Transcript Clinical Genetics

Clinical Cytogenetics: Disorders of the
Autosomes
Autosomal Disorders
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Only 3 well-defined non-mosaic chr disorders
compatible with postnatal survival in which there is
trisomy for an entire chr. (13,18,21)
 Each is associated with growth retardation, MR and
multiple congenital abnormalities. But each has a
distinctive phenotype
 Abnormalities determined by extra dosage of the
particular genes on the additional chr.
 Specific genes on the extra chr. responsible for
abnormal phenotypes
Down Syndrome (Trisomy 21)
Most common genetic cause of moderate MR
~ 1 child in 800 is born with DS. Incidence is
higher in mothers >35 yrs.
Two noteworthy features of its pop. distribution:
– Increased maternal age
– Peculiar distribution within families: concordance in
monozygotic twins but almost complete discordance
in dizygotic twins and other family members
Maternal age
dependence on
incidence of DS.
Phenotype
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Can be diagnosed at birth or shortly thereafter by its
dysmorphic features, may vary among patients, but produce a
distinctive phenotype.
Hypotonia 1st abnormality observed
Short stature, brachycephaly with a flat occiput
Neck is short, with loose skin on nape
Nasal bridge flat
Ears low set, characteristic folded appearance
Eyes have Brushfield spots around margin of iris
Mouth open, often showing a furrowed, protruding tongue
Characteristic epicanthal folds and upslanting palpebral fissures
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Hands short and broad, often wit a single
transverse palmar crease and incurved 5th
digit, or clinodactyly.
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Wide gap b/w 1st and 2nd toes with a furrow
extending proximally on palmar surface.
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Major concern is MR. developmental delay is usually
obvious by end of 1st year. IQ is usually 30 to 60.
 Congenital heart disease in at least 1/3 of DS infants
(higher in abortuses)
 There is a high degree of variability in phenotype;
specific abnormalities detected in almost all, others
seen only in subset of cases.
 Birth defects reflect effects of overexpression of
gene(s) during early development e.g., a significant
proportion of chr. 21 genes are expressed at higher
levels in DS brain and heart samples as compared to
euploid individuals.
Prenatal and Postnatal Survival
At all maternal ages, there is some loss b/w 11th and
16th wks, and an additional loss later in pregnancy.
 Probably ~ 20-25% of trisomy 21 survive to birth.
 Among DS coceptuses,
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– those least likely to survive are those with congenital heart
disease
– ~ ¼ of liveborns with heart defects die before 1st birthday
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There is 15-fold increase in risk of leukemia among
DS who survive neonatal period
 Premature dementia, associated with
neuropathological findings characteristic of Alzheimer
disease affects DS patients several decades earlier than
in general pop.
The chromosomes in DS
Trisomy 21
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Karyotyoing is necessary for confirmation and
basis for genetic counseling. It is essential for
determining recurrence risk.
 In ~ 95%, 47,XX/XY,+21, resulting from meiotic
non-disjunction.
 Risk of having a child with trisomy 21 increases
with maternal age, esp. after 30.
 Meiotic error usually maternal (~90% of cases),
predominantly meiosis-I. ~ 10% paternal, usually
meiosis-II.
Robertsonian Translocation
~ 4% of DS, 46 chr’s one of which a Rob
translocation b/w 21q and q arm of another
acrocentric (usually 14 or 22). E.g.,
46,xx,rob(14;21)(q10;q10),+21. Such a chr is a.k.a
der(14;21). In effect patient is trisomic for 21q
 No relation to maternal age
 Has a relatively high recurrence risk in families
esp. when mother is the carrier
 Karyotyping for parents and other relatives is
essential for accurate counseling
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Carrier has 45 chr’s.
 There are 6 possible types of gametes, 3 of which
do not lead to viable offspring.
 Of the 3 viable: one is normal, one is balanced and
one is unbalanced. Theoretically produced in equal
numbers.
 Studies have shown that unbalanced chr.
complement appears in ~ 10-15% of the progeny
of a carrier mother (only a few % when father is
the carrier).
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Chromosomes of gametes that theoretically can be
produced by a carrier of rob(14;21)
21
14
21
14
Robertsonian Translocation 14q21q transmitted by a carrier
mother.
21q21q translocation
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Seen in a few % of DS
Thought to originate as an isochromosome
Many cases arise post-zygotically, hence
recurrence risk is low.
 Still, important to evaluate if a parent is a carrier
(or mosaic). What type of gametes would a
21q21q carrier produce? What about potential
progeny?
 Mosaic carriers are at increased risk of recurrence.
Prenatal diagnosis should be considered.
Mosaic DS
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~ 2% of DS, usually with normal/trisomy 21
karyotype.
 Phenotype may be milder, with wide
variability among mosaic patients.
 Mildly affected are less likely to be
karyotyped
Partial Trisomy 21
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Part of 21q is present in triplicate, very rare.
 DS with no cytogenet. visible chr.
abnormality is even more rarely identified.
Etiology of Trisomy 21
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Something about maternal meiosis-I is the
underlying cause in high % of trisomy 21.
 “older egg” model: the older the egg, the greater
the chance that chr’s will fail to disjoin correctly.
 Older eggs may be less able to overcome a
susceptibility to non-disjunction established by
recombination (recall recombination pattern and
non-disjunction) machinery.
 Etiological events may have taken place many
years ago, when mother’s primary oocytes were
still in prophase of meiosis-I.
Risk of DS
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DS can be detected prenatally by cytogenetic or
array CGH analysis of CVS or amniotic fluid cells
 ~ 80% performed because of increased maternal
age or prenatal biochemical screening.
 A commonly accepted guideline: a woman is
eligible for prenatal diagnosis if risk that fetus has
DS outweighs the risk that amniocentesis or CVS
will lead to fetal loss. The risk depends on
maternal age and on both parent’s karyotypes
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Pop. incidence of DS in live births is ~ 1 in 800.
At ~ age 30, risk begins to rise sharply, reaching 1
in 25 births in oldest maternal age group.
Although younger mothers have lower risk, their
birth rate is much higher, and therefore > ½ of
mothers of all DS babies are <35.
Risk of DS due to translocation or partial trisomy
is unrelated to maternal age
Paternal age seems to have no influence on risk
Recurrence risk
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Recurrence risk trisomy 21 (or some other
autosomal trisomy), after one such child has been
born in a family is ~ 1% overall.
The risk is ~ 1.4% for mothers <30
Reason for increased risk for younger women in
not known (one possibility is unrecognized
germline mosaicism in one parent).
A history of trisomy 21 elsewhere in the family
does not appear to increase risk of having a DS
child.
Recurrence risk for DS due to translocation is
much higher
Trisomy 18 – Edwards Syndrome
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Features include:
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MR and failure to thrive
Often, severe malformation of heart
Hypertonia
Head has prominent occiput, and jaw recedes
Ears low-set and malformed
Sternum short
Clenched fist, with 2nd and 5th digits overlapping 3rd and
4th.
– “Rocker bottom” appearance of feet
– Single creases on palms and arch patterns on most or all
digits.
Trisomy 18 – Edwards syndrome
1/7500 live births
Karyotype: 47, XX (or XY), +18
Prenatal detection: strong association
with abnormal anatomy –
choroid plexus cysts,
CNS malformation,
CHD (ventricular septal & outflow
tract defects) abnormalities
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Incidence in liveborns is 1 in 7500 births
Incidence at conception is much higher, but ~ 95% are
aborted spont.
Survival for > a few months is rare
At least 60% of patients female (preferential survival?)
Increased maternal age is a factor.
Trisomy 18 phenotype, like trisomy 21, can result from
a variety of rare karyotypes other than complete trisomy.
Karyotyping of affected infants/fetuses is essential for
counseling
In ~ 20%, translocation involving all or most chr.18
(either de novo or inherited from a balanced carrier)
Trisomy 18 may be mosaic, with variable but usually
milder expression
Trisomy 13 – Patau Syndrome
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Growth retardation and severe MR,
accompanied by severe CNS malformations.
 Forehead is sloping; microcephaly and wideopen sutures; may be micophthalmia, iris
coloboma, or even absence of the eye
 Ears malformed
 Cleft lip and cleft palate are often present
 Hands and feet may show postaxial
polydactyly, and hands clench as in trisomy 18
 Feet as in trisomy 18, “rocker bottom”
appearance
 Palms often have simian crease
Trisomy 13 – Patau Syndrome
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Internally, usually congenital heart defects and
urogenital defects.
 Of this constellation of defects, the most
distinctive:
– general facial appearance with cleft lip and palate
– Ocular abnormalities
– Polydactyly
– Clenched fists and rocker-bottom feet
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Incidence is ~ 1 in 15,000-25,000 births
About ½ die within 1st month
Associated with increased maternal age, and extra
chr. usually from nondisjunction in maternal
meiosis-I.
Karyotyping is indicated to confirm diagnosis
~ 20% caused by unbalanced translocation
Recurrence risk is low; even when one parent is a
carrier of translocation, empirical risk that a
subsequent child will have the syndrome is <2%.
Autosomal Deletion Syndromes
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Overall, cytogenetically visible autosomal
deletions occur with an estimated incidence
of 1/7000 live births.
Cri du Chat Syndrome
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Terminal or interstitial deletion of part of
5p.
 Name was given because crying infants
sound like a mewing cat.
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Accounts for ~1% of all institutionalized
MR patients
 Facial appearance is distinctive, with
microcephaly, hypertelorism, epicanthal
folds, low-set ears sometimes with
preauricular tags, and micrognathia.
 Other features: moderate to severe MR and
heart defects
A. Note characteristic face with hypertelorism, epicanthus and
retrognathia. B. Phenotype-karyotype map, based on arr-CGH
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Most cases are sporadic; 10-15% are offspring of
translocation carriers.
 Breakpoints and extent of deleted segment of 5p
vary in patients, critical region missing in all is 5p15
 Many of the phenotypes due to haploinsufficiency
for gene(s) within 5p15.2, and distinctive cat cry
from deletion of gene(s) within a small region in
band 5p15.3.
 Degree of MR usually correlates with size of
deletion.
Genomic Disorders: Microdeletion
and Duplication Syndromes
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Many dysmorphic syndromes associated with small
(sometimes cytogenet. visible) deletions that lead to a
form of genetic imbalance referred to as segmental
aneusomy.
 These deletions produce clinically recognizable
syndromes. Can be detected by high-resolution
banding, FISH, arr-CGH
 The term contiguous gene syndrome has been applied
to many of them. i.e., haploinsuf. for multiple
contiguous genes within deleted region
 For other disorders, phenotype is apparently due to
deletion of a single gene, despite association of a chr.
deletion with the condition.
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For each syndrome extent of del in different
patients is similar, suggesting existence of
deletion-prone sequences.
 Fine mapping has shown that breakpoints
localize to low-copy repeated sequences and
that aberrant recombination b/w nearby
copies of the repeats causes deletions (which
span several 100-1000 kb).
 This general sequence-dependent mechanism
has been implicated in several contiguous
gene rearrangement syndromes, which have
therefore been termed genomic disorders.
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Several deletions/duplications mediated by unequal
recombination have been documented within
proximal 17p.
 E.g., a cytogenet. visible segment of 17p11.2 of ~
4Mb is deleted de novo in ~ 70-80% of patients with
Smith-Magenis syndrome (SMS), a usually sporadic
condition characterized by multiple congenital
anomalies and MR.
 The major features of SMS include mild to moderate
mental retardation, delayed speech and language
skills, distinctive facial features, sleep disturbances,
and behavioral problems.
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Unequal recombination b/w large blocks of
flanking repeated sequences (nearly 99%
identical) results in SMS deletion,
del(17)(p11.2-p11.2), as well as the
reciprocal duplication dup(17)(p11.2p11.2), seen in patients with a milder,
neurobehavioral phenotype
SMS: del (17)(p11.2)
Table 6-1. Examples of Genomic Disorders Involving Recombination Between LowCopy Repeat Sequences
REARRANGEMENT
Disorder
Location
Type
Size (kb)
Repeat Length (kb)
Smith-Magenis syndrome
17p11.2
Deletion
4000
175-250
1400
24
3000,
1500
225-400
dup(17)(p11.2p11.2)
Charcot-Marie-Tooth (CMT1A)/HNLPP
Duplication
17p12
Duplication
Deletion
DiGeorge syndrome/velocardiofacial
syndrome
22q11.2
Cat-eye syndrome/22q11.2 duplication
syndrome
Deletion
Duplication
Prader-Willi/Angelman syndromes
15q11-q13
Deletion
3500
400
Williams syndrome
7q11.23
Deletion
1600
300-400
Neurofibromatosis
17q11.2
Deletion
1400
85
Sotos syndrome
5q35
Deletion
2000
400
Azoospermia (AZFc)
Yq11.2
Deletion
3500
230
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Figure 6-8 Model of rearrangements
underlying genomic disorders. Unequal
crossing over between misaligned sister
chromatids or homologous
chromosomes containing highly
homologous copies of a long repeated
DNA sequence can lead to deletion or
duplication products, which differ in the
number of copies of the sequence. The
copy number of any gene or genes (such
as A, B, and C) that lie between the
copies of the repeat will change as a
result of these genome rearrangements.
For examples of genomic disorders, the
size of the repeated sequences, and the
size of the deleted or duplicated region
DiGeorge syndrome
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A particularly common microdeletion that is frequently
evaluated in clinical cytogenetics laboratories involves
chromosome 22q11.2 and is associated with diagnoses of
DiGeorge syndrome, velocardiofacial syndrome, or
conotruncal anomaly face syndrome.
All three clinical syndromes are autosomal dominant
conditions with variable expressivity, caused by a deletion
within 22q11.2, spanning about 3 Mb. This microdeletion,
also mediated by homologous recombination between lowcopy repeated sequences, is one of the most common
cytogenetic deletions associated with an important clinical
phenotype and is detected in 1 in 2000 to 4000 live births
(Fig. 6-9).
Patients show characteristic craniofacial anomalies, mental
retardation, and heart defects. The deletion in the 22q11.2
deletion syndromes is thought to play a role in as many as 5%
of all congenital heart defects and is a particularly frequent
cause of certain defects.
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Figure 6-9 Chromosomal deletions, duplications, and rearrangements in 22q11.2 mediated by
homologous recombination. Normal karyotypes show two copies of 22q11.2, each containing three
copies of an approximately 200-kb repeated segment (dark blue) within a 3-Mb genomic region, which
is composed of two duplicated segments (light blue and grey). In DiGeorge syndrome (DGS) or
velocardiofacial syndrome (VCFS), the full 3-Mb region (or, less frequently, the proximal 1.5 Mb
within it) is deleted from one homologue. The reciprocal duplication is seen in patients with dup(22)
(q11.2q11.2). Tetrasomy for 22q11.2 is seen in patients with cat-eye syndrome. Note that the duplicated
region in the cat-eye syndrome chromosome is in an inverted orientation relative to the duplication
seen in dup(22) patients.
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The typical deletion removes approximately 30
genes, although a related, smaller deletion is
seen in approximately 10% of cases.
 Haploinsufficiency for at least one of these
genes, TBX1, which encodes a transcription
factor involved in development of the
pharyngeal system, has been implicated in the
phenotype; it is contained within the deleted
region and is mutated in patients with a similar
phenotype but without the chromosomal
deletion.
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In contrast to the relatively common deletion of
22q11.2, the reciprocal duplication of 22q11.2 is
much rarer and leads to a series of dysmorphic
malformations and birth defects called the 22q11.2
duplication syndrome.
 Diagnosis of this duplication generally requires
analysis by FISH on interphase cells or array CGH.
 Some patients have a quadruple complement of this
segment of chromosome 22 and are said to have cateye syndrome, which is characterized clinically by
ocular coloboma, congenital heart defects,
craniofacial anomalies, and moderate mental
retardation.
 The karyotype in cat-eye syndrome is 47,XX or
XY,+inv dup(22)(pter→q11.2).
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The constellation of different disorders associated
with varying dosage of genes in this segment of
chromosome 22 (see Fig. 6-9) reflects two major
principles in clinical cytogenetics.
 First, with few exceptions, altered gene dosage for any
extensive chromosomal or genomic region is likely to
result in a clinical abnormality, the phenotype of
which will, in principle, depend on haploinsufficiency
for or overexpression of one or more genes encoded
within the region.
 Second, even patients carrying what appears to be the
same chromosomal deletion or duplication can present
with a range of variable phenotypes. Although the
precise basis for this variability is unknown, it could
be due to non-genetic causes or to differences in the
genome sequence among unrelated individuals.