Genetics for the Sonographer

Jeffrey Kuller, MDProfessor of Obstetrics and Gynecology

OUTLINE

• Testing for aneuploidy

• Increased maternal age

• Previous aneuploid pregnancy

• Hemoglobinopathies

• Sickle cell disease

• Evaluation of mental retardation (including Fragile XSyndrome)

• Genetics of miscarriage

• Recurrent pregnancy loss

INCREASED MATERNAL AGE

•Risk for chromosomal abnormalities inthe fetus increases with advancingmaternal age• Etiology thought to be related to

increased risk for a nondysjunctionalevent in the ovum

TESTING OPTIONS

• Invasive testing

• Amniocentesis

• Chorionic villus sampling

• Noninvasive testing

• First trimester screening - Nuchal translucencycombined with PAPP-A and b-hCG

• Second trimester screening•Triple and Quad screening•Detailed ultrasound

RISK FOR ANEUPLOIDY

•Risk depends on when data interpreted35-year-old woman’s risk of having

a fetus with Down syndrome:1/270 @ second trimester1/365 @ term

WHY AGE 35?

Rate of detection approximately equal torate of procedure-related loss

DOWN SYNDROME(Trisomy 21)

•Most common chromosome abnormalityin liveborns•Comprises approximately 1/2 of all

chromosome abnormalities in liveborns• Always associated with mental

retardation• 50% born with a congenital heart defect• Lowered live expectancy (age 35)

DOWN SYNDROME

•Majority of pregnancies occur inyounger women (80%)• 95% of cases due to Trisomy 21• 5% of cases due to translocation Down

syndromeUsually inherited from one of theparents who carries a “balanced”rearrangement

OTHER CHROMOSOMEABNORMALITIES ASSOCIATED WITH

INCREASED MATERNAL AGE

• Trisomy 18• Trisomy 13• 47, XXY (Klinefelter)• 47, XYY• 47, XXX

PATERNAL AGE

• Few studies have demonstrated a slightlyincreased risk for chromosome abnormalitiesin pregnancies when father is > 55

• Other reports have failed to confirm thesefindings

• Advanced paternal age is associated withincreased risk for new autosomal dominantmutations in offspring

PRIOR ANEUPLOIDY

• The risk for a chromosome abnormalityis a couple who have a previous childwith a trisomy is approximately 1-2%•When the mother reaches age 35, the

risk becomes the same as her age-related risk

PRIOR ANEUPLOIDY

•Couple with previous conception withTrisomy 21 has risk for other aneuploidconceptions, not just Down syndrome• Thought to be due to the fact that the

couple has increased predisposition tonondisjunction of any of thechromosomes in the egg or sperm

MONSOMY X(Turner Syndrome)

• Shield chest•Cardiovascular defects (Coarctation or

VSD) in 10 - 16%•Renal abnormalities in 38%•Wide carrying angle

MONSOMY X(Turner Syndrome)

• Streak gonads with absent oocytes• Decreased adult height (141 - 146 cm)• Normal intellectual function but:•Verbal IQ > performance IQ•Cognitive defects (space-form blindness)

• Hypoestrogenic• Short broad neck

KLINEFELTER SYNDROME47, XXY

• Seminiferous tubule dysgenesis

• Decreased androgen production causes lack of normalsecondary sexual development

• Slightly taller than normal males

• Scoliosis kyphosis, pectus abnormality more common thannormal males

• Increased breast tissue common and 20x rate of breastcancer as normal males

• More likely to be mentally retarded or socially maladjusted

• Personality described as passive, adapt poorly to newsituations

47, XYY

• Patients usually have grossly normaltestes and normal external genitalia•Mean testosterone levels normal

• Tall stature, mental retardation,antisocial behavior are more commonthan in men with normal karyotypes• Likelihood of incarceration perhaps 1%

(0.1% for normal males)

47, XXX

•Most normal phenotype

•More likely to be mentally retarded

•May experience delayed menarche orpremature ovarian failure• Somatic anomalies not usually present

HEMOGLOBIN

• Hemoglobin is a tetramer of 2 pairs of distinctglobin chains

• Hemoglobin A (normal adult hemoglobin):• 2 alpha chains• 2 beta chains

• Each individual has:• 4 genes that code for alpha globin chains

(chromosome 16)• 2 genes that code for beta globin chains

(chromosome 11)

HEMOGLOBINOPATHIES

• 5% of the world population are carriersfor disorders of hemoglobin• Structural variants alter the hemoglobin

molecule e.g. sickle cell anemia

•Decreased production of one or more ofthe globin chains result it thethalassemias

SICKLE CELL ANEMIA

•Currently the only genetic disorderallowing for direct diagnostic testing• Every person with sickle cell anemia

has the same mutation (substitution ofvaline for glutamic acid at position 6 ofthe beta globin chain)

CARRIER TESTING FORSICKLE CELL ANEMIA

•Hb electrophoresis recommended for atrisk individuals• Sickle prep is good screening test but

can not distinguish heterozygote fromhomozygote or determine presence ofHb C

FRAGILE X SYNDROME

•Most common inherited cause of mentalretardation• Estimated frequency of•1/1100-1500 males•1/2000-3000 females

• Inherited as X-linked dominant conditionwith incomplete penetrance

FRAGILE X SYNDROMEClincal Characteristics

•Relatively large head circumference• Long face, prominent forehead, large

ears, macro-orchidism•Hyperactive with speech characterized

by perseverance repetition• Autistic behavior sometimes seen

TESTING FORFRAGILE X SYNDROME

• Associated with folate sensitivecytogenetically identifiable fragile site atband X q 27.3• Fragile X gene (FMR-1) isolated in 1991•Contains a region of unstable DNA with

a (CGG) repeat sequence• Preferred diagnostic test is molecular

FMR-1 GENE

• Normal variation in number of CGG repeatsranges from 6 - 45 copies

• Small amplification (50 - 230 copies)represent premutations (not usuallyassociated with clinical expression ofphenotype)

• Larger amplifications(> 230 copies) representfull mutations and are found in clinicallyaffected males and females and some carrierfemales

FMR-1 PREMUTATIONS

•Remain stable during spermatogenesis•Can amplify to full mutation in

organogenesis• Female premutation carrier can

therefore have clinically affected sonsor daughters, but can also transmit thepremutation in a stable form

PRENATAL DIAGNOSIS

• Available by CVS or amniocentesiswhen mother identified as a carrier ofpremutation or full mutation• Testing performed cytogenetically and

by DNA analysis since experience stilllimited in DNA analysis

UNDEFINED FAMILIALMENTAL RETARDATION

• Thorough 3 generation pedigree•Obtain medical records on affected

individuals•Offer cytogenetic testing to rule out

translocation/inversion and Fragile Xtesting

GENETIC ETIOLOGIES OFMISCARRIAGE

•Chromosome abnormalities cause atleast 50% of spontaneous abortions• Autosomal trisomies form the largest

group of cytogenetically abnormalspontaneous abortions•Monsomy X is the single most common

chromosome abnormality inspontaneous abortion

STRUCTURAL CHROMOSOMEREARRANGEMENTS

•Uncommon cause of spontaneousabortion• Implicated in recurrent miscarriage•Most common parental rearrangement

is translocation

BALANCEDTRANSLOCATIONS

•Robertsonian•Reciprocal•While parents are phenotypically

normal, the offspring may demonstrateunbalanced rearrangements such aschromosomal duplications or deletions

Genetic Science Learning Center:http://gslc.genetics.utah.edu/units/disorders/karyotype/robertsonian.cfm

Robertsonian Translocation

Genetic Science Learning Center:http://gslc.genetics.utah.edu/units/disorders/karyotype/robertsonian.cfm

Robertsonian Translocation

Genetic Science Learning Center:http://gslc.genetics.utah.edu/units/disorders/karyotype/robertsonian.cfm

Robertsonian Translocation

RECURRENT PREGNANCYLOSS

• In a summary of reports published priorto 1988, 3% of parents hadchromosomal abnormalities• This is 6x the rate in the general

population• Translocations and inversions most

common rearrangement

WHEN TO KARYOTYPEPARENTS?

• After 3 consecutive miscarriages• After 2 miscarriages, if:•Couple particularly anxious•Women ≥ 35 years of age at time of

evaluation