염색체질환 Chromosome Disorders
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인류유전학 Human GeneticsBack to Basic
임상유전학 (clinical genetics)
= 유전의학 (medical genetics)
세포유전학 (cytogenetics)
분자유전학 (molecular genetics)
약리유전학 (pharmacogenetics)
집단유전학 (population genetics)
인종유전학 (racial genetics)
생리유전학 (physiological genetics)
유전생화학 (biochemical genetics)
방사선유전학 (radiation genetics)
Genetic Disorders
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Cytogenetic Disorders
– Cytogenetic disorders involving autosomes
– Cytogenetic disorders involving sex
chromosomes
Mendelian Disorders
– Autosomal dominant disorders
– Autosomal recessive disorders
– Sex-linked (X-linked) disorders
Disorders with Multifactorial Inheritance
Disorders with Variable Genetic Backgrounds
– Congenital malformations
– Ehlers-Danlos syndromes(EDS)
– Neoplasm
Clinically Important
Autosomal Abnormalities
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Trisomy: 21, 18, 13, 8, 22, 9,
mosaicism for trisomic and normal cells
Partial Trisomy (duplication): 1q, 13q, 9p, 4p, 10q,
11q, 7q, 14q, 1q, 3p, 4q, 8q, 10p, 11p, 15q, 20p
Monosomy: 21, 22
Partial Monosomy (deletion of part): 5p, 13q, 4p, 18p,
18q, 11q, 7p, 9p, 12p
Polyploidy : Triploidy, Tetraploidy
Chromosome breakage: Fanconi anemia,
Bloom syndrome, Ataxia telangiectasia,
Xeroderma pigmentosa
Down Syndrome (Trisomy 21) Back to Basic
Examples of
Karyotype
Incidence Maternal
age
Trisomy 21 type 47,XX,+21
Translocation type
46,XX,der(14;21)(q10;q10),+21
46,XX,+21,der(21;22)(q10;q10)
Mosaic type
47,XX,+21/46,XX
95%
Increased
4-5%
Normal
1%
Normal
Clinical Features (1 in 1000 births)
Mental retardation, Flat facial profile, Oblique palpabral fissure,
Muscle hypotonia, Hyperflexibility, Lack of Moro reflex, Abundant
neck skin, Broad and short trunk, Dysplastic ears, Horizontal palmar
crease, Dysplastic pelvis,
Dysplastic middle pharynx, Epicanthic folds, Acute leukemias
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Nondisjunctional phenomenon on meiosis
47,XY,+21
46,XY,der(21)t(21;21),+21
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Wide “sandal” gap
Down syndrome with
downslanting palpebral
fissures and a slightly
protruding tongue.
Prominent epicanthal fold
Light smudgy opaque pupil,
called a Brushfield spot.
Simian crease
(bilateral single
palmar crease)
Patau Syndrome (Trisomy 13) Back to Basic
Karyotype
Trisomy 13 type
Translocation
Mosaic type
Incidence
47,XX,+13
>80%
46,XX,der(Dq;13q),+13
10%
47,XX,+13/46,XX
5%
Clinical Features (1 in 6000 births)
Microcephaly and mental retardation, Scalp defect,
Microphthalmia, Cleft palate, Polydactyly,
Rocket-botton feet, Abnormal ears,
Apneic spells and myotonic seizures,
Cardiac dextroposition and VSD,
Extensive visceral defects
cleft palate, atrial septal
defect, inguinal hernia,
and postaxial polydactyly
of the left hand.
polydactyly, particularly
of all extremities, strongly
suggests trisomy 13.
Edwards Syndrome (Trisomy 18)
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Karyotype
Incidence
Trisomy 18 type
47,XX,+18
90%
Translocation type
46,XX,der(Dq;18q),+18
rare
Mosaic type
47,XX,+18/46,XX
10%
Clinical feature (1 in 5000 births)
Mental retardation, failure to thrive,
prominent occiput, micrognathia and low-set ears,
hypertonicity, flection of fingers, cardiac, renal and
intestinal defects, short sternum and small pelvis,
abduction deformity of hip
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mental retardation, failure
to thrive, prominent
occiput, micrognathia and
low-set ears, hypertonicity,
overlapping fingers
(clenched fist)
cardiac, renal and
intestinal defects,
short sternum and
small pelvis,
abduction deformity of hip
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A child with multiple
congenital anomalies with
small face, micrognathia
small chest & low-set ear
Cri du Chat (Cat-cry) Syndrome
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Karyotype : 46,XX,5p- 46,XY,5pIncidence : 1 in 50,000 births
Maternal age : Normal
Clinical features
Mental retardation
Microcephaly and round facies
Mewing cry
Epicanthic folds
Cri du Chat (Cat-cry) Syndrome
hypertelorism,
epicanthus, retrognathia
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Phenotype-karyotype map, based
on array CGH analysis of del(5p)
Wolf-Hirschhorn Syndrome
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chromosome deletion 4p syndrome,
Karyotype : 46,XX (XY),4pIncidence : 1 in 50,000 births
Maternal age : Normal
Clinical features
Mental retardation, Microcephaly
and abnormal facies. Cardiac, renal,
and genital abnormalities.
wide-spaced eyes and
repaired cleft lip
Most are stillborn or die in infancy
46,XY,del(4)(p16)
Wolf-Hirschhorn SyndromeBack to Basic
de novo deletion (WHSC1, WHSC2) ----- 87%
WHSC1=Wolf-Hirschhorn syndrome candidate 1
Translocation of 4p ------ 13%
Prader-Willi syndrome
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Definetion: a syndrome characterized by infantile
hypotonia, hypogonadism, and obesity
Epdermiology:
• incidence: 1/10,000 - 1/25,000 live births
• age of onset: newborn
• risk factors: paternal chromosomal damage
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PWS : hypotonia, feeding difficuty, developmental delay, hypogonadism,
hyperphagia and obesity, dysmorphic face, hypopigmentation,
intellectual disability, short status
AS (Angelman Syndrome) : developmental delay, mental retardation,
dysmorphic face, happy and puppet syndrome, easily provoked laughter
Genetic Pathogenesis
1) del(15)(q11q13) - interstitial deletions of 15q11-q13 (SNRPN , UBE3A )
2) uniparental disomy (UPD)
father (PWS) mother (AS)
3) others : Imprinting defects
DiGeorge Syndrome (DGS)Back to Basic
22q11 Deletion Syndrome
Velocardiofacial Syndrome (VCFS)
Disease characteristics:
• Congenital heart disease (74%)
• Palatal abnormalities (69%)
• Characteristic facial features
• Learning difficulties (70 - 90%)
Diagnosis: 22q11 submicroscopic deletion
Clinical Application of FISH
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Microdeletion syndromes (=contiguous gene syndrome)
Prader-Willi syndrome (del 15q11.2-q13)
Angelman syndrome (del 15q11-q13)
DiGeorge/CATCH 22 syndrome (del 22q11)
Williams syndrome (del 7q11.23)
WAGR syndrome (Wilm's tumor, aniridia, genitourinary
malformation and mental retardation) (del 11p13)
Langer-Giedion syndrome (del 8q24)
Miller Dieker syndrome (del 17p13.3)
Smith-Magenis syndrome (del 17p11.2)
Retinoblastoma (del 13q13)
Marker chromosome (mar)
= Very small unidentified chromosome
Supernumerary chromosome
Extra structurally abnormal chromosome
Hematologic malignancies
BMT follow-up using X/Y
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True Hermaphroditism
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Karytype : 46,XX(most cases) 47,XXY/46,XX 46,XX/46,XY(rare)
Incidence : rare
Clinical features : Testicular and ovarian tissue
Varying genital abnormalities
Double Y Females (Jacob Syndrome)
Karytype : 47,XYY
Incidence : 1 in 1000 male births
Clinical features : Phenotypically normal, Most over 6 feet tall,
Increased aggressive behavior(?)
Multiple X Females
Karytype : 47,XXX
48,XXXX
Incidence : 1 in 1200 female births
Clinical features : Mental retardation, Menstrual irregularities,
Many normal and fertile
Klinefelter Syndrome
Incidence
1 in 850 male births
Karyotyoe 47,XXY (classic) 46,XY/47,XXY
Clinical feature : Testicular atrophy, Azospermia, Eunuchoidism
Gynecomastia, Female hair distribution, mental retardation
Turner Syndrome (Gonadal Dysgenesis)
Incidence : 1 in 3000 female births
Karyotype : 45,X (classic type) 46,X,i(Xq) 45,X/46,XX
46,XXp- 46,XXq- 46,X,r(X)
Clinical features
Short stature, Primary amenorrhea, Infertility,
Webbing of neck, Cubitus valgus, Peripheral lymphedema,
Broad chest & wide-spread nipples
Fragile X Syndrome
Incidence : about 1 in 1500 males.
Affected female carriers are
typically normal.
Most of the affected males have
mental retardation, and their testes
are larger than normal.
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Hermes
Aphrodite
Hermaphroditus
The Nymph Salmacis and Hermaphroditus
by François-Joseph Navez (1829)
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to 35-24-35
Basic
168cm, 48kg,
여자보다 더 아름다운
그녀 하리수 (1975생· 본명 이경엽)
TRANSGENDER
SEX REVERSAL
Pseudohermaphroditism (假性半陰陽症)
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여성 가성반음양증 (female pseudohermaphroditism)
여성거짓남여중간몸증
빈도 : 5,000-15,000 출생아당 1명
자궁, 질강, 난소는 정상
외성기는 애매모호하거나 남성화
선천성부신과형성증
(congenital adrenal hyperplasia, CAH)이 주원인
21-hydroxylase deficiency
17-hydroxyprogesterone 증가
염색체검사 : 46,XX
남성 가성반음양증 (male pseudohermaphroditism)
Androgen insensitivity syndrome (testicular feminization)
- due to deletion of X-linked androgen receptor gene
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Cystourethrogram
(방광요도조영술)
Hypospadias (尿道下裂)
Cryptorchism (潛伏睾丸)
Ambiguous or masculinized
external genitalia (외성기의 남성화)
