Genetic Disorders
INTRODUCTION:
DEFINITION OF TERMS
 CHROMOSOMES- cellular structures where
genes are located
 GENES- basic units of heredity
carry information necessary to determine
specific biologic structures & functions
 ex. ABO Ag in RBC membrane coded by
chromosome 9
 LOCUS- position in the chr where
particular gene is located; all gene loci occur
in pairs except X & Y genes
INTRODUCTION:
DEFINITION OF TERMS
 ALLELES- alternative genes in a single locus
 ex. Kell blood group system
 alleles K & k
 KK- homozygous
Kk- heterozygous
 HOMOZYGOUS GENES- gene pair that are alike
 HETEROZYGOUS GENES- gene pair that are not
alike
 GENOTYPE- actual gene composition that make the
trait
 PHENOTYPE- manifestation of the structure/
form produced by the genes
INTRODUCTION:
DEFINITION OF TERMS
 DOMINANT GENES- genes that
are always expressed in the phenotype
whether homozygous or heterozygous
 RECESSIVE (AMORPH) GENES- genes that
are masked if paired w/ a dominant gene,
thereby only expressed when paired w/
another recessive gene
INTRODUCTION:
DEFINITION OF TERMS
 EUPLOIDY- multiples of the haploid # that is
considered normal
 HAPLOID
(N)= 23- OCCURS IN MEIOSIS
 DIPLOID
(2N)= 46- OCCURS IN MITOSIS
 ANEUPLOID- not exact multiples of the
haploid #; only 1 pair of chr involved,
therefore, germ cells have 2 copies of the
same chr or lack the affected chr entirely
 HYPODIPLOID 2N- 1, -2, ETC. (MONOSOMY)
 HYPERDIPLOID 2N+ 1, +2, ETC. (TRISOMY)
INTRODUCTION:
DEFINITION OF TERMS
 POLYPLOID- multiples of haploid #;
entire set of chrs fail to divide & all the chrs
are segregated in a single daughter cell
 TRIPLOID (3N)= 69
 TETRAPLOID (4N)= 92
Congenital Disorders
 Non Genetic:
 Developmental defects – Malformations
 Genetic Disorders
 Chromosomal
 Gene - Mendelian
 Multifactorial
Mutations:
 Genome: whole set – Polyploidy 4n, 8n etc.
 Chromosomal: change in chromosome
 Number: Trisomy, monosomy
 Structure: Deletion, Translocation etc.
 Gene: Submicroscopic
 Point mutation – single base sequence
 Deletions
 Insertions
Cytogenetic Abnormalities:
 Abnormal # of chrs:
 Non-disjunction - Down’s Syndrome
 Anaphase lag - Turner’s xxx
 Abnormal Structure: (normal #)
 Deletion - 5q- Cri - du - chat syndrome
 Inversion -
 Translocation - Ph Chromosome - t(9:22) CML,
GENETIC PATHOLOGY:
 DEFINITION: Abnormalities or disease states that
may or may not be congenital, transmitted by genes
or chromosomal aberrations, that may be heritable
(familial) or mutational
 If mutational, may give the following outcomes:
 Heritable
 Disappear
 Lethal
 Sterility
 Malignancy
CATEGORIES:
 CHROMOSOMAL ABNORMALITIES/
MUTATIONS
 GENE ABNORMALITIES/ MUTATIONS
 POLYGENIC/ MULTIFACTORIAL
ABNORMALITIES
I. CHROMOSOMAL ABNORMALITIES/
MUTATIONS
GENERAL CONCEPTS:
 Children born to older women show more
chromosomal aberrations than children born
to younger women
 Most major chromosomal abnormalities are
incompatible w/ life
 Detectable by karyotyping (chromosomal
analysis) w/ or w/o banding techniques (use
of stains)
I. CHROMOSOMAL ABNORMALITIES/
MUTATIONS::: TYPES:
 NONDISJUNCTION (Chromosomal numerical
aberration)- failure of chrs to sort themselves
in equal #s into daughter cells
 SUBTYPES:
 POLYPLOIDY- see previous definition
 ANEUPLOIDY- see previous definition
 MOSSAICISM/ MYXOPLOIDY
Non-disjunction:
I. ANEUPLOIDY: TRISOMY
 TRISOMY- presence of 3 homologous
chromosome in a cell
 AUTOSOMAL TRISOMY- viable throughout
pregnancy, even live born but die soon after
birth except Down's syndrome
 TRISOMY 21- DOWN'S SYNDROME
 TRISOMY 18- EDWARD'S SYNDROME
 TRISOMY 13- PATAU'S SYNDROME
I. ANEUPLOIDY: TRISOMY
 SEX CHR. TRISOMY- abnormal
development but non lethal; # of X chr. is
directly proportional to mental retardation
while number of Y chr. is directly proportional
to aggressive behavior
 TRIPLE X
I. ANEUPLOIDY: MONOSOMY
 MONOSOMY- absence of one of a pair of
homologous chr
 AUTOSOMAL MONOSOMY- IUFD is the usual
outcome
 SEX CHR. MONOSOMY- compatible w/ life only
if the conserved chr is an X, if not it will be less
viable
• TURNER'S SYNDROME- 45, XO
Hydrops Fetalis – Monosomy X:
I. ANEUPLOIDY:
MOSSAICISM/ MYXOPLOIDY
 MOSSAICISM/ MYXOPLOIDYnondisjunction at a later cell division resulting
to population of normal & trisomic or
monosomic cells coexisting in an individual
 AUTOSOMAL MOSSAICISM- rare & lethal
 SEX CHR. MOSSAICISM- common
• GONADAL DYSGENESIS- TURNER'S
SYNDROME 45, XO
• KLINEFELTER'S SYNDROME 47 XXY
I. CHROMOSOMAL ABNORMALITIES/
MUTATIONS::: TYPES: I. MORPHOLOGIC/
STRUCTURAL SUBTYPES:
 DELETION- loss of chromosomal material
following a break in the chr arm or partial
monosomy
 CRI DU CHAT- partial monosomy of p5
 RETINOBLASTOMA- q13
 WILM'S TUMOR ANIRIDIA SYNDROME- p11
I. MORPHOLOGIC/
STRUCTURAL SUBTYPES:
 TRANSLOCATION- transfer of segment of
chromosomal material to another chromosome
leading to imbalance of material in each daughter
cell between non homologous chr
 RECIPROCAL- acentric segments of chr exchanged for
similar segment from a heterologous chr; use banding
techniques for detection
 ROBERTSONIAN (CENTRIC FUSION)- 2 acrocentric chr
broken near centromere, exchange 2 arms and form new
large metacentric chr and a small fragment, devoid of
centromere & lost during subsequent division
I. MORPHOLOGIC/
STRUCTURAL SUBTYPES:
 TRANSLOCATION
 BALANCED- transfer w/ no loss of genetic
material; individuals are normal except for
infertility & if fertile, have a high risk of having
malformed offspring
 UNBALANCED- transmitted in the haploid
gamete & paired w/ a new set of genes from the
other parent
• MALIGNANT LYMPHOMA- between 8 & 14
• LEUKEMIAS- between 22 & 9
• DOWN'S SYNDROME- chr 21
I. MORPHOLOGIC/
STRUCTURAL SUBTYPES:
 TRANSLOCATION
 ISOCHROMOSOMAL- faulty division of
centromere at the transverse plane of the long
axis w/ formation of a pair of isochromosome (one
short arm & one long arm)
• TURNER'S SYNDROME
I. MORPHOLOGIC/
STRUCTURAL SUBTYPES:
 INVERSION- break of a chr at 2 points,
followed by inversion of the intermediate
segments & reunion results in the formation of
a chr w/ rearranged distribution of genes
 PERICENTRIC- rotation occurs around the
centromere
 PARACENTRIC- rotation occurs only on the
acentric portion of the arm
I. MORPHOLOGIC/
STRUCTURAL SUBTYPES:
 RING CHROMOSOME- break in the
telomeric ends of the chr followed by deletion
of the broken acentric segments & end to end
fusion of the remaining portion
II. GENE ABNORMALITIES/ MUTATIONS
GENERAL CONCEPTS:
 Single gene defect detectable in the phenotype
 Modified by penetrance, expressivity & whether
defect is dominant, intermediate, recessive or X
linked
 Dominant pattern of inheritance usually due to
alteration of aa sequence in the gene
 Recessive pattern of inheritance (inborn errors of
metabolism) usually is due to manufacture of
abnormal enzymes or enzyme deficiencies
 Follows Mendelian patterns of inheritance
PATTERNS OF INHERITANCE:
AUTOSOMAL DOMINANT
 Autosome- gene location
 Gene expression- both homozygous & heterozygous
state
 Transmission of traits in every generation unless
Low penetrance or modified by gene mutations
 Unaffected family members do not transmit trait to
offspring; affected family members usually
heterozygous & transmit trait to only half of the
offspring
M=F
PATTERNS OF INHERITANCE: AUTOSOMAL
DOMINANT
 Pp x pp
 Pp : Pp : pp : pp
 DIABETIS INSIPIDUS
 MUSCULAR DYSTROPHY
 POLYDACTYLISM
 MARFAN'S SYNDROME
 ACHONDROPLASTIC DWARFISM
 HUNTINGTON'S CHOREA
 GARDNER'S SYNDROME
 GOUT
 HEMOCHROMATOSIS
PATTERNS OF INHERITANCE: AUTOSOMAL
RECESSIVE
 Autosome- gene location
 Gene expression only in the homozygous state
 Both parents usually heterozygous for the trait &
clinically unaffected
 Symptoms appear in 25% of offspring
 50% of all siblings will be heterozygous for the trait
thus assymptomatic
M=F
PATTERNS OF INHERITANCE: AUTOSOMAL
RECESSIVE
 Nn x Nn
 CYSTIC FIBROSIS
 NN : Nn : Nn : nn
 GLYCOGEN STORAGE
DISEASES
 ANDROGENITAL
SYNDROME
 ALBINISM
 ALKAPTONURIA
 DEAF MUTISM
 MUCOPOLYSACCHARI
DOSIS
 LIPID STORAGE
DISEASE
 GALACTOSEMIA
 WILSON'S DISEASE
 PHENYLKETONURIA
 TYROSINOSIS
 FAMILIAL GOITROUS
CRETINISM
 BILIRUBIN METABOLIC
ABNORMALITIES
PATTERNS OF INHERITANCE:
X LINKED RECESSIVE
 X chromosome - Gene location
 Expression of traits
 100% heterozygous male
 Rare homozygous female
 Partial heterozygous female if X Chromosome inactivation
occurs
 Transmission via asymptomatic female
 Each son of heterozygous female carrier has 1 in 2 chances of
having the disease
 Affected males do not transmit trait to their sons, only to their
daughters; Unaffected males do not transmit the gene
PATTERNS OF INHERITANCE:
X LINKED RECESSIVE
 FEMALE
X
MALE
(HEMOPHILIAC)
 XX
x
Xh Y
 XXh : XY : XXh : XY
 FEMALE (CARRIER) x
MALE (NORMAL)
 Xh X
x
XY
 Xh X : Xh Y : XX : XY
 HEMOPHILIC
 COLOR
BLINDNESS
 G6 PD
DEFICIENCY
 MUSCULAR
DYSTROPHYDUCHENNE
TYPE
PATTERNS OF INHERITANCE:
X LINKED DOMINANT
 Rare
 Affected heterozygous female transmit to 50%
sons & 50% daughters
 Affected males transmit to 100% daughters &
none to their sons
 VIT. D RESISTANT RICKETS
PATTERNS OF INHERITANCE:
Y LINKED
 Not clinically significant
 Hairy ears
III. POLYGENIC/ MULTIFACTORIAL
ABNORMALITIES
GENERAL CONCEPTS:
 Environmentally influenced interactions of a
number of different gene pairs
 HYPERTENSION
 DIABETIS MELLITUS
 PEPTIC ULCER
 OTHER CONGENITAL HEART DISEASES
CHROMOSOMAL DISEASES:
SEX CHROMOSOMAL ABNORMALITIES
 X DEFICIENCY
 TURNER'S SYNDROME 45, XO
• Short stature female w/ webbed neck, cubitus
valgus, immature genitalia w/ small fibrotic (streak)
ovaries, coarctation of aorta; mostly abort; no Barr
Bodies; almost 50% are mossaics w/ less stigmata
 ULLRICH NOONAN SYNDROME (46, XX or XY
::: 46, X(Xq)
• Turner like phenotype; often w/ pulmonary stenosis;
giant Barr Bodies
CHROMOSOMAL DISEASES:
SEX CHROMOSOMAL ABNORMALITIES
 KLINEFELTER'S SYNDROME 47, XXY
 Most common of X chromosomal abnormality
 Tall eunuchoid male w/ gynecomastia, small
testis w/o spermatogenesis (infertile)
 Mossaics occur
CHROMOSOMAL DISEASES:
SEX CHROMOSOMAL ABNORMALITIES
 MISCELLANEOUS SYNDROMES
 TRIPLE X (47 XXX)- mildly retarded; normal
female phenotype
 47 XYY- tall, aggressive, mildly retarded male;
increased incidence among criminal
CHROMOSOMAL DISEASES:
SEX CHROMOSOMAL ABNORMALITIES
 INTERSEX STATES- HERMAPHRODITISM
 TRUE HERMAPHRODITE- XX or XY or both;
variable phenotype, both ovaries & testis are
present
 PSEUDOHERMAPHRODITES (NORMAL
GENECITY)
• Male phenotypically female; testicular feminization
• Female phenotypically male; virilizing ovarian or
adrenal tumors
CHROMOSOMAL DISEASES:
AUTOSOMAL ABNORMALITIES
 More severe effects than X chr anomalies
 Monosomies more severe than trisomies
 The larger chromosome involved, the more
serious the phenotypic disorder
CHROMOSOMAL DISEASES:
AUTOSOMAL ABNORMALITIES
 DOWN'S SYNDROME- TRISOMY 21,
MONGOLISM; 47 G21+
 Most common of the trisomies; maternal risks
increases w/ age; incidence equal in both sexes;
usually due to maternal nondisjunction
 Floppy infants w/ psychomotor retardation,
mongoloid facies, epicanthic folds, flat nose,
cardiovascular anomalies, simian palm creases,
cryptorchidism, increased incidence of leukemia
 Variant - Translocation type (heritable)- occurs at any
maternal age; 46 XY -D; +tDqGq
Downs Karyotype: Trisomy-21
Downs
Sy.
Trisomy
-21
Downs Syndrome - Trisomy-21
Downs Syndrome - Trisomy-21
Simian Crease
Downs Syndrome:
 Mental retardation
 Neck folds
 Epicanthic folds
 Flat facial profile
 Simian crease
 Hypotonia
 Umbilical hernia
 Leukemia
CHROMOSOMAL DISEASES:
AUTOSOMAL ABNORMALITIES
 EDWARD'S SYNDROME (16 - 18 TRISOMY, E
TRISOMY); 47, E18+
 Female predilection; low set ears, epicanthic folds,
micrognathia, CVS anomalies, overlapping 2nd & 5th
finger, rocker bottom feet, renal anomalies, early death
 PATAU'S SYNDROME (13 - 15 TRISOMY, D
TRISOMY); 47, D13+
 Least common, both sexes equally affected; low set ears,
micropthalmia, brain anomalies, cleft lip & palate,
overlapping 2nd & 5th finger, CVS anomalies, rocker
bottom feet
Cleft Lip - Trisomy 13:
Polydactyly - Trisomy 13:
CHROMOSOMAL DISEASES:
AUTOSOMAL ABNORMALITIES
 CRI DU CHAT SYNDROME, 5p Rare, common in females, cat cry, moon faced,
retarded, micrognathia, antimongoloid slant, CVS
anomalies
 D13p-, D13q-, E18q-, TRIPLOIDY
 Severe anomalies, lethal
 PHILADELPHIA CHROMOSOME, G22q Associated w/ CML; good prognosis
Syndactyly - Triploidy
Philadelphia Chromosome (Ph)
 Reciprocal translocation t(9;22)
 Results in bcr/abl gene fusion
 c-abl (Abelson) chr 9
 bcr (break point cluster region) chr 22
 Protein w/ tyrosine kinase activity - plays
critical role in pathogenesis
CML - t(9;22) - (Ph chr)
DISEASES DUE TO GENE ABNORMALITIES
AND MUTATIONS:
AUTOSOMAL DOMINANT ABNORMALITIES
 ACHONDROPLASIA
 Defective endocndral ossification
 Most common type of dwarfism
 High incidence of early death
 80% sterility
 HUNTINGTON'S CHOREA
 Progressive neurologic disorder w/ choreic movements,
seizures, dementia, death
 Average onset is 35 years of age so offspring is born
before parent is affected
 Reproduction not impaired
DISEASES DUE TO GENE ABNORMALITIES
AND MUTATIONS:
AUTOSOMAL DOMINANT ABNORMALITIES:
 MARFAN SYNDROME
 Complex defective formation of collagen & elastin
 Tall, long extremities (arachnodactyly), subluxation of lens,
cystic medial necrosis of aorta w/ dissecting aneurysm
 Mechanism is single gene w/ multiple effects (pleiotropy),
variable expression, forme fruste expression, may skip
generations
 GARDNER SYNDROME
 Complex cyst of the skin, osteomas, lower intestinal polyps
with development of colonic ca
 Pleiotropy
Cell
Cycle
Mitosis
Meiosis
 Reduction Division (4n-2n)
 Prophase-1(Synapsis, g.rec)
 Metaphase-1
 Anaphase-1
 Telophase-1
 Equatorial Division (2n-n)
 Prophase-2
 Metaphase-2
 Anaphase-2
 Telophase-2