Файл: Genetics [BRS].pdf

b.

The 

BLM gene

is one of the genes involved in the cause of BS. The BLM gene located on

chromosome 15q26 encodes for 

RecQ helicase

,

which unwinds the DNA double helix

during repair and replication.

c. Prevalence.

The prevalence of BS is high in the Ashkenazi Jewish population.

d. Clinical features include:

hypersensitivity to DNA-damaging agents, long, narrow face,

erythema with telangiectasias in butterfly distribution over the nose and cheeks, high-
pitched voice, small stature, small mandible, protuberant ears, absence of upper lateral
incisors, well-demarcated patches of hypopigmentation and hyperpigmentation,
immunodeficiency with decreased IgA, IgM, and IgG levels, and predisposition to sev-
eral types of cancers.

5. Hereditary nonpolyposis colorectal cancer (HNPCC)

a.

HNPCC is an autosomal dominant genetic disorder caused by mutations in 

DNA mis-

match repair enzymes, which

results in the inability to remove single nucleotide mis-

matches or loops that occur in microsatellite repeat areas.

b.

The four genes involved in the cause of HNPCC include: 

i. MLH1 gene

located on chromosome 3p21.3 which encodes for DNA mismatch

repair proteinMlh1.

ii. MSH2 gene

located on chromosome 2p22-p21, which encodes for DNA mismatch

repair protein Msh2

iii. MSH6 gene

located on chromosome 2p16 which encodes for DNA mismatch repair

protein Msh6

iv. PMS2 gene

located on chromosome 7p22 which encodes for PMS1 protein homolog 2.

c.

These genes are the human homologues to the Escherichia coli

mutS gene

and 

mutl gene

that code for DNA mismatch repair enzymes.

d. Prevalence.

HNPCC accounts for 1% to 3% of colon cancers and 

1% of endometrial

cancers.

e. Clinical features include:

onset of colorectal cancer at a young age, high frequency of

carcinomas proximal to the splenic flexure, multiple synchronous or metachronous
colorectal cancers, and presence of extracolonic cancers (e.g., endometrial and ovarian
cancer, adenocarcinomas of the stomach, small intestine, and hepatobiliary tract), and
accounts for 3% to 5% of all colorectal cancers.

III. SUMMARY TABLE OF CYTOGENETIC DISORDERS (Table 11-1)

IV. SELECTED PHOTOGRAPHS OF CYTOGENETIC DISORDERS

(Figures 11-3, 11-4, 11-5, 11-6)

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Summary Table of Cytogenetic Disorders

Cytogenetic Disorder

Chromosomal Defect

Clinical Features

Numerical Chromosomal Abnormalities (Aneuploidy)

Trisomy 13 (Patau 

Aneuploidy; 13

Profound mental retardation, congenital heart defects, 

syndrome; 47,

13)

cleft lip and/or palate, omphalocele, scalp defects, 
and polydactyly

Trisomy 18 (Edwards 

Aneuploidy; 18

Mental retardation, congenital heart defects, small 

syndrome; 47,

18)

facies and prominent occiput, overlapping fingers, 
cleft lip and/or palate, and rocker-bottom heels

Trisomy 21 (Down 

Aneuploidy; 21 

Moderate mental retardation (the leading cause

syndrome; 47,

21)

DSCR

of mental retardation), microcephaly, microphthalmia,
colobomata, cataracts and glaucoma, flat nasal bridge,
epicanthal folds, protruding tongue, simian crease in
hand, increased nuchal skin folds, appearance of an
“X” across the face when the baby cries, and congeni-
tal heart defects. Alzheimer neurofibrillary tangles and
plaques are found in Down syndrome patients after 30
years of age. A condition mimicking acute megakary-
ocytic leukemia (AMKL) frequently occurs in children
with Down syndrome and they are at increased risk 
for developing acute lymphoblastic leukemia (ALL)

Trisomy 47, XXY (Klinefelter 

Aneuploidy; extra X

Varicose veins, arterial and venous leg ulcer, scant body 

syndrome; 47,XXY; 

and pubic hair, male hypogonadism, sterility with 

48,XXXY; 47,XXY/46,XY)

fibrosus of seminiferous tubules, marked decrease in 
testosterone levels, elevated gonadotropin levels, 
gynecomastia, IQ slightly less than that of siblings, 
learning disabilities, antisocial behavior, delayed 
speech as a child, tall stature and eunuchoid habitus, 
found only in males

Monosomy X (Turner 

Aneuploidy; loss of X

Short stature, low-set ears, ocular hypertelorism, ptosis, 

syndrome; 45,X; 45,X/46,XX; 

SHOX gene

low posterior hairline, webbed neck due to a remnant 

45,X/46, 

iXq)

of a fetal cystic hygroma, congenital hypoplasia of lym-
phatics causing peripheral edema of hands and feet,
shield chest, pinpoint nipples, congenital heart defects,
aortic coarctation, female hypogonadism, ovarian
fibrous streaks (i.e., infertility), primary amenorrhea, 
and absence of secondary sex characteristics, found
only in females 

Structural Chromosomal Abnormalities (Deletions/Microdeletions)

Wolf-Hirschhorn syndrome 

4p16.3 deletion

Prominent forehead and broad nasal root (“Greek 

WHCR

warrior helmet”), short philtrum, down-turned 
mouth, congenital heart defects, growth retardation,
and severe mental retardation

Cri du chat syndrome

5p15.2 deletion

Round facies, a catlike cry, congenital heart defects, 

CDCCR

microcephaly, and mental retardation

CLCR

Prader-Willi syndrome

Paternal 15q11.2-13 

Poor feeding and hypotonia at birth, but then followed 

microdeletion; Imprinting 

by hyperphagia (insatiable appetite), hypogonadism, 

SNRPN allele

obesity, short stature, small hands and feet, behavior
problems (rage, violence), and mild-to-moderate 
mental retardation

Angelman syndrome

Maternal 15q11.2-13 

Gait ataxia (stiff, jerky, unsteady, upheld arms), seizures, 

microdeletion; Imprinting

happy disposition with inappropriate laughter, severe 

UBE3A allele

mental retardation (only 5–10 word vocabulary), 
developmental delays are noted at 

6 months, and 

age of onset is 

1 year of age

22q11.2 Deletion syndrome

22q11.2 microdeletion

Facial anomalies resembling first arch syndrome 

(DiGeorge, Velocardiofacial, 

DGCR

(micrognathia, low-set ears) due to abnormal neural 

Conotruncal anomaly face, 

TBX1 gene

crest cell migration, cardiovascular anomalies due to 

Opitz/BBB, Cayler 

abnormal neural crest cell migration during formation  

cardiofacial)

of the aorticopulmonary septum (e.g., tetralogy of
Fallot), velopharyngeal incompetence, cleft palate,
immunodeficiency due to thymic hypoplasia, hypocal-
cemia due to parathyroid hypoplasia, and embryologi-
cal formation of pharyngeal pouches 3 and 4 fail to
differentiate into the thymus and parathyroid glands 

(continued)

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(continued)

Cytogenetic Disorder

Chromosomal Defect

Clinical Features

Structural Chromosomal Abnormalities (Deletions/Microdeletions)

Miller-Dieker syndrome

17p13.3 microdeletion

Lissencephaly (smooth brain, i.e., no gyri), microcephaly, 

LIS1 gene

a high and furrowing forehead; death occurs early. 

14-3-3

 gene

Lissencephaly should not be mistakenly 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)

WAGR syndrome

11p13 microdeletion 

W

ilms tumor, aniridia (absence of the iris), genitourinary 

WT1 gene

abnormalities (e.g., gonadoblastoma), and mental 

PAX6 gene

r

etardation. Wilms tumor is the most common renal

malignancy of childhood

, which usually presents bet-

ween 1–3 years of age. WT presents as a large, soli-
tary, well-circumscribed mass that on cut section is
soft, homogeneous, and tan–gray in color. WT is inter-
esting histologically in that this tumor tends to recapit-
ulate 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 sporadic and unilateral

Williams syndrome

7q11.23 microdeletion

Facial dysmorphology (e.g., prominent lips, wide mouth, 

WBSCR

periorbital fullness of subcutaneous tissues, short 

ELN gene

palpebral tissues, short upturned nose, long philtrum), 

LIMK1 gene

cardiovascular disease (e.g., elastin arteriopathy, 
supravalvular aortic stenosis, pulmonic valvular 
stenosis, hypertension, septal defects), endocrine 
abnormalities (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

Translocations

Robertsonian translocation

t(14q21q) translocation

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).

Reciprocal translocation

t(11;22)(q23.3;q11.2) 

Partial trisomy and partial monosomy

translocation

Acute promyelocytic leukemia

t(15;17)(q22;q21) reciprocal 

Pancytopenia (i.e., anemia, neutropenia, and 

translocation 

thrombocytopenia), including weakness and easy 

PMLl/RAR

 oncogene

fatigue, infections of variable severity, and/or hemor-
rhagic findings (e.g., gingival bleeding, ecchymoses,
epistaxis, or menorrhagia), and bleeding secondary to
disseminated intravascular coagulation. A rapid
cytogenetic diagnosis of this leukemia is essential 
for patient management because these patients 
are at an extremely high risk for stroke

Chronic myeloid leukemia

t(9;22)(q34;q11.2) reciprocal 

Systemic symptoms (e.g., fatigue, malaise, weight loss, 

translocation

excessive sweating), abdominal fullness, bleeding 

Philadelphia chromosome

episodes due to platelet dysfunction, abdominal pain 

ABL/BCR oncogene 

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

(continued)

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(continued)

Cytogenetic Disorder

Chromosomal Defect

Clinical Features

Isochromosomes

Isochromosome Xq 

46, 

i(Xq)

Found in 20% of females with Turner syndrome, usually 

Centromere divides 

as a mosaic cell line along with a 45,X cell line 

transversely

(i.e.,45,X/46, 

i[Xq])

Isochromosome 12p

47, 

i(12p)

Testicular germ cell tumors

Centromere divides 

Pallister-Killian syndrome: mental retardation, loss of 

transversely

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

Chromosome Breakage

Xeroderma pigmentosa

Nucleotide excision repair 

Sunlight (UV radiation) hypersensitivity with sunburnlike 

enzymes; 9q22.3, 3p25

reaction, severe skin lesions around the eyes and 

XPA, XPC genes

eyelids, and malignant skin cancers (basal and 
squamous cell carcinomas and melanomas) whereby 
most individuals die by 30 years of age

Ataxia-telangiectasia

DNA recombination repair 

Ionizing radiation hypersensitivity, cerebellar ataxia with 

enzymes; 11q22 

depletion of Purkinje cells, progressive nystagmus, 

ATM gene

slurred speech, oculocutaneous telangiectasia initially 
in the bulbar conjunctiva followed by ear, eyelid, 
cheeks, and neck, immunodeficiency, 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

Fanconi anemia 

DNA recombination repair 

DNA crosslinking agent hypersensitivity, short stature, 

enzymes; 16q24

hypopigmented spots, café-au-lait spots, hypogo-

FA-A gene

nadism, microcephaly, hypoplastic or aplastic thumbs,
renal malformation including unilateral aplasia or
horseshoe kidney, acute leukemia, progressive 
aplastic anemia, head and neck tumors, medulloblas-
toma, and is the most common form of congenital
aplastic anemia 

Bloom syndrome

DNA repair enzymes

Hypersensitivity to DNA-damaging agents, long, narrow 

15q26

face, erythema with telangiectasias in butterfly 

BLM gene

distribution over the nose and cheeks, high-pitched 
voice, small stature, small mandible, protuberant ears, 
absence of upper lateral incisors, well-demarcated 
patches of hypopigmentation and hyperpigmentation, 
immunodeficiency with decreased IgA, IgM, and IgG 
levels, and predisposition to several types of cancers

Hereditary nonpolyposis 

DNA mismatch repair 

Onset of colorectal cancer at a young age, high  

colorectal cancer

enzymes

frequency of carcinomas proximal to the splenic 

3p21.3,2p22, 2p16,7p22

flexure, multiple synchronous or metachronous 

MLH1, MSH2,MSH6, 

colorectal cancers, and presence of extracolonic 

PMS2 genes

cancers (e.g., endometrial and ovarian cancer,
adenocarcinomas of the stomach, small intestine, 
and hepatobiliary tract), and, accounts for 3%–5% 
of all colorectal cancers

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A

B

C

D

E

F

G

H

I

J

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