Medical Genetics

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					Medical Genetics in 2006

Harry Ostrer, M.D.
Human Genetics Program
NYU School of Medicine
       A Conceptual History of Medical Genetics

1900          Mendel’s Laws rediscovered
1901          Dominant inheritance of brachydactyly
1902          Inborn errors of metabolism
1918          Anticipation described
1931          Cytoplasmic inheritance of mitochondrial DNA
1937          Linkage of color blindness and hemophilia
1955          Human diploid chromosome number is 46
1970          Amniocentesis for chromosomal disorders
1970          Tay-Sachs screening
1976          Human globin genes cloned
1987          Predictive genetic testing for Huntington disease
1991          Medical genetics became an ABMS specialty
2001          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


Temporal balding
Cataracts                       Weakness
Hoarseness                      Balding
Myotonia                        Cardiac arrhythmia
Daytime somnolence
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          CTG Repeat       Age of Onset   Average Age of Death
                                         Size            (Years)            (Years)

Premutation   None                      38 to ~49        Normal             Normal

   Mild       •Cataracts                50 to ~150        20-70           60 - normal
              •Mild myotonia

 Classical    •Weakness               ~100 to ~1000-      10-30              48-55
              •Myotonia                   1500
              •Cardiac arrhythmia
Congenital    •Infantile hypotonia      ~1000 to        Birth to 10           45
              •Respiratory deficits      >2000
              •Mental retardation
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
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
                            BRCA1-              BRCA1+
                            or                  or
                            BRCA2-              BRCA2+

           BRCA1 BRCA2                                BRCA1 BRCA2

               RAD51                                      RAD51

              failed DNA repair                      DNA repair
    p53+                             p53-

          checkpoint activation             no checkpoint activation

    p53                 p21          p53               p21

    cell cycle arrest                unregulated growth
                                  Event-Free Survival By Mutation Status
                                                                                Mutation +
Proportion Event-Free

                                                                                Mutation -




                              0      24    48      72     96     120     144    168        192   216

                                     from Robson, et al. J Clin Oncol 16:1642-1649, 1998
  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

                            No       Hazards
          Oophrectomy oophorectomy     ratio
Breast        21/99       60/142       0.47
 cancer     (21.2%)      (41.3%)   (0.42-0.77)
Ovarian       8/259       58/282       0.04
 cancer      (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


   fatty acid
     New York Newborn Screening Program

Endocrine disorders             More common among African-
                                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
Genetic disorders              Infectious disease
Biotinidase deficiency         HIV
Cystic fibrosis                 More common among
Deafness                        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               MSUD
                       Canavan                 GSD1A
                       Cystic fibrosis         Fragile X
Other Caucasians
Cystic fibrosis
Fragile X
                       Familial dysautonomia
                       Mucolipidosis IV
                 Greeks, Italians
                 Africans, Asians
Tay-Sachs Disease Is Prevalent Among Ashkenazi
      Jews Because of Founder Mutations

                    Progressive neurological
      ACGT          disease
                                           G-C                    G-A
  Exon 11 4bp ins           IVS12 splice site        Exon 5 Gly269Ser
       90%                       8%                         1%

                     Prototype for carrier testing
                              Impact of Carrier Testing for Tay-Sachs
Number of Affected Children



                              30                                                             Jewish
                              20                                                             Non-Jewish



                                        Kaback, Int J Technol Assess Health Care. 10:592-603, 1994
   Frequency of Carriers for Autosomal
Recessive Diseases Among Ashkenazi Jews

   Cystic Fibrosis
   Canavan disease
   Gaucher disease                1:9
   Bloom syndrome
   Fanconi anemia
   Niemann-Pick disease
   Familial dysautonomia                      1:4
   Fragile X
   GSD1A                                            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

 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
            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                    N      FPR      Sensitivity

Orlandi (1997)              744    5.0     6 of 7        (87%)
Biagiotti (1998)            232    5.0    24 of 32       (76%)
De Biasio (1999)          1,467    3.3    11 of 13       (85%)
De Graaf (1999)             300    5.0    31 of 37       (85%)
Spencer (1999)            1,156    5.0   187 of 210      (89%)
Krantz (2000)             5,718    5.0    30 of 33       (91%)
Niemimaa (2001)           1,602    5.4     4 of 5        (80%)
Wapner (BUN) (2002)       8,514    5.0    48 of 61       (79%)
Schucter (2002)           4,939    5.0    12 of 14       (86%)
Von Kaisenberg (2002)     3,864    6.6    16 of 19       (84%)
Bindra (2002)            15,030    5.0    74 of 82       (90%)
Spencer (2003)           10,458    5.0    23 of 25       (92%)
Sheffield (2003)         18,140    5.0    60 of 64       (94%)
Borrell (2004)            2,780    3.3     7 of 8        (88%)
CUBS (2004)               5,084    5.9    14 of 15       (93%)
Nicolaides (2005)        75,821    5.2    301 of 325     (93%)
Total                   155,849    5.0    848 of 950     (89%)
Interphase Amniotic Fluid FISH Analysis
      for Chromosomal Aneuplodies

            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   Predisposition to   Predisposition to
             superior athletic   breast cancer       sociopathic
             ability                                 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

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