)
(89%)
(91%)
(80%)
(79%)
(86%)
(84%)
(90%)
(92%)
(94%)
(88%)
(93%)
(93%)
(89%)
Interphase Amniotic Fluid FISH Analysis
for Chromosomal Aneuplodies
Protocol
2-4 ml clear amniotic fluid
Centrifuged, fixed and dropped on slide
Hybridized with chr 13, 18, 21, X, Y probes
Count at least 50 cells
>85% aneuploid  abnormal
>85% euploid  normal
Others  indeterminate
How Do Genes Influence Who We Are?
Phenotype:
Predisposition to
superior athletic
ability
Predisposition to
breast cancer
Predisposition to
sociopathic
behavior
Genetic testing "will enable every set of parents that
has a little baby to get a map of the genetic structure
of their child." They will be able to "plan that child's
life: to organize the diet plan, the exercise plan, the
medical treatment that would enable untold numbers
of people to have far more full lives."
President Bill Clinton, 1996 Campaign