finals 20% Flashcards
- Genetic abnormalities can already
be diagnosed even before birth
(within the womb)
Prenatal Cytogenetics
- Genetic abnormalities can be
diagnosed after birth
Postnatal Cytogenetics
- Babies are born at a normal
pregnancy but manifests a
genetic abnormality later in life
(either physical or mental
disabilities)
Childhood and Adult Cytogenetics
_______ Syndrome
Features:
○ Flat nose bridge
○ Slanted eyes
○ Broad and prominent palpebral fissures
down
Rate of biological eliminations:
○ __% of 45,X
95
rate of biological eliminations
__% of Trisomy 13
90
rate of biological eliminations
__% of Trisomy 18
80
rate of biological eliminations: __% of Trisomy 21
65
15% of recognized pregnancies end in
spontaneous fetal loss, 80% of which occur
during the ____trimester (first 3 months)
first
- the most common
chromosomal error in spontaneous losses
45,X (Turner Syndrome)
- the most common trisomy seen in
abortus
Trisomy 16
INDICATIONS FOR __________ CYTOGENETICS:
1. Screening for maternal age-related risk
2. Family history of previous child with
chromosomal abnormalities
3. Abnormal levels of AFP (Alpha-fetoprotein)
in a screening test
PRENATAL
- A fetal abnormality detected on ultrasound
- A parent who is a carrier of unbalanced
gametes - A parent who is a carrier of X-linked genetic
disorder
are indications for _________ cytogenetics
prenatal
Karyotype analysis on both biological parents is used
to differentiate between an inherited rearrangement
and a ?
“de novo” anomaly in the child
This pose less risk for
related impairment than “de novo” inheritance but
may recur in future pregnancies
Inherited rearrangement
Approximately 0.6% - 1% if all newborns have
gross chromosomal abnormality
___________ cytogenetics
postnatal cytogenetics
INDICATIONS FOR __________ CYTOGENETICS:
1. Presence of multiple congenital anomalies
2. Suspected aneuploidy (e.g: features of
Down Syndrome)
POSTNATAL
● Some genetic disorders manifest in later life
● One of the most difficult diagnostic problem such
that other than cytogenetic studies, molecular
biochemical studies may be needed
____________CYTOGENETICS
CHILDHOOD AND ADULT CYTOGENETICS
INDICATIONS FOR ______________
CYTOGENETICS
1. Unexplained mental retardation or
developmental delay
2. Suspected unbalanced autosome (ex:
Prader-Willi syndrome)
3. Suspected sex chromosomal abnormality
(ex: Turner syndrome)
CHILDHOOD AND ADULT
- Suspected fragile-X syndrome
- Infertility – to rule out sex chromosomal
abnormality - Multiple spontaneous abortions – to rule
out the parents as carriers of balanced
translocations where both parents should
be evaluated
are indications for?
adult and chldhood cytogeneticx
Defect on Chromosome 15
○ Insatiable appetite
○ Higher threshold for pain
what syndrome is thiz
prader-willi syndrome
○ Outbursts of rage
○ There may be sleep disorders and
abnormalities
○ Compulsive behaviors such as
picking at the skin and even
psychoses
what syndrome iz this
prader-willi
Defect on Chromosome 15
○ Uncontrollable laughing
○ Ataxia
○ Mental disabilities
○ Physical disabilities
what syndrome
angelman syndrome
Specific chromosome rearrangements are directly
associated with ?
tumorigenesis
- Confirm a clinical diagnosis
- Monitor disease progression – relapse and
disease progression - Monitor patient’s response to therapy –
successful treatment results in cytogenetic
remission
are indicators for?
cancer cytogeneticx
a valuable tool in clinical oncology studies
FISH
In ______, we label the antibodies with
fluorescent dye that are used against the
antigen (mga chromosomal
abnormalities). If they bind together, they
will fluoresce
FISH
_________of signals - occur if the translocation
results in separation of two probes generating
two-different colored signals in place of the
original single-color signal
Splitting
________ of signals occur if the translocation results
in the relocation of 2 different probes into proximity
causing generation of a new color
Fusion (CENTRIC OR ROBERTSONIAN TRANSLOC)
t(9;22)(q34;q11.2)
acute lymphoblastic leukemia (ALL),
t(8:;21)(q22;q22)
acute myeloid leukemia (AML),
t(9;22)(q34.1;q11.2);
chronic myeloid leukemia (CML),
_____—- for BCR locus on chromosome
22
Green
___________________- will give two green and two red signals for the ABL and BCR alleles in each cell
Normal chromosome
formed with the
● fusion of green and red signals
A yellow signal
The ABL is located in the near end of the long arm
of chromosome 9 and the BCR gene is near the
centromere of the long arm of chromosome 22.
PHILADELPHIA CHROMOSOME
The chromosome break occurs in the ABL and
BCR gene which prompts the translocation.
PHILADELPHIA CHROMOSOME
The derivative chromosome 22 is also known as
the ?
Philadelphia chromosome
It detects all nucleated cells both normal
and abnormal,
FISH
Karyotyping can only be performed on
_______ cells
dividing
The ________- will identify the chromosomal abnormalities
karyotype
________ will establish the baseline frequency
of leukemic clones which can be used as
reference point for all the patients’ future
testing
FISH
__________- has also been used to study
leukemic cell lines
Multicolor FISH
Which of the following specimens is not used
for prenatal cytogenetic testing?
A. Umbilical cord blood
B. Fetal bladder aspirate
C. Amniotic fluid
D. Chorionic villi
B. FETAL BLADDER ASPIRATE
Although chromosomal abnormalities are
present in 1:3 conceptuses, only 6:1000 live
births manifest the disorder. Which of the
following explains this low incidence at birth?
A. Repair mechanism of recognized errors
B. Biological elimination of recognized errors
C. Poor identification of genetic abnormalities
D. Low interest on genetic abnormalities
B. Biological elimination of recognized errors
Genetic abnormalities are not seen in which of
the following individuals
A. Seemingly normal
B. With gross deformities
C. With confirmed genetic disorder
D. None of these
NONE
Philadelphia chromosome or abl-bcr fusion
gene is a diagnostic of which of the following
hematopoietic malignancy?
A. Acute myelogenous leukemia
B. Acute lymphoblastic leukemia
C. Chronic myelogenous leukemia
D. Chronic lymphocytic leukemia
C. Chronic myelogenous leukemia
Diseases with abnormal chromosomal number or alterations in structure of one or more chromosomes
cytogenetics disorders
complete sets of chromosomes with
none extra or missing.
The normal cells are diploid, having 2 sets of 23 chromosomes
euploidy
opposite of euploidy; where 1 or more individual chromosomes are with extra or missing from a euploid set
aneuploidy
missing pair of homologs
■ Ex: pair of chromosomes 6
nullisomy
1 chromosome is missing
■ Ex: Monosomy X (45,X); occurs at
embryonic stage; lethal
monosomy
3 copies of a particular
chromosome in an otherwise diploid cell
■ Ex: Trisomy 21 (47, XX or XY
+21); embryonic or fetal stage which may be lethal
trisomy
TRISOMY __ (DOWN SYNDROME)
● Mostcommon of the chromosomal disorders
● Majorcause of mental retardation
● Bands21q22.12-21q22.3
trisomy 21
➢ Mentalretardation
➢ Prominentepicanthic fold
➢ Flatfacial profile
➢ Simiancrease
➢ Congenitalheart defects
are manifestations of
trisomy 21
➢ Umbilicalhernia
➢ Intestinalstenosis
➢ Hypotonia→ muscleweakness→ called Floppy
babies
➢ Heartdefects (40%)
hypogonadism
are manifestations of
TRISOMY 21
Facial features of?
➢ Flatfaces ➢ Smallears ➢ Protrudingtongue
trisomy 21
Clinical manifestations of?
➢ Lowbirth weight
➢ Heartdefect
➢ Overlappingfingers
➢ Rockerbottomfeet
trisomy 18 Edward syndrome
Clinical manifestations of?
➢ Mentalretardation
➢ Microcephaly(smaller head)
➢ Microphthalmia(smaller eyes)
➢ Polydactyly(extra fingers)
➢ Cleftlip and palate
trisomy 13 patau syndrome
SEX CHROMOSOME ANEUPLOIDIES incidence:
1:500 livebirths
● Phenotypicallymilder than autosomal aneuploidies
● Subtle, chronic problems associated with sexual
development and fertility
● Difficultto diagnose at birth and usually
recognized at puberty
sex chromosome aneuploidies
● Difficultto diagnose at birth and usually
recognized at puberty (when secondary sex characteristics develop)
● Thehigher the number of X chromosomes in both
male and female, the higher the possibility of mental retardation
sex chromosome aneuploidies
➔ 47, XXX females and 47, XYY males
➔ Klinefelter Syndrome
➔ Turner Syndrome
➔ Pseudohermaphroditism
➔ Hermaphroditism
sex chromosome aneuploidies
● Oftengo undetected throughout life
● Incidence1:1000
● Fullyfertile and have chromosomally normal
children
47 XXX FEMALES AND 47 XYY MALES
● XXYmales have increased risk for behavioral
problems and are anti-social with criminal tendencies which has been negated by subsequent findings
47 XXX FEMALES AND 47 XYY MALES
Clinical manifestations of??
➢ Tallerthan average
➢ Somewith generalized learning difficulties
identified in school screening programs
47 XXX FEMALES AND 47 XYY MALES
● Oneof the most frequent sec chromosomal
disorders
● Incidence: 1:500 live male births
● Oneof the most common causes of hypogonadism
in male
KLINEFELTER SYNDROME
● Rarelydiagnosed before puberty
● Postpubertalhypogonadism
● Infertilitydue to small atrophic testicles with
hyalinized seminiferous tubules and azoospermia
KLINEFELTER SYNDROME
Clinical manifestations of?
➢ Distinctivebody habitus
➢ Talland thin with long legs
➢ Smallpenis
➢ Absenceof 2nd malesex characteristics
KLINEFELTER SYNDROME
➢ Gynecomastia(breast development)
➢ LowerIQ
➢ IncreasedFSH and estradiol
are clinical manifestations of
KLINEFELTER SYNDROME
○ Morephysical abnormalities
○ Cryptorchidism(testicles are
undescended)
○ Hypospadias(orifice of urethra is located
on the under surface of the penis
PolysomicX (47,XXY/48,XXXY)
○ cause din sha ng Klinefelter Syndrome
○ Prognathism
○ Severetesticular hypoplasia
○ Radioulnarsynostosis (connection
between radius and ulna - difficulty in movement
PolysomicX (47,XXY/48,XXXY)
● Mostcommon sex chromosomal anomaly in
female
● Onlyviable in live born monosomy
turner syndrome
Thecritical region for female differentiation is at the
region of the short arm just proximal to the centromere
○ ABSENCE→ ??
turner syndrome
➢ Lowposterior hairline
➢ Heartand renal anomalies
➢ Cubitusvalgus and shield chest
➢ Autoantibodyto thyroid (50%)
➢ Glucoseintolerance
➢ Obesity
are manifestations of
turner syndrome
_______ sex - determined presence or
absence of Y chromosome → IfY is present, individual is a
Genetic
______ sex - histologic characteristics of the gonads
→ Ifone has seminiferous tubules with developing sperm cells, individual is a male
→ Ifone has ovarian follicles, individual i s a female
gonadal
______ sex - depends on the presence of
derivatives of mullerian or wolfian ducts
ductal
__________produced by TDF initiates the male
developmental pathway
proteins
● Disagreementbetween gonadal (XX) and
phenotypic (male) sex
● Congenitaladrenal hyperplasia due to deficiency of
enzyme 21-hydroxylase
FEMALE PSEUDOHERMAPHRODITISM (XX MALE
Clinical features of?
➢ Normalovaries and internal genitalia
➢ Externalgenitalia is ambiguous or virilized
FEMALE PSEUDOHERMAPHRODITISM (XX MALE
Mostcomplex of all disorders of sexual
differentiation
○ Androgeninsensitivity/Testicular
feminization
■ Androgen receptor gene mutation,
located in the long arm: Xq11-Xq12
○ TDF/SRY is absent in the Y chromosome
due to translocation
MALE PSEUDOHERMAPHRODITISM (XY FEMALE)
Clinical features of
➢ Lackof any internal genitalia
➢ Blind vagina
➢ Testes in the abdomen or inguinal canal causing
infertility
MALE PSEUDOHERMAPHRODITISM (XY FEMALE)
● Exceedinglycomplex (sexual ambiguity)
● Truehermaphrodites = both ovarian and testicular
tissues (one on each side or ovotestes
HERMAPHRODITISM
● Extremelyrare
● Mostcommon karyotype: 46,XX (50%); the rest
mostly are mosaic: 46,XX/46,XY karyotype; rarely 46,XY
HERMAPHRODITISM
- Diseases with abnormal chromosomal number or
alterations in structure of one or more chromosomes
CYTOGENETIC DISORDERS
● Terminal deletion of the short arm of chromosome
4, del(4)(p16)
WOLF-HIRSCHHORN SYNDROME (4P-)
Clinical manifestations of?
➢ Microcephaly
➢ Frontal bossing
➢ Micrognathia (small jaw)
➢ Hypotonia
➢ Epicanthal folds
➢ Developmental delay
WOLF-HIRSCHHORN SYNDROME (4P-)
● Greek warrior facial helmet appearance due to
arched eyebrows, prominent glabella,
hypertelorism, and long beaked nose
WOLF-HIRSCHHORN SYNDROME (4P-)
● Special education and are at risk for seizures
➔ Diagnosis: Karyotyping and FISH
wolf-hirschhorn syndrome
● Deletion of the short arm of chromosome 5, del
(5)(p15)
CRI-DU-CHAT SYNDROME (5P-)
Clinical manifestations of?
➢ High-pitched cat like cry
➢ Low birth weight
➢ Slow growth
➢ Hypotonia
➢ Microcephaly
➢ Hypertelorism
➢ Epicanthal folds
➢ Cardiac anomalies
➢ Mental retardation
cri-du-chat syndrome
Patients have delayed development and may
reach cognitive and social level of a 5 or 6 year old
cri du chat syndrome
nvolve a fraction of a single
chromosome band (>500 kb) and may be large
enough to identify by karyotype analysis but most
may require FISH for detection
Microdeletions
involve a single to several
hundred base pair and are identified by molecular
technology
Molecular Deletions
- those that are due
to deletions that encompass several adjacent,
unrelated genes resulting in variable phenotypic
expression
Contiguous Gene Syndrome
● Deletion of the elastin gene (ELN gene) on the
proximal long arm of chromosome 7 (7q11.23)
● Unequal meiotic crossover → interstitial deletion
WILLIAM’’S SYNDROME
Elastin is important in:
○ Heart
○ Blood vessels
○ Skin
○ Vocal cords
→ is absent among these patients, thus the clinical
features except behavioral anomalies which may be
explained as a contiguous gene syndrome
what syndrome
william’s syndrome
Clinical manifestations of?
➢ Low IQ with behavioral anomalies
➢ Hypersensitivity to sound
➢ Blue eyes with stellate pattern in the iris
➢ Prominent lips with hoarse voice
➢ Supravalvular aortic stenosis and other cardiac
defects
➢ Hypertension
➢ Premature aging of the skin
➢ Hypercalcemia
william’s syndrome
● Due to del 8p24.11-q24.13, involving the TRPSI,
TRPSII, EXTgenes
LANGER-GIEDION SYNDROME
Clinical manifestations of?
➢ Craniofacial dysmorphism
➢ Exostosis
➢ Skeletal abnormalities
➢ Mild to severe mental deficiency
➢ Fine scalp hair
➢ Large and prominent ears
➢ Missing teeth
➢ Trichorhinophalangeal syndrome
langer-giedon syndrome
● Wilm’s tumor, Aniridia, Genitourinary defects, and
mental Retardation (75%)
● Deletion on the short arm of chromosome 11
(11p13.3) involving WT1 gene, AN2 gene causing
contiguous gene syndrome
WAGR SYNDROME
Deletion of one copy of PAX6 gene → aniridia &
MR; brain-derived neurotrophic factor (BDNF gene)
→ hyperphagia and obesity
wagr syndrome
Patients with _______has 1:3 chance of developing
Wilm’s tumor but patients with Wilm’s tumor have
1:50 chance of having aniridia.
aniridia
● del 13q14.1-q14.2, involving Rb gene
● May also occur by hypermethylation of the
promoter sequence
RETINOBLASTOMA
● Patients have risk of developing tumors of the
retinoblast cells of the eye
● PHL > 1:18000
● 90% diagnosed before 5 y/o
→ Diagnosis: Karyotyping or Southern Blot
retinoblastoma
● Best known microdeletion syndromes
● Share the same interstitial deletion of the proximal
long arm of chromosome 15 del(1)(q11.2-q13),
PRADER-WILLI AND ANGELMAN SYNDROME
● Broad Thum-Hallux syndrome, AD, mostly
acquired
● del 16p13.3, CREBBP gene, regulates cell growth
and division for normal fetal development: EP300
gene, small % of cases
RUBINSTEIN-TAYBI SYNDROME
Clinical manifestations of ??
➢ Beaked nose
➢ Prominent columella
➢ Hypoplastic maxilla
➢ Down slanted palpebral fissures
➢ Broad thumbs
➢ First toes
➢ Hirsutism
➢ Short stature
➢ Mental retardation
➢ Speech delay
RUBINSTEIN-TAYBI SYNDROME
● del 17p11.1, RAI1 gene
● Not inherited
● Deleted during formation of reproductive cells
SMITH-MAGENIS SYNDROME
Clinical manifestations of?
➢ Brachycephaly
➢ Broad nasal bridge
➢ Prominent jaw
➢ Short broad hands
➢ Hyperactivity
➢ Mental retardation
➢ Delayed speech
➢ Self-destructive behavior
smith-magenis syndrome
● Two stereotypic behaviors: spasmodic upper-body
squeeze or “self-hug” and hand licking and page
flicking “lick and flip”, are specific to SMS
→ Diagnosis: Karyotyping and or FISH
smith-magenis syndrome
● Microdeletion of the distal short arm of
chromosome 17 (17p13.3), involving the LIS1
gene, with the deletion of at least 2 genes
MILLER-DIEKER SYNDROME AND LISSENCEPHALY
_____________ is associated with profound mental
retardation and seizures
Lissencephaly
● Possible the most common microdeletion
syndrome, occurring in 1:4000 live births, but not
often recognized
● 3 Mb deletion on the proximal long arm of
chromosome 22 (22q11.2), GCSL gene
VELOCARDIOFACIAL SYNDROME
Usually diagnosed in newborns because of:
○ feeding difficulties due to palatal
abnormalities (cleft palate)
○ cardiac defects (75%)
○ characteristics with facial dysmorphisms
with prominent nose and retrognathia
velocardiofacial syndrome
● del22q11.2, 10p, 1q, 6q involving GCSL gene
DIGEORGE SYNDROME
➢ Cleft palate
➢ Heart defect
➢ Hypoplasia of the thymus with resultant T-cell
immunodeficiency
➢ Parathyroid hypoplasia giving rise to severe
hypocalcemia, and seizures
are Clinical manifestations of
digeorge syndrome
● del Xp22.32, involving the STS gene
ICHTHYOSIS
Clinical manifestations of?
➢ Scaly skin
➢ Short stature
➢ Hypogonadism
➢ Mental retardation
itchthyosis
● del Xp22.3, involving the KAL1 gene
Clinical manifestations:
➢ Hypogonadism
➢ Inability to smell
kallman syndrome
● Mutation in single gene with large effects
MENDELIAN DISORDERS
expressed in mathematical
terms
penetrance
If a trait is seen in all individuals carrying
the mutant gene but is expressed
differently among individuals, the
phenomenon is called ?
variable expressivity
_____________ SYNDROME
● 600 mutations, mostly missense
● Fibrillin-I or FBNI gene → Fibrillin I protein
● FBNI on 15q21.1; FBN2 on 5q23.31
AD - MARFAN
Fibrillin I protein
○ Component of microfibrils
○ Provides skeleton on which tropoelastin is
deposited to form elastic fibers (aorta,
ligaments and ciliary zonules)
what syndrome
ad- marfan
➢ Mitral valve prolapse (MVP) → mitral regurgitation
(MR)
➢ Aneurysm of the ascending aorta → valve
incompetence → left ventricular hypertrophy (LVH)
→ heart failure (HF)
are manifestations of what syndrome?
ad-marfan
● Defect in synthesis of fibrillar collagen
● Encompasses the 3 patterns of transmutants:
○ May be transmitted through autosomal
recessive
○ As a sex-linked disorder
● Group of clinically and genetically heterogeneous
disorders
AD (AR, X-LINKED) - EHLERS-DANLOS SYNDROME (EDS)
________ may be caused by mutations involving
structural proteins or enzymes
EDS
Common manifestations 0f ________________ involve the:
➢ Skin (hyperextensibility)
➢ Ligaments
➢ Joints (hypermobility)
AD (AR, X-LINKED) - EHLERS-DANLOS SYNDROME (EDS)
● 1:2,500 live births, carrier rate of 1:20
● Most common lethal genetic diseases affecting
Caucasians CFTR gene, 7q31.2
AR - CYSTIC FIBROSIS
Disorder of ion transport in epithelial cells of
exocrine glands and lining epithelial cell of the
respiratory, GI and reproductive tracts
ar-cystic fibrosis
● Hereditary deficiency of one of the enzymes
involved in glycogen synthesis or degradation.
● Enzymatic defects dictate the organ of involvement
(distribution)
AR - GLYCOGENOSIS
________ Forms
➔ Von Gierke/Type I
◆ Glucose-6-phosphate deficiency
➔ Liver phosphorylase and Debranching enzymes
➔ Hepatomegaly and hypoglycemia
Hepatic
________ Forms
➔ McArdle disease/Type V
◆ Muscle phosphorylase deficiency
➔ Type VII
◆ Muscle phosphofructokinase deficiency
➔ Failure of ATP production → muscle cramps and
lactate level fail to rise
Myopathic
● Deletion, Xp21
● May result from frameshift mutation, point mutation
● 2/3 familial, 1/3 de novo
SLD - DUCHENNE MUSCULAR DYSTROPHY
● Females are carriers, asymptomatic, increased
creatine kinase
● Males manifest at 5 y/o, wheelchair-dependent at
10-12
SLD - DUCHENNE MUSCULAR DYSTROPHY
● Normal at birth
● Delayed walking due to muscle weakness
● Pelvic girdle muscles are the first to weaken
● Pseudohypertrophy of leg muscles
SLD - DUCHENNE MUSCULAR DYSTROPHY
● Pseudohypertrophy of leg muscles
○ Increase fiber size then replacement by
connective tissue, fat
● Heart involvement → failure and arrhythmia →
death
SLD- DUCHENNE MUSCULAR DYSTROPHY
● Diminished dystrophin
● Mutation causes synthesis of abnormal, smaller
protein
BECKER MUSCULAR DYSTROPHY
● Onset during late childhood or adolescence (later
than Duchenne)
● Heart disease
● Normal lifespan
BECKER MUSCULAR DYSTROPHY
● Second leading cause of mental retardation
and is the primary cause of inherited mental
retardation
● 1:1550 for affected males and 1:8000 for affected
females
SLD - FRAGILE X SYNDROME
● Break or gap in the structure of the X
chromosome that can be detected cytogenetically
SLD - FRAGILE X SYNDROME
In SLD-FRAGILE X SYNDROME, A normal transmitting male and carrier female have _________ repeats (premutations) whereas affected individuals, 200 – 4000 repeats (full
mutation)
55 – 200
Clinical manifestations of WHAT SYNDROME in affected males:
➢ Mentally retardation
➢ Long face with macrognathia
➢ Large everted ears
➢ Macroorchidism (90% of postpubertal males)
SLD-FRAGILE X SYNDROME
Clinical features of fragile X syndrome worsen with
each generation (anticipation).
T OR F
TRUE! Padagdag ng padagdag ang clinical
manifestations per generation
