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b.
The
TBX1 gene
,
which encodes for
T-box transcription factor TBX10 protein
is most likely
one of the genes that is deleted in DS and results in some of the clinical features of DS.
c.
DS encompasses the phenotypes previously called
DiGeorge syndrome, velocardiofacial
syndrome, conotruncal anomaly face syndrome, Opitz g/BBB syndrome
,
and
Cayler cardio-
facial syndrome.
d. Prevalence.
The prevalence of DS is 1/6,000 births in the U.S. population.
e. Clinical features include:
facial anomalies resembling first arch syndrome (microg-
nathia, low-set ears) due to abnormal neural crest cell migration, cardiovascular
anomalies due to abnormal neural crest cell migration during formation of the aorti-
copulmonary septum (e.g., Tetralogy of Fallot), velopharyngeal incompetence, cleft
palate, immunodeficiency due to thymic hypoplasia, hypocalcemia due to parathyroid
hypoplasia, and embryological formation of pharyngeal pouches 3 and 4 fail to differ-
entiate into the thymus and parathyroid glands.
4. Miller-Dieker syndrome (MD; agyria; lissencephaly)
a.
MD is caused by a microdeletion on
chromosome 17p13.3.
b.
The
LIS1 gene
(
lis
sencephaly) which encodes for the
LIS1 protein
is most likely one of
the genes that is deleted in MD and results in some of the clinical features of MD. The
LIS1 protein contains a coiled-coil domain and a tryptophan-aspartate repeat domain
both of which interact with microtubules and multiprotein complexes within migrat-
ing neurons.
c.
The
14-3-3
gene
,
which encodes for the
14-3-3
protein
is another likely gene deleted in
MD and results in some of the clinical features of MD. The 14-3-3
protein phosphory-
lated serine and phosphorylated threonine domains both of which interact with micro-
tubules and multiprotein complexes within migrating neurons.
d. Prevalence.
The prevalence of MD is unknown.
e. Clinical features include:
lissencephaly (smooth brain, i.e., no gyri), microcephaly, a
high and furrowing forehead, death occurs early. Lissencephaly should not be mistak-
enly diagnosed in the case of premature infants whose brains have not yet developed
an adult pattern of gyri (gyri begin to appear normally at about week 28).
5. WAGR syndrome
a.
WAGR is caused by a microdeletion on
chromosome 11p13.
90% of WAGR individuals
have a de novo deletion.
b.
The
WT1 gene
(
W
ilms
t
umor gene 1) which encodes for the
WT1 protein
(a zinc finger
DNA-binding protein) is most likely one of the genes that is deleted in WAGR and
results in the genitourinary clinical features of WAGR. WT1 protein is required for the
normal embryological development of the genitourinary system. WT1 protein isoforms
synergize with
SF-1
(steroidogenic factor-1) which is a nuclear receptor that regulates
the transcription of a number of genes involved in reproduction, steroidogenesis, and
male sexual development.
c.
The
PAX6 gene
(
pa
ired bo
x
), which encodes for the
PAX6 protein
(a paired box tran-
scription factor) is another likely gene that is deleted in WAGR and results in the
aniridia and mental retardation clinical features of WAGR.
d. Prevalence
. The prevalence of WAGR syndrome is unknown. However, the prevalence
of Wilms tumor is 1/125,000 in the U.S. population.
e. Clinical features include: W
ilms tumor,
a
niridia (absence of the iris),
g
enitourinary
abnormalities (e.g., gonadoblastoma), and mental
r
etardation. Wilms tumor is the
most
common renal malignancy of childhood
,
which usually presents between 1 to 3 years of
age. WT presents as a large, solitary, well-circumscribed mass that on cut section is soft,
homogeneous, and tan–gray in color. WT is interesting histologically in that this tumor
tends to recapitulate different stages of embryological formation of the kidney so that
three classic histological areas are described: a stromal area, a blastemal area of tightly
packed embryonic cells, and a tubular area. In 95% of the cases, the WT tumor is spo-
radic and unilateral.
6. Williams syndrome (WS)
a. WS
is caused by a microdeletion of the
Williams-Beuren syndrome critical region
(WBSCR)
on
chromosome 7q11.23.
90% of WS individuals have a de novo deletion.
Chapter 11
Cytogenetic Disorders
105
LWBK274-C11_101-122.qxd 06/02/2009 04:06 PM Page 105 Aptara
b.
The
ELN gene
(elastin) which encodes for the
elastin protein
is most likely one of the
genes that is deleted in WS and results in some of the clinical features of WS.
c.
The
LIMK1 gene,
which encodes for a
brain-expressed lim kinase 1 protein
is another
likely gene that is deleted in WS and results in some of the clinical features of WS.
d. Prevalence.
The prevalence of WS is 1/7,500 in a Norway population.
e. Clinical features include:
facial dysmorphology (e.g., prominent lips, wide mouth, peri-
orbital fullness of subcutaneous tissues, short palpebral tissues, short upturned nose,
long philtrum), cardiovascular disease (e.g., elastin arteriopathy, supravalvular aortic
stenosis, pulmonic valvular stenosis, hypertension, septal defects), endocrine abnor-
malities (e.g., hypercalcemia, hypercalciuria, hypothyroidism, early puberty), prenatal
growth deficiency, failure to thrive in infancy, connective tissue abnormalities (e.g.,
hoarse voice, hernias, rectal prolapse, joint and skin laxity), and mild mental deficiency
with uneven cognitive disabilities.
C. Translocations
result from breakage and exchange of segments between chromosomes.
1. Robertsonian translocation (RT)
■
An RT is caused by translocations between the long arms (q) of acrocentric (satellite)
chromosomes where the breakpoint is near the centromere. The short arms (p) of these
chromosomes are generally lost.
■
Carriers of an RT are
clinically normal
because the short arms, which are lost, contain
only inert DNA and some rRNA (ribosomal RNA) genes, which occur in multiple copies
on other chromosomes.
■
One of the most common translocations found in humans is the
Robertsonian transloca-
tion t(14q21q)
.
■
The clinical issue in the Robertsonian translocation t(14q21q) occurs when the carriers
produce gametes by meiosis and reproduce. Depending on how the chromosomes seg-
regate during meiosis, conception can produce offspring with translocation trisomy 21
(live birth), translocation trisomy 14 (early miscarriage), monosomy 14 or 21 (early mis-
carriage), a normal chromosome complement (live birth), or a t(14q21q) carrier (live
birth).
■
A couple where one member is a t(14q21q) carrier may have a baby with translocation
trisomy 21 (Down syndrome) or recurrent miscarriages.
2. Reciprocal translocation (RC)
■
An RC is caused by the exchange of segments between two chromosomes, which forms
two derivative (der) chromosomes each containing a segment of the other chromosome
from the reciprocal exchange.
■
b.
One of the most common inherited reciprocal translocations found in humans is the
t(11;22)(q23.3;q11.2).
■
The translocation heterozygote, or carrier, would be at risk of having a child with abnor-
malities due to passing on only one of the derivative chromosomes. That would result in
a child who would be partially trisomic for one of the participant chromosomes and par-
tially monosomic for the other.
3. Acute promyelocytic leukemia (APL) t(15;17)(q22;q21)
a.
APL t(15;17)(q22;q21) is caused by a reciprocal translocation between chromosomes 15
and 17 with breakpoints at bands q22 and q21, respectively.
b.
This results in a fusion of the
promyelocyte gene (PML gene)
on 15q22 with the
retinoic
acid receptor gene (RAR
gene
) on 17q21, thereby forming the
PML/RAR
oncogene.
c.
The
PML/RAR
oncoprotein
(a transcription factor) blocks the differentiation of promye-
locytes to mature granulocytes such that there is continued proliferation of promyelo-
cytes.
d. Clinical features include:
pancytopenia (i.e., anemia, neutropenia, and thrombocy-
topenia), including weakness and easy fatigue, infections of variable severity, and/or
hemorrhagic findings (e.g., gingival bleeding, ecchymoses, epistaxis, or menorrhagia),
and bleeding secondary to disseminated intravascular coagulation. A rapid cytogenetic
106
BRS Genetics
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Chapter 11
Cytogenetic Disorders
107
A
B
C
D
Sperm
Oocyte
Zygote
Sperm
Oocyte
Zygote
14
21
14
21
Robertsonian
t(14q21q)
Reciprocal
t(11;22)(q23.3;q11.2)
+
=
+
=
+
=
+
=
+
=
+
=
+
=
+
=
+
14
21
14
21
21
14
Lost
*
21
*
14
21
21 21
*
14
14
21
14
21
+
=
14
*
14
21
14
21
14
21
14
21
14
21
14
21
14
21
21
*
14 14
21
14 14
21 21
14 14
21
14
21
14
21
14
21
14
21
*
22
11
11
*
*
*
22
22
22 22
11
11
22
11
22
*
*
11
22
11
11
11 11
22
22
11
22
22
11
11
22
+
Translocation
trisomy 21
Translocation
trisomy 14
Partial
trisomy 22
and partial
monosomy
11
Partial
trisomy 11
and partial
monosomy
22
Monosomy
21
Monosomy
14
Normal
Carrier
*
*
FIGURE 11-2. Translocations. (A) Robertsonian t(14q21q).
This is one of the most common Robertsonian translocations
found in humans. (B) Diagram shows the six conditions that may result depending on how chromosomes 14 and 21 segre-
gate during meiosis when the carrier of the Robertsonian translocation is the male. *
robertsonian translocation chro-
mosome. (C) Reciprocal translocation t(11;22)(q23.3;q11.2). This is one of the most common reciprocal translocations
found in humans. (D) Diagram shows the two conditions that may result depending on how chromosomes 11 and 22 seg-
regate during meiosis when the carrier of the reciprocal translocation is the male. *
reciprocal translocation chromo-
some
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108
BRS Genetics
diagnosis of this leukemia is essential for patient management because these patients
are at an extremely high risk for stroke.
4. Chronic myeloid leukemia (CML) t(9;22)(q34;q11.2)
a.
CML t(9;22)(q34;q11.2) is caused by a reciprocal translocation between chromosomes
9 and 22 with breakpoints at q34 and q11.2 respectively. The resulting der(22) is referred
to as the
Philadelphia chromosome
.
b.
This results in a fusion of the
ABL gene
on 9q34 with the
BCR gene
on 22q11.1, thereby
forming the
ABL/BCR oncogene.
c.
The
ABL/BCR oncoprotein
(a tyrosine kinase) has enhanced tyrosine kinase activity that
transforms hematopoietic precursor cells.
d. Prevalence.
The prevalence of CML is 1/100,000 per year with a slight male predomi-
nance.
d. Clinical features include:
systemic symptoms (e.g., fatigue, malaise, weight loss, exces-
sive sweating), abdominal fullness, bleeding episodes due to platelet dysfunction,
abdominal pain may include left upper quadrant pain, early satiety due to the enlarged
spleen, tenderness over the lower sternum due to an expanding bone marrow, and the
uncontrolled production of maturing granulocytes, predominantly neutrophils, but
also eosinophils and basophils.
D. Isochromosomes
occur when the centromere divides transversely (instead of longitudinally)
such that one of the chromosome arms is duplicated and the other arm is lost.
1. Isochromosome Xq [46,
i (Xq)]
■
Isochromosome Xq is caused by a duplication of the q arm and loss of p arm of chromo-
some X.
■
Isochromosome Xq is found in 20% of females with
Turner syndrome,
usually as a mosaic
cell line along with a 45,X cell line [ i.e.,45,X/46,
i(Xq)].
2. Isochromosome 12p [47,
i (12p)]
■
The occurrence of isochromosomes within any of the autosomes is generally a lethal sit-
uation although isochromosomes for small segments do allow for survival to term.
■
Isochromosome 12p is associated with
testicular germ cell tumors.
The
CCND2 gene
located on
chromosome 12p13
encodes for
cyclin D2
,
which regulates the cell cycle at the
G1 checkpoint. Overexpression of cyclin D2 has been demonstrated in a variety of tes-
ticular germ cell tumors.
■
Isochromosome 12p is also associated with a rare polydysmorphic syndrome called
Pallister-Killian syndrome.
Clinical features include: mental retardation, loss of muscle
tone, streaks of skin with hypopigmentation, high forehead, coarse facial features, wide
space between the eyes, broad nasal bridge, highly arched palate, fold of skin over the
inner corner of the eyes, large ears, joint contractures, and cognitive delays.
E. Ring Chromosomes
■
Ring chromosomes are formed when breaks occur somewhere on either side of the cen-
tromere.
■
The newly created fragments (and thus the genes on them) are lost and the remaining
pieces of the short and long arms join with each, forming a ring.
■
Ring chromosomes are unstable and tend to be lost during mitosis, creating a mosaic
cell line.
■
A ring chromosome X is found in
15% of individuals with Turner syndrome, usually as
a mosaic cell line with a 45,X cell line.
F. Inversions
■
Inversions are the reversal of the order of DNA between two breaks in a chromosome.
■
Pericentric inversion
breakpoints occur on both sides of the centromere.
■
Paracentric inversion
breakpoints occur on the same side of the centromere.
LWBK274-C11_101-122.qxd 06/02/2009 04:06 PM Page 108 Aptara
■
Carriers of inversions are usually normal. The diagnosis of an inversion is generally a
coincidental finding during prenatal testing or the repeated occurrence of spontaneous
abortions or stillbirths.
■
The risk for an inversion carrier to have a child with an abnormality or to have repro-
ductive loss is due to crossing-over in the inversion loop that forms during meiosis as the
normal and inverted chromosomes pair.
■
When the chromosomes separate, duplications and deletions of chromosomal material
occur.
G. Chromosome breakage
is caused by breaks in chromosomes due to sunlight (or ultraviolet)
irradiation, ionizing irradiation, DNA crosslinking agents, or DNA damaging agents. These
insults may cause
depurination of DNA
,
deamination of cytosine to uracil
,
or
pyrimidine dimer-
ization
, which must be repaired by DNA repair enzymes.
1. Xeroderma pigmentosum (XP)
a.
XP is an autosomal recessive genetic disorder caused by mutations in
nucleotide exci-
sion repair enzymes
,
which results in the inability to remove pyrimidine dimers and
individuals who are hypersensitive to
sunlight (UV radiation).
b.
The
XPA gene
and the
XPC gene
are two of the genes involved in the cause of XP. XPA
gene located on chromosome 9q22.3 encodes for a DNA repair enzyme. The XPC gene
located on chromosome 3p25 also encodes for a DNA repair enzyme
c. Prevalence.
The prevalence of XP is 1/250,000 in the U.S. population.
d. Clinical features include:
sunlight (UV radiation) hypersensitivity with sunburnlike
reaction, severe skin lesions around the eyes and eyelids, and malignant skin cancers
(basal and squamous cell carcinomas and melanomas) whereby most individuals die
by 30 years of age.
2. Ataxia-telangiectasia (AT)
a.
AT is an autosomal recessive genetic disorder caused by mutations in
DNA recombina-
tion repair enzymes
on chromosome 11q22-q23, which results in individuals who are
hypersensitive to
ionizing radiation
.
b.
The
ATM gene (AT mutated)
is one of the genes involved in the cause of AT. The ATM gene
located on chromosome 11q22 encodes for a protein where one region resembles a
PI-3
kinase
(phosphatidylinositol-3 kinase) and another region resembles a
DNA repair
enzyme/cell cycle checkpoint protein.
c. Prevalence.
The prevalence of AT is 1/20,000 to 100,000 in the U.S. population.
d. Clinical features include:
ionizing radiation hypersensitivity, cerebellar ataxia with deple-
tion of Purkinje cells, progressive nystagmus, slurred speech, oculocutaneous telangiecta-
sia initially in the bulbar conjunctiva followed by ear, eyelid, cheeks, and neck, immunod-
eficiency, and death in the second decade of life. A high frequency of structural
rearrangements of chromosomes 7 and 14 is the cytogenetic observation with this disease.
3. Fanconi anemia (FA)
a.
FA is an autosomal recessive genetic disorder caused by mutations in
DNA recombination
repair, which
results in individuals who are hypersensitive to
DNA crosslinking agents.
b.
The
FA-A gene
(involved in 65% of FA cases) is one of the genes involved in the cause of
FA. The FA-A gene located on chromosome 16q24 encodes for a protein that normal-
izes cell growth, corrects sensitivity to chromosomal breakage in the presence of mito-
mycin C, and generally promotes genomic stability.
c. Prevalence.
The prevalence of FA is 1/32,000 in the Ashkenazi Jewish population.
d. Clinical features include:
DNA crosslinking agent hypersensitivity, short stature,
hypopigmented spots, café-au-lait spots, hypogonadism microcephaly, hypoplastic or
aplastic thumbs, renal malformation including unilateral aplasia or horseshoe kidney,
acute leukemia, progressive aplastic anemia, head and neck tumors, medulloblastoma,
and is the most common form of congenital aplastic anemia.
4. Bloom syndrome (BS)
a.
BS is an autosomal recessive genetic disorder caused by mutations
DNA repair enzymes
on chromosome 15q26 which results in individuals who are hypersensitive to
DNA-
damaging agents.
Chapter 11
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