Chromosome

Mutations: Autosomal
Aneuploidies
Miguel Lorenz C. Parawan, RMT
Objectives

1. Students will be able to explain the mechanisms and

etiology by which nondisjunction occur.
2. Students will be able to determine aneuploidies (e.g.
trisomies, tetrasomies, monosomies).
3. Students will be able to identify key characteristic features
of the different aneuploidies, as well as determine its case
incidence and genetic phenotype.
4. Students will be able to define terminologies related to
aneuploidies.
Aneuploidies
Week 9
Aneuploidy

● Aneuploidy refers to cytogenetic abnormalities

in which all or part of one or more
chromosomes is duplicated or deleted.
○ Numerical abnormalities are whole chromosomes, either missing
from or extra to the normal pair.
○ Structural abnormalities are when part of an individual
chromosome is missing, extra, switched to another chromosome, or
turned upside down.
Numerical Aberration
Mechanism and
Etiology
Autosomal Aneuploidies
Nondisjunction

● Errors in meiosis (nondisjunction) result in gametes

that contain abnormal numbers of chromosomes and,
following fertilization, produce aneuploid conceptus.
● The association between autosomal aneuploidy and
maternal age has long been recognized.
In 1933, Penrose demonstrated that maternal age was the key
factor for the birth of Down syndrome children.
Nondisjunction
● Studies using Fluorescence in situ hybridization (FISH) or
primed in situ labeling (PRINS) have shown that the
frequency of autosomal aneuploidy in human sperm is
relatively uniform for all chromosomes studied (chromosomes
3, 7, 8, 9, 10, 11, 13, 16, 17, 21).
Images using FISH
Meiosis I and II

Nondisjunction can
occur during either
meiosis I (MI) or
meiosis II (MII).
Meiosis I Nondisjunction

● In Meiosis I (MI), homologous chromosomes pair and

form bivalents.
● Malsegregation of homologous chromosomes can
occur in one of two ways:
The first involves nondisjunction of the bivalent chromosomes with both
homologs going to the same pole.

The second type of error involves premature separation of the sister

chromatids of one homolog of a chromosome pair.
Meiosis I Nondisjunction
Cause: Nondisjunction of the bivalent
chromosomes
( a ) Prophase I.
( b ) Metaphase I.
( c ) Anaphase I.
( d ) Telophase I, with both homologs of
one chromosome pair segregating
together.
( e ) Products of meiosis I.
( f ) Metaphase II.
( g ) Anaphase II.
( h ) Meiotic products — two gametes
lack one chromosome and two gametes
contain two copies of one chromosome
Meiosis I Nondisjunction
Cause: Premature sister chromatid
separation
( a ) Prophase I.
( b ) Metaphase I.
( c ) Anaphase I, with premature separation of
centromere of one chromosome.
( d ) Telophase I, with one prematurely
separated chromatid segregating with its
homologous chromosome.
( e ) Products of meiosis I.
( f ) Metaphase II.
( g ) Anaphase II.
( h ) Meiotic products — two gametes with a
normal chromosome complement, one gamete
lacking one chromosome, and one gamete
containing two copies of one chromosome.
Meiosis II Nondisjunction

● In MII, sister chromatids separate.

● Malsegregation occurs when both chromatids

go to the same pole.
Meiosis II Nondisjunction

( a ) Prophase I.
( b ) Metaphase I.
( c ) Anaphase I.
( d ) Telophase I.
( e ) Products of meiosis I.
( f ) Metaphase II.
( g ) Anaphase II, with both sister chromatids
segregating together.
( h ) Meiotic products — two gametes with a
normal chromosome complement, one gamete
lacking one chromosome, and one gamete
containing two copies of one chromosome.
Autosomal
Aneuploidies
SUMMARY OF COMMON
AUTOSOMAL ANEUPLOIDIES
ANEUPLOIDY CHROMOSOMAL ANEUPLOIDY CHROMOSOMAL
ABERRATION ABERRATION

HYPERPLOIDY
8 5p
9 8p
13 Tetrasomy 9p
Trisomy 16 (Partial Aneuploidies) 12p
18 18p
20
21
22
SUMMARY OF COMMON
AUTOSOMAL ANEUPLOIDIES

ANEUPLOIDY CHROMOSOMAL ABERRATION ANEUPLOIDY

HYPOPLOIDY

21
Monosomy Nullisomy
22
SUMMARY OF COMMON SEX
CHROMOSOME ANEUPLOIDIES

ANEUPLOIDY NOMENCLATURE

45, X (45, XO) Turner syndrome

47, XXY Klinefelter syndrome

47, XXX Triple X syndrome, Trisomy X

47, XYY Jacobs syndrome (YY syndrome)

48, XXYY Double-man syndrome, XXYY syndrome

HYPERPLOIDY
Trisomy
Tetrasomy
TRISOMY

Trisomy 8
Trisomy 9
Trisomy 13
Trisomy 16
Trisomy 18
Trisomy 20
Trisomy 21
Trisomy 22
TRISOMY 18
EDWARDS’ SYNDROME

● Karyotype nomenclature: 47,(XX or XY),+18

● Distribution: 1 in 6,000– 8,000 births
● It is more frequent in females, with a male-to-female
ratio of 1:3–4.
● The risk for trisomy 18 also increases with maternal
age.
TRISOMY 18
EDWARDS’ SYNDROME

● Key clinical features: Mental and growth deficiencies,

neonatal hypotonicity followed by hypertonicity,
craniofacial dysmorphism, short sternum, hernias,
single umbilical artery, small pelvis, cryptorchidism,
hirsutism, and cardiac anomalies.
TRISOMY 18
TRISOMY 21
DOWN SYNDROME

● Karyotype nomenclature: 47,(XX or XY),+21

● Distribution: 1 in 700 births
● It is the most common single known cause of mental
retardation and is more frequent in males, with a
male-to-female ratio of 1.2:1.
● Reported to have a 10- to 20-fold increase in the risk
for leukemia, most commonly Acute Megakaryoblastic
Leukemia (AML).
TRISOMY 21
DOWN SYNDROME

● Key clinical features: Craniofacial appearance with

upward-slanting palpebral fissures, epicanthal folds,
flat nasal bridge, small mouth, thick lips, protruding
tongue, flat occiput, and small and overfolded ears.
TRISOMY 21
TRISOMY 13
PATAU SYNDROME

● Karyotype nomenclature: 47,(XX or XY),+13

● Distribution: 1 in 12,000 births
● It is seen slightly more in females than in males, with
the risk for trisomy 13 increasing with maternal age.
TRISOMY 13
PATAU SYNDROME

● Key clinical features: Holoprosencephaly spectrum,

scalp defects, microcephaly with sloping forehead,
large fontanels, capillary hemangioma ,
microphthalmia, cleft lip, cleft palate, abnormal
helices, flexion of the fingers, polydactyly, hernias,
single umbilical artery, cryptorchidism, bicornuate
uterus, cardiac abnormalities.
TRISOMY 13
TRISOMY 8
WARKANY SYNDROME

● Karyotype nomenclature: 47,(XX or XY),+8

● Distribution: It is rare, with an unknown incidence.
● More than 100 cases have been reported in the
literature, most of them mosaics.
● The male-to-female ratio is 2–3:1.
TRISOMY 8
WARKANY SYNDROME

● Key clinical features: Prominent forehead, deep-set

eyes, strabismus, broad nasal bridge, upturned nares,
long upper lip, thick and everted lower lip, high arched
or cleft palate, micrognathia and large dysplastic ears,
long and thin trunk, hemivertebrae, spina bifida,
kyphoscoliosis, hip dysplasia, multiple joint
contractures, camptodactyly, dysplastic nails, and
absent or dysplastic patella.
TRISOMY 8
TRISOMY 9

● Karyotype nomenclature:
○ Mosaic: [47,+9/46]
○ Non-mosaic: 47,(XX or XY),+9
● Distribution: It is rare, with an unknown incidence.
● More than 40 cases of liveborns or term stillborns
with trisomy 9 have been reported.
● The male-to-female ratio is close to 1:1.
TRISOMY 9

● Key clinical features: High narrow forehead, short

upward-slanting palpebral fissures, deep set eyes,
microphthalmia, low-set malformed auricles, bulbous
nose, prominent upper lip, micrognathia, overlapping
fingers, hypoplastic external genitalia, and
cryptorchidism.
TRISOMY 9
TRISOMY 16

● Karyotype nomenclature: 47,(XX or XY),+16

● Trisomy 16 is the most frequently observed autosomal
aneuploidy in spontaneous abortuses.
○ Full trisomy 16 is almost always lethal during early embryonic
or fetal development, although a single case of a stillborn at
35 weeks gestation has been recorded.
TRISOMY 16

● Key clinical features: Postnatal growth retardation,

mild developmental/speech delay, craniofacial
asymmetry, ptosis, fl at broad nasal bridge, lowset
dysplastic ears, hypoplastic nipples, umbilical hernia,
deep sacral dimple, scoliosis, nail hypoplasia, and
single transverse palmar crease
TRISOMY 16
TRISOMY 22
EMANUEL SYNDROME

● Karyotype nomenclature: 47,(XX or XY),+22

● More than 20 live borns have been reported in the
literature.
● Most non-mosaic patients die in the first months of
life.
TRISOMY 22
EMANUEL SYNDROME

● Key clinical features: Intrauterine growth restriction,

low-set ears and midfacial hypoplasia.
● Other frequently seen abnormalities are
microcephaly, hypertelorism with epicanthal folds,
cleft palate, micrognathia, webbed neck, hypoplastic
nails, anal atresia/stenosis, and hypoplastic genitalia.
TRISOMY 22
TRISOMY 20

● Karyotype nomenclature: 47,(XX or XY),+20

● One of the most frequent autosomal aneuploidies
detected prenatally, but its occurrence in liveborns is
very rare.
TRISOMY 20

● Key clinical features: Spinal stenosis, vertebral fusion,

kyphosis, hypotonia, lifelong constipation, sloped
shoulders, and signi fi cant learning disabilities,
microcephaly, facial dysmorphism, cardiac defects,
and urinary tract anomalies.
TRISOMY 20
TETRASOMY

Tetrasomy 5p
Tetrasomy 8p
Tetrasomy 9p
Tetrasomy 12p
Tetrasomy 18p
TETRASOMY 5p

● Karyotype nomenclature: 47,(XX or XY),+i(5)(p10)

● Results from the presence of a supernumerary
isochromosome for the entire short arm of
chromosome 5.
● Key clinical features: hypotonia, seizures/abnormal
electroencephalogram (EEG), psychomotor retardation,
macrocephaly, facial dysmorphism, and respiratory
difficulties.
TETRASOMY 8p

● Karyotype nomenclature: 47,(XX or XY),+i(8)(p10)

● Results from the presence of a supernumerary
isochromosome for the entire short arm of
chromosome 8.
● Key clinical features: mental retardation, speech and
motor delay, dilatation of cerebral ventricles, mild
facial dysmorphism and vertebral abnormalities.
TETRASOMY 9p

● Karyotype nomenclature: 47,(XX or XY),+i(9)(p10)

● Results from the presence of a supernumerary
isochromosome for the entire short arm of
chromosome 9.
TETRASOMY 9p

● Key clinical features: Low birth weight, growth and

developmental delay, craniofacial anomalies
(microphthalmia, low-set malformed ears, bulbous tip
of the nose, cleft lip/palate, micrognathia), short neck,
skeletal anomalies, joint contracture, nail hypoplasia,
and urogenital anomalies
TETRASOMY 12p
PALLISTER-KILLIAN SYNDROME

● Karyotype nomenclature: 47,(XX or XY),+i(12)(p10)

● Results from the presence of a supernumerary
isochromosome for the entire short arm of
chromosome 12.
● Key clinical features:
○ Growth parameters at birth are usually normal.
○ Profound hypotonia is present in the newborn period, while
contractures develop later in life.
TETRASOMY 12p
PALLISTER-KILLIAN SYNDROME

● Key clinical features:

○ Sparse scalp hair, especially bitemporally, is observed in
infancy, with coarsening of facial features over time.
○ Craniofacial dysmorphism includes prominent forehead, large
malformed ears, hypertelorism, epicanthal folds, broad flat
nasal bridge, short nose, upturned nares, long philtrum, thin
upper lip, and high arched palate.
○ Severe mental retardation and seizure are seen in those who
survive.
TETRASOMY 18p
PALLISTER-KILLIAN SYNDROME

● Karyotype nomenclature: 47,(XX or XY),+i(18)(p10)

● Results from the presence of a supernumerary
isochromosome for the entire short arm of chromosome
18.
● Key clinical features: Low birth weight, microcephaly,
feeding problems, various degrees of psychomotor
retardation, spasticity, seizures, narrow shoulders and
thorax, small iliac wings, scoliosis, camptodactyly, and
simian creases.
HYPOPLOIDY
Monosomy
Nullisomy
MONOSOMY

● Autosomal monosomies are extremely rare in either

liveborns or abortuses, reflecting the severity of the
genetic imbalance resulting from the loss of an entire
chromosome.
● The only monosomies that have been reported are
monosomy 21 and mosaic monosomy 22.
MONOSOMY 21

● The most prominent features included intrauterine

growth restriction, postnatal growth and mental
retardation, hypertonia, facial dysmorphism with
downward slanting palpebral fissures, large low-set
ears, and micrognathia.
● A complex cardiac malformation, malrotation of the
bowel, uterus didelphys, small dysplastic ovaries, and
focal cystic dysplasia of the lung were noted.
MONOSOMY 21
MONOSOMY 22

● Among the cases of mosaic

monosomy 22, no dysmorphic
features were noted.
○ Two patients had growth and
developmental deficiencies, microcephaly,
and mild facial dysmorphism.
○ The fourth patient was a 30-week
premature infant with facial features of
DiGeorge syndrome, hypertonicity, limited
extension of major joints, and flexion
contractures of all fingers.
NULLISOMY

● The loss of both pairs of homologous chromosomes;

individuals are called nullisomics and their
chromosomal composition is (2n-2).
○ Nullisomic humans would not be able to survive.
COMMON SEX
CHROMOSOME
ANEUPLOIDIES
Turner’s syndrome
Klinefelter syndrome
Triple X syndrome
Jacob’s syndrome
Double-man syndrome
TURNER SYNDROME

● Karyotype nomenclature: 45,X

● Distribution: 1 in 2,500 live-born females
● Key abnormalities of fetus: cystic hygroma and
hydrops
● One of the most common chromosome abnormalities
in spontaneous abortions.
○ 99% of conceptuses result in spontaneous loss, usually by 28
weeks
● Variants:
○ 46, XX
○ 47, XXX
TURNER SYNDROME

● Decreased mean birth weight (average weight 2,800 g),

posteriorly rotated ears, neck webbing, and edema of
hands and feet.
● Adults with Turner syndrome have a four- to fivefold
increased rate of premature mortality, mainly due to
complications of congenital heart disease.
● Standard treatment includes use of growth hormone
and estrogen.
KLINEFELTER SYNDROME

● Karyotype nomenclature: 47,XXY

● Distribution: 1 in 575–1,000 newborn males
● Variants:
○ 47, XYY
○ 48, XXYY
○ 48, XXXY
○ 49, XXXXY
○ 49, XXXYY
KLINEFELTER SYNDROME

● Taller than average stature, might have a eunuchoid

build with long limbs and pear-shaped hips, testicular
and penile size is usually small during childhood,
although prepubertal phenotype is often
unremarkable.
● Gynecomastia occurs in up to 50% of 47,XXY males
during adolescence. Most enter puberty normally,
although there is usually inadequate testosterone
production and most require testosterone
supplementation.
TRIPLE X SYNDROME

● Karyotype nomenclature: 47,XXX

● Distribution: 1 in ~1,000 live female births
● The most frequent sex chromosome disorder present
at birth in females.
● Formerly termed as a superfemale.
● Variants:
○ 48,XXXX
○ 49,XXXXX
TRIPLE X SYNDROME

● The majority are physically normal, although there is a

slight increase in the frequency of minor anomalies.
● These women have moderately tall stature, There
appears to be an increased risk of seizures.
● Most have good health, although a small number
have ovarian dysfunction and premature ovarian
insufficiency sometimes associated with autoimmune
thyroid disease.
TRIPLE X SYNDROME
JACOBS SYNDROME

● Karyotype nomenclature: 47,XYY

● Distribution: 1 in 800–1,000 males
● This arises through nondisjunction at paternal
meiosis II.
● Variants:
○ 48, XYYY
○ 49, XYYYY
JACOBS SYNDROME

● Most infants are normal in appearance. Pubertal

development is usually normal.
● Patients often have severe facial acne, are described
as tall and thin, and have good general health.
● Most blend into the population as normal individuals.
Better outcomes seem to be associated with a
supportive, stable environment.
DOUBLE-MAN SYNDROME

● Karyotype nomenclature: 48,XXYY

● Distribution: 1 in 50,000 male births
● This is the most common variant of Klinefelter
syndrome.
● There is overlap between this condition and both
Klinefelter and XYY syndrome.
DOUBLE-MAN SYNDROME

● Men are tall-statured, with adult height above 6 ft, a

eunuchoid body habitus, and long thin legs.
● There is hypergonadotropic hypogonadism, small
testes, and sparse body hair.
● Gynecomastia occurs frequently.