The Human Genome Project:

How Does This Project Offer a New Paradigm for
Health Promotion?

Edward R.B. McCabe, M.D., Ph.D.
Physician-in-Chief
Mattel Children’s Hospital at UCLA

Impact of the Human Genome Project on the Practice of Medicine

·            Improved diagnosis
·            Technology development
·            Improved treatment and prevention
·            Predictive medicine

Improved Diagnosis

·            DNA not impacted by age, diet, treatment
·            Applicable to newborn screening programs
·            Presymptomatic genetic screening

Screening

Methodical examination of a population to identify individuals with disease or predisposed to disease

Newborn Screening

            ·            Classical paradigm for presymptomatic genetic screening

            ·            Historical precendent for successful genetic public health programs

-                     Change natural course by:

Screening

Confirmatory diagnosis

Intervention

            ·            Programs established in the 1960s

            ·            Parents with children with mental retardation led the political effort to       

                                     legislate newborn screening to prevent consequences of untreated

                                    phenylketonuria (PKU)  

Newborn Screening for PKU:  Neonate with a Positive Test

A newborn was samples at 25 hours of age and was found to have an elevated blood Phenylalanine concentration of 8mg/dl (normal < 4 mg/dl)

PKU:  Response to Positive Screen

            ·            Quantitative analysis of phenylalanine and tyrosine

            ·            If confirmed than initiate special diet

-                     May use breast milk as a substitute

·            Collect blood and urine for biopterin studies on all patients with confirmed

                        phenylalanine elevation

PKU Treatment

            ·            Diet restricted in phenylalanine and supplemented with tyrosine

            ·            Initiate diet by four weeks of age

            ·            Maintain plasma phenylalanine concentrations

                        -            Routine care      3-8mg/dl

                        -            Preconceptual and pregnancy 2-6mg/dl

            ·            Continue throughout life

Gaston et al., NEJM 314:1593, 1986 Concluded:

            ·            Children should be screened for sickle cell disease

            ·            Those with sickle cell disease should receive penicillin prophylaxis by

                                    four months of age

Newborn Screening for the Hemoglobinopathies:  Role of DNA Confirmation

A neonate has an initial hemoglobin electrophoresis screen result that is reported:  FAS.  Review of the medical record reveals a red  cell transfusion prior to sampling for the newborn screen.

Future Directions in Neonatal Hemoglobinopathy Screening

            ·            Apply molecular technology to transfused neonates

            ·            Determine frequencies of a-thal and b-thal alleles in specific ethnic groups

            ·            Improve technology

            ·            Test new technology

Diagnostic Odyssey

A four-year-old male presents with failure to thrive and a chronic cough.  His parents stated that they had seen at least 10 physicians for a total of more than 70 visits with no definitive diagnosis.

Cystic Fibrosis

            ·            Malnutrition from pancreatic failure

            ·            Obstructive pulmonary disease and infection

Screening for Cystic Fibrosis

            ·            Immunoreactive trypsin (IRT) is elevated in blood of neonates with CF even when patients have adequate pancreatic function

            ·            IRT is measured by radioimmunoassay (RIA)

Neonatal CF Screening:  Two-Tiered Approach

            ·            Used by all neonatal CF screening programs

-                     First tier – Elevated IRT

-                     Second tier – DNA analysis for CF mutations

·            Permitted Wisconsin program to reduce IRT threshold, reducing false

                        negatives, without increasing false positives

Delayed Language Skills

An 18-month-old male is seen because he is not communicating verbally.  He appears bright and attentive, and makes his wishes known to his parents and two older siblings by gestures.

Newborn Hearing Screening

            ·            Identify presymptomatically

            ·            Intervene before irreparable damage is done

            ·            Screen 100% of the population

Genetic Causes of Deafness

            ·            Frequency of deafness in childhood 1/500 with 50% due to genetic causes

            ·            Approximately 80% of inherited deafness is non-syndromic and autosomal recessive

·            Mutations in the gap junction protein, connexin 26, represent ~50% of autosomal recessive, non-syndromic  inherited deafness

Connexin 26 (Cx26)

            ·            Cx26 mutations may account for 40% of childhood deafness, 1/2500 live born infants

            ·            Carrier rate of Cx26 mutations is as high as 4% of the population or 1/25

Connexin 26 Mutations

            ·            35delG accounts for ~75-80% of mutant alleles (Cohn et al., Pediatrics 103:546-50, 1999)

            ·            Among Ashkenazim (Morell et al., NEJM 339:1500-5, 1998)

-                     167delT – 4.03% heterozygosity

-                     35delG – 0.73% heterozygosity

·            Conclude Cx26 mutation analysis beneficial in NBS followup

Deafness after Aminoglycoside Treatment

A term neonate was delivered 18 hours after spontaneous rupture of membranes.  The mother developed a fever two hours prior to delivery.  At four hours of age, the neonate was lethargic with a poor suck.  After a septic work-up, he was started on antibiotics, including an aminoglycoside.  Hearing screening was subsequently positive and a careful family history revealed deafness with a maternal inheritance pattern.

Aminoglycoside-Induced Hearing Loss

·            Paradigm for predisposition

-                     Many are exposed

-                     Not all have hearing loss

·            Dose-related susceptibility

-                     Those who are predisposed may be susceptible as a lower dose

·            Nonsyndromic hearing loss may occur in the same families among

                        individuals not exposed to aminoglycosides

·            Mitochondrial mutations are suggested by maternal pattern of inheritance

Aminoglycoside-Induced Hearing Loss (Fischel-Ghodsian, MGM, 65:97-107, 1998)

            ·            Specific mitochondrial DNA mutations are associated with ototoxic hearing loss

            ·            Nuclear encoded genes may modify clinical features (e.g. age at presentation, requirement for drug exposure) among family  members

            ·            Hypothesis for aminoglycoside induced ototoxicity

-                     Mitochondria originally derived from bacterial endosymbiants

-                     Aminoglycosides target bacterial ribosomal RNA (rRNA)

-                     Mitochondrial mutations in susceptible individuals may predispose

Mitochondrial rRNA and protein synthetic machinery to effects from aminoglycosides

Family History of Breast Cancer

A 17-year-old girl complains of “breast pain.”  Examination indicates tenderness over the costochondral junctions consistent with osteochondritis.  As you talk with her, she remains anxious, and you learn that her mother, maternal aunt and maternal great aunt died of breast cancer between 37 and 43 years of age.

Familial Breast Cancer:  Issues

            ·            What is the predictive value of genetic screening for breast cancer mutations?

-                     Study populations

*                    Size

*                    Bias

*                    Ethnicity

·            Is there a preventive approach, and what is its success?

-                     Intervention

*                    Risk/Benefit

*                    Age appropriateness

Changes in Genetic Screening Paradigms

            ·            Moving from traditional analytes (small molecules and proteins) to

                                    molecular genetic testing (DNA and RNA)

-                     Unanticipated consequences

*                    Implications for family unit

*                    Confidentiality/privacy

·            Change from Mendelian disease ascertainment to predictive testing

·            Rapid movement from research to clinical laboratory

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