CLINICAL CYTOGENETICS Flashcards
- An abnormal amount of DNA
- Usually used in reference to an abnormal number of chromosomes
Aneuploidy
Number of chromosomes in the normal diploid cell, as well as their size distribution
Karyotype
- Can be found in apparently normal looking individuals
- Patients with phenotypic/trait anomalies
- Patients with diagnosed genetic disorders
Cytogenetic Abnormalities
- advanced maternal age
- multiple pregnancy losses (>3)
- known or suspected family history of genetic disease or multifactorial disorder
- ethnicity at increased risk for genetic disease
- teratogen
- abnormal ultrasound findings
- abnormal maternal serum screen results
indications for prenatal diagnosis
- Responsible for 50%-60% spontaneous abortion
- 52% due to autosomal trisomies
- 1 for every 3 spontaneous abortions have chromosomal abnormalities
- Seen in 6:1000 live births
- 90% of 1st month death? – Trisomy 18
- Remain at 6 months level
- Trisomy 13 – Not compatible with life
- Striking – cyclops
- Trisomy 16 – fetal loss in 1st trimester
Prenatal Cytogenetic Abnormalities
- 95% of 45,X
- 90% of Trisomy 13
- 80% of Trisomy 18
- 65% of Trisomy 21
- 15% of recognized genetically abnormal pregnancy end in spontaneous fetal loss
- 80% occur during the 1st trimester
Rate of biological elimination:
- Done to screen for any possible genetic alterations
- Usually done for those who become pregnant at an older age
- Advanced maternal age = incidence of chromosomal abnormalities
Prenatal Chromosomal Analysis
Types of Prenatal Chromosomal Analysis
- Amniocentesis
- Chorionic villus biopsy
- Umbilical cord blood
- Collecting amniotic fluid and culturing the cells to create a karyotype of the growing fetus inside
- Can also be done by measuring the amount of Alpha fetoprotein (AFP) in the fluid
Amniocentesis
- Transcervical/transabdominal chorionic venous sampling
- The chorionic villi are wispy projections of placental tissue that share the baby’s genetic makeup
Chorionic villus biopsy
- Aka Cordocentesis
- Fetal blood is extracted, cultured, and assessed for any abnormalities
Umbilical cord blood biopsy
- Detects neural tube defects which occur in 2:1000 pregnancies
- Not related to mother’s age
- Can also predict Down’s syndrome
Alpha fetoprotein (AFP)
Indications for Prenatal Chromosomal Analysis
- Screening for maternal age-related risk
- Family history of previous child with chromosomal abnormality
- Abnormal levels of AFP in a screening test
- A fetal abnormality detected on ultrasound
- A parent who is carrier of unbalanced gametes
- A parent who is a carrier of X-linked genetic disorder
- 0.6% - 1.0% newborns have gross chromosomal abnormality
- Karyotype analysis is needed
- Indications:
- Presence of multiple congenital anomalies
- Suspected aneuploidy e.g. features of Down Syndrome
Postnatal Chromosomal Analysis
- Indications:
- Unexplained mental retardation or developmental delay
- Suspected sex chromosomal abnormality (Turner Syndrome)
- Suspected unbalanced autosome (Prader-Willi Syndrome)
- Loss of function of genes in Chromosome 15
- Begins as hypotonia, feeding difficulties, delayed development
- During childhood, insatiable appetite, overeating, obesity
- During adulthood, Diabetes mellitus type 2
- Indications:
- Suspected Fragile-X Syndrome
- Infertility
- Multiple spontaneous abortions
Childhood and Adult Cytogenetics
Trisomy 21 or Down Syndrome
Trisomy 13 or Patau Syndrome
Trisomy 18 or Edwards Syndrome
Autosomal Aneuploidies
47XXX females and 47XYY males
Klinefelter Syndrome
Turner Syndrome
Pseudo-hermaphroditism
Sex Chromosome Aneuploidies
- Most common of the chromosomal disorder
- Major cause of mental retardation
- US – 1:700 live births
- Risk increases with the mother’s age
Trisomy 21 or Down Syndrome
92.5% - 95% of Trisomy 21 are
47,XX+21
<3% of Trisomy 21 are:
mosaic with 2 cell lines
(47,XX+21/46,XX or 47XY+21/46XY)
5% of Trisomy 21 have:
46 chromosomes, extra 21 part of Robertsonian or other translocation
- average life expectancy 30 years
- characteristic phenotype
- learning disability (IQ 20-60)
- developmental delay / hypotonia
- delayed puberty / early menopause
Clinical Features of Trisomy 21
- 96% portal tract anomalies / duodenal atresia
- 50% congenital cardiac lesions
- 60% pre-senile dementia
Major Causes of Morbidity and Mortality of Trisomy 21
- Transverse palmar creases (simian crease)
- Heart defects (40%)
- Ostium primum
- Atrial septal defects
- A-V valve malformations
- Ventricular septal defects
- Hypogonadism
Symptoms of Trisomy 21
- Acute Leukemia
- Acute lymphoblastic leukemia
- Acute myeloblastic leukemia
- Infections
- Alzheimer’s Disease
Risks of Trisomy 21
- Triple copies of chromosome 13
- Incidence = 1:4000 to 1:15000 live births
- Caused by: Meiotic nondisjunction
- Associated with increase in Maternal age
Trisomy 13 or Patau Syndrome
Translocation type of Trisomy 13
(46XX,+13,del(13,14)(q10;q10))
Mosaic type of Trisomy 13
(46,XX/47,XX+13)
- Microcephaly
- Mental retardation
- Microphthalmia
- Cleft lip and/or cleft palate
- Cyclopia
- Transverse palmar crease
- Polydactyly of hands and/or feet
- Cardiac defect – VSD
- Renal defect
- Rocker-bottom feet
- Punched-out scalp
Signs and Symptoms of Trisomy 13
- Incidence = 1:8000 live births
- Caused by Meiotic nondisjunction
- Associated with increase in maternal age
Trisomy 18 or Edwards Syndrome
Karyotype of Trisomy 18
Trisomy type (47,XX+18)
Mosaic type of Trisomy 18
(46,XX/47,XX+18)
- Low birth weight
- Mental retardation
- Micrognathia
- Hypoplasia of the muscles
- Prominent occiput
- Low-set malformed ears
- Short neck
- Overlapping fingers
- Heart defects – VSD
- Renal malformations
- Hip abduction
- Rocker bottom feet
- Note: rarely survive beyond 1 year
Signs and Symptoms of Trisomy 18
- Trisomy 13 & 18 less compatible with life, die within the 1st month of life
- Survive: cannot walk, talk or care for themselves
- Option: termination of pregnancy
- Counseling
Summary
- People with sex chromosome aneuploidy have extra or missing sex chromosomes
- 1:500 live births
- Phenotypically milder
- Chronic problems associated with sexual development and fertility
- Recognized at puberty
Sex Chromosome Aneuploidies
- Incidence = 1:1000
- Features: Taller than average
- Generalized learning difficulties
- XXX female and XYY males are fully fertile and have chromosomally normal children
- XYY male
47, XXX females, 47, XYY males
- Incidence = 1:500 live male births
- One of the most common cause of hypogonadism in male
- Cause is meiotic non-disjunction (maternal)
- Clinical features are rarely diagnosed before puberty
Klinefelter Syndrome
Karyotype of Klinefelter Syndrome
47,XXY = 82%
Mosaic type of Klinefelter Syndrome
46,XY/47,XXY or 47,XXY/48XXXY = 15%
- Tall and thin with relatively long legs
- Postpubertal hypogonadism
- Infertility – atrophic testicles
- Hyalinized seminiferous tubules
- Azoospermia
- Small penis
- Absent 2 male sex characteristics
- Gynecomastia
- Lower IQ
- Increased FSH and Estradiol
Signs and Symptoms of Klinefelter Syndrome
- 46,XY/47,XXY mosaic – presents with milder form of abnormality
- Normal testicular development depending on the relative proportion of XXY to XY
- Increased likelihood of fertility with greater increase in XY cells than XXY cells
Karyotype of Klinefelter Syndrome
- More physical abnormalities
- Cryptorchidism - Inability of testes to descend
- Hypospadias - Lack of development of penis
- Prognathism - Extension of lower jaw
- Severe testicular hypoplasia
- Radioulnar synostosis
Polysomic X (47,XXY/48,XXXY)
Inability of testes to descend
Cryptorchidism
Lack of development of penis
Hypospadias
Extension of lower jaw
Prognathism
- Most common sex chromosomal anomaly in females
- Represents the only viable born monosomy
Turner Syndrome
Karyotype of Turner Syndrome
50% = 45, X
Mosaic 10% = 45,X/46,XX
Structural abnormalities of Turner Syndrome
20% = 46,Xi (Xq)
15% = X chromosome del: (46X,del(Xq) or 46X,del(Xp))
* Rings 46,Xr(X))
* Presence of Y chromosome
- Critical region – region of short arm just proximal to the centromere
- X chromosome – maternal origin
- Paternal meiotic nondisjunction - most common cause of error
Turner Syndrome
- Short stature
- Absent 2 female sex characteristics
- Gonadal dysgenesis and amenorrhea
- Normal IQ with learning difficulties
- Bilateral neck webbing
- Low posterior hair line
- Heart and renal anomalies
- Cubitus valgus
- Shield chest
- Autoantibody to thyroid (50%)
- Glucose intolerance
- **Obesity **
Clinical Features of Turner Syndrome
- SRY – Sex-Determining Region of the Y chromosome
- TDF – Testes Determining Factor
- SRY produces a protein called TDF that promotes the development of a testis: the primitive sex cords proliferate and penetrate into the medulla to form the testicular cords
Other Sex Chromosome Abnormalities
- XX male
- Disagreement between:
- Gonadal (XX) - female
- Phenotypic (male) sex
- Clinical Features:
- Normal development of ovaries and internal genitalia
- External genitalia is ambiguous or virilized
Female Pseudo-hermaphroditism
Causes of Female Pseudo-hermaphroditism
Causes:
* Congenital Adrenal Hyperplasia (CAH)
1. Deficiency of enzyme 21-hydroxylase
2. Causing increase androgen production
* Cryptic translocation between X and Y chromosome
* Pseudoautosomal regions
- Homologous distal ends of the short arms of X and Y chromosomes which serves as primary site of X and Y chromosome pairing during meiosis
- Recombination may occur between X & Y alleles resulting in the transfer of unique Y loci together with the SRY to the tip of X-chromosome (rearranged X chromosome)
Pseudoautosomal regions
- Gonadal (XY) male
- Phenotypically female
- Caused by:
- Complete androgen insensitivity syndrome (Testicular Feminization)
- Due to mutations in the gene for androgen receptor located at Xq11-Xq12 (X-linked recessive trait)
- TDF/SRY is absent in the Y chromosome due to translocation
Male Pseudo-hermaphroditism
- Lack of any functional internal genitalia
- Blind vagina
- Testes in the abdomen or inguinal canal causing infertility
- Rarely, lack of 2 intact copies of proximal X short arm
Clinical Features of Male Pseudo-hermaphroditism
- Prader-Willi Syndrome and Angelman Syndrome
- Interstitial deletion of the proximal long arm of chromosome 15,del(15)(q11.2q13)
Microdeletion Syndromes
- Involves deletion of maternally-derived chromosome 15
- Molecular basis – affects the gene, ubiquitin protein ligase (UBE3A gene located within the 15q12 region)
Angelman Syndrome
- Severely mentally retarded
- Cannot carry a normal conversation, inappropriate laughter (happy puppet)
- Hyperactive
- Short stature
- Microcephaly
- Seizure and ataxia
Clinical Features of Angelman Syndrome
- Deletion of paternally-derived chromosome 15
- No single gene has been implicated, series of gene located at 15q11.2-13 are believed to be involved
Prader-Willi Syndrome
- Small, hypotonic at birth
- Obese because of overeating
- Small hands and feet
- Hypogonadism
- Bad temper
Clinical Features of Prader-Willi Syndrome
- Routine or High-resolution cytogenetic analysis
- Prader-Willi syndrome – 60%
- Angelman syndrome – 10-20%
- FISH – 80-85% of cases
- Fluorescence In-Situ Hybridization
Testing for Microdeletion Syndromes
