39

Key Concepts!

Single gene disorders

Chapter Four
Multifactorial diseases
Gene Abnormalities Genomic imprinting
Trinucleotide repeats
and Huran Health Retrotransposons

INTRODUCTION

Human genetics deals with the variations between humans.

These variations are, in part, reflections of differences that exist
at the DNA level. Variations that influence gene function are
usually referred to as mutations. ther variations that do not
affect health or functioning of an organism are called polyF
morphisms. Mutations may arise in somatic cells or germ cells,
but only germ cell changes are heritable. The ever on-going gene
periments" of nature have resulted in a wide variety of mutant
Pnenotypes, which might have remained unknown in laboratory
Conditions. Because of this enormous "gene-mine," we are now in

position to manipulate advantage. Such a study

them to our
mutations that
immense clinical applications. By and large, cause forma-
It may
PTOduce disease are manifested in two ways.
induce reduction or
o f structurally defective protein or mayDisorders caused by the
DSence of protein biosynthesis.
Strans nission of a single mutant gene
show either autosomal or
dominant or recessive.
Tnked inheritance. Genes are never

th ranslation products, however, produce clinical patterns

"recessive. There are approxi-
r e termed a s "dominant" or and account for more than
y 1200 single gene disorders
of admissions. Single gene disorders can be
all hospital
Cent
SIfied into autosomal and sex chromosome-linked disorders.

There are around 1200 single

gene disorders uwhtch accountjor
more than 5 percent of all hospital
admissions in US alone
40 HuMAN GENETICS

OT

O0oO
Fig. 4.1: Autosomal dominant inheritance

AUTOSOMAL DIsORDERS
Autosomal Dominant Disorders
Autosomal dominant disorders arise due to defect in at least one
gene out of a pair of genes on autosomes (Fig. 4.1).

Distinguishing Features
1. Disease usually
appears in each generation.
2. Delayed age of onset.
3. Vertically transmitted.
4. Mostly affect structural
5. proteins.
Variability in clinical expression.
6. Affected individual has affected parent.
an
7. Male and female
8.
offsprings are equally affected.
Capability of transmission is same in both
affected
parents.o
9. Each child of affected parent is at 50 percent
an
risk
inheriting the abnormal gene.
10. In absence of male-to-male
dominant trait cannot be transmission, an autosoma
dominant inheritance. distinguished from an X-linked
11. Most patients are heterozygotes for the mutant allele.
Autosomal dominant disorders are
vertically transmitted, affect both
sexesequally,appearin each
generation and usually occur late in y
Examples Huntington's chorea
Adult polycystic kidney disease
Marfan syndrome
Neurofibromatosis
Myotonic dystrophy.
 GENE ABNORMALITIES AND HUMAN HEALTH 41
Autosomal Recessive Disorders

.tosomal
Aut
somal recessive disorders
recessive occur when both the
affected. Since genes on
tOSomes are
tosomes are
two abnormal
genes are required
for obtaining a gven
clinical phenotype, their incidence is low
mpared to autosomal dominant disorders. Further, males and
females are equaly affected (Fig. 4.2).

OD
Fig. 4.2: Autosomal recessive inheritance

Autosomal recessive disorders appear early, affect both

sexes equally, may skip few generations and
is widespread in consanguineous matings

Characteristic Features
. The disorder usually appears suddenly in the family.
2. Males and females are equally affected.
3, Less variable in clinical expression.
4.
Early age of onset.
l i p l e cases may not occur especially in small families.
Consanguinity greatly increases the rate ofincidence.
o s t of the offsprings are normal in the family.
O.An affected offspring may or may not have an affected

9. parent. homozygotes have more uniform clinical symptoms.

10ected
many cases, enzyme proteins are affected.
Examples Sickle cell anemia
B-Thalassemia
Cystic fibrosis
Tay-Sachs disease
Fanconi's anemia.
 42 HUMAN GENETICs

X-LINKED DISORDERS
X-linked disorders arise due to defect in genels) of X chromo.
some. Since a female has two X chromosomes, she may be
heterozygous (when only one X is affected) or homozygous
(involving both X's) for the mutant gene. The X-linked disorders
in females can, therefore, be dominant (heterozygous) or reces-
sive (homozygous). However, males with only one X (hemi
zygous), display full impact of syndrome regardless of how the
mutant gene presents itself in females. An important feature of
all X-linked inheritance is the absence of father-to-son transmis
sion of the trait, as father always contributes Y chromosomes to
their son. They can, however, transmit the X-linked defective
gene to their daughters.

Males, being hemizygous, are

more prone to X-linked disorders

X-Linked Dominant Disorders

X-linked dominant disorders arise from an affected heterozygote
female (Fig. 4.3).

TO
OC

Fig. 4.3:X-linked dominant inheritance

Characteristic Features
1. Both sexes are affected, but males (being
are

more severely affected.

hemizygous)
2. All the daughters of affected father are omm
affected. There is C
plete absence of father-to-son transmission.
Affected heterozygous females transmit these disorders to
3. Affecte
male and female children equally.
4. Apparently such pedigrees resemble autosomal dominant

don ckof of
disorders, but presence of excess affected females and ant
male-to-male transmission confims the X-linked dom
pattern.
 HUMAN HEALTH 43
GENE ABNORMALITIES AND

such
dominant
a X-linked trait is lethal in males,
5. Sometimes dermal hypoplasia.
In
incontinentia pigmenti and focal
as
affected persons are females.
Thus, there
such situations, all
have
female-to-female transmission. Affected females
is direct excess of
abortions
a
of live-born sons and an
deficiency
shown to be male fetuses).
which may be
show complete
X-linked dominant disorders
son transmission
absence of father to

Xg bloodD-resistant
Examples Vitamin group
rickets
Oral facial digital syndrome
Melnick-Needles syndrome.

X-Linked Recessive Disorders

homo-
arise in female recessive
X-linked recessive disorders
or less frequently male hemizygotes
(Fig. 4.4).
zygotes

OTO
doodoo-
ODobbopodod

Fig. 4.4: X-linked recessive inheritance

Characteristic Features

. Males are mostly affected.

2. Affected males are related through carrier females.
3. Rarely the illness may occur in females like Turner syndrome.
4. Affected males transmit their defective gene only to daughters,
that become carriers. The canriers expresses the effect of the
mutant gene in an average of 50 percent of her cells because
of randonm X inactivation. There is complete absence of male-
to-male transmission.
5. The disease may appear to
skip a generation.
6. An affected female equally transmits the defective gene to her
children.
44 HUMAN GENETICS

7. At each pregnancy the female carrier has a 25 percent chance

of having an affected son.

X-linked recessiue disorders

affect males more than females

Examples Deuchenne muscular dystrophy

Becker muscular dystrophy
Lesch-Nyhan disease
Hemophilia A and B
Fabry Disease.

SEX-LIMITED AND SEX-INFLUENCED PHENOTYPESS

Male limited sexual precocity is an autosomal disorder that is
manifested by the development of adolescence in males at about
4 years of age. Females are unaffected but can transmit this
disease to their sons. Another example is male pattern baldness.
It appears to be transmitted as an autosomal dominant trait but
requires a testosterone level achieved only in males. In fact,
females carriers show thinning of hair especially if they are given
testosterone exogenously.
An
example of sex-influenced phenotype is hemochromatosis,
Le. massive deposition of iron in liver. The disease is most com-
mon in males while females appear to be protected by their
menstrual loss.

MULTIFACTORLAL DISEASES
The term multifactorial inheritance refers to the participation of
more than one gene in determining a particular phenotype. The
number of genes implicated is often unknown. Two or more
mutant genes in combination with environment cause multi-
factorial disorders. Because environmental component plays an
important role in these diseases, the termn polygenic inheritance
is misleading. A person who inherits the "right" combination of
these "wrong" genes passes beyond a threshold of risk at which
the environmental component determines the severity of the
disease. The rate of recurrence of the disorder is same for all first
degree relatives. As the degree of relation becomes more distant.
the likelihood of a relative inheriting the same combination or
genes becomes less. Since the precise number of genes respon-
sible for polygenic traits is unknown, the risk of inheritance for a
relative to contact the same disease is difflcult to calculate.

Multifactorial disorders are hereditary

diseases controlled by mnore than one gene
 GENE ABNORMALITIES ANDHUMan HEaLTH 45

Essential hypertension, coronary heart

disease,
cleft lip
peptic ulcer disease, schizophrenia.
Exanples

hetes
abetes nmellitus,
m ellit

spina bifida.
cleft palate,
and
GENOMIC IMPRINTING

not be possible to
to mendelian principles, it should
cording chromo-
the parental origin of identical homologous
distinguish believe that the parental origin of
zygote. We generally
mes in a
of the phenotype.
is irrelevant to the expression
So m

a mutant gene
wrong. Whole
chromo-
this principle n a s been proved
However. or e v e n single genes may
chromosomal regions
specitic
Somes,
(inactivated) by someinexplicable way during germ
be marked then
and consequent phenotype of the zygote
cell lineage of the gene[s). In
dependent o n the parental origin
becomes of a
is possible for a
child to receive two copies
principle, it
from one and no copy from the
parent
chromosome
particular known a s uniparental disomy, e.g.
other parent-a phenomenon to have
In 1988, o n e girl w a s reported
cystic fibrosis (Fig. 4.5). 7 and no
her mother's chromosome
inherited 2 copies of
the most clear example
chromosome 7 from her father. Probably
humans c o m e s from
the study of two
of genomic imprirnting in
indistinguishable dis-
but cytogenetically
clinically distinct Prader-Willi syndromes.
In both the
orders-the Angelman and DNA
ql1-q13 is affected. The
cases, chromosome 15 region arises on mater-
former, deletion
analysis has shown that in the syndrome,
chromosome 15, whereas in Prader-Willi
ally derived chromosome 15. With the
a n s e s on the paternally derived
Prader-Willi and Angelman syn-
POSsible exceptions of the in humans is still
genomic imprinting
Omes, the evidence for that methylation of DNA may
It appears
inconclusive. In
ewhat expression of imprinted genes.
the
4Key tactor in regulating t r a n s m i t t e d genes
paternally
were

experimental animals, genes

e and maternally
transmitted

nd to be undermethylated

hypermethylated. describes a change

Genomic imprinting
during passage
gene that
occurs
in a
the result
or o v a with
through the sperm maternal alleles have
that paternal and
in very early embryo
different properties

RINUCLEo REPEATS
type of mutation
recognized
rinucleotide
thateotide
that inv repeat is a recently
of tandemly repeated
nucleotide
lvolves the expansion
46 HUMAN GENETICS

this type are

disease.
Type 3
It involves exp
lated region of
#7# 7
4#7 absent
RETROTRANSPosOM
Paternal disomy
Maternal nullisomy
Retrotransposon is an
Parents
c a n lead
genome that
Sperm
Ovum
(and thus usually unr
mobilize via an RNA fe
The "new DNA" thus-
genome (Fig. 4.6).
mutation in humans-
mechanism till now,
more frequently as in
Offspring with CF The pedigree sym
are depicted in Figur

Fig. 4.5: Human genomic imprinting leading to cystic fibrosis

triplets. Trinucleotide repeats are found in normal individuals SUMMARY

and arecapable of being occasionally expanded numerically. But
if the number of repeats exceeds a certain Not everything in 1
threshold, the repeat as infection and te
array becomes unstable, and additional size increases are likely
to occur in Also, it is incorr
succeeding generations. This type of unstable muta- congenital. Hunti
tion can cause
pathogenic conditions. Expansions of unstable have a variable a
trinucleotide repeats have been associated so far with a number
of different genetic diseasess years for sympton
including fragile X, myotonic of healthy parent=
dystrophy (DM) and Huntington disease. While ten possible family cannot es
trinucleotides can occur at the DNA level, only CTG and CCG
families are su9
repeats are frequently involved in the disorders described so
The trinucleotide repeats fall in three far gene(s) which C

to the class of
categories, correspondin inheritance has
phenotypes. Notable among
TNT repeats are sets of 3 nucleotides male transmissS
while recessive
that occur in abnormally
hgr normal, still bec
numbers in some patients disorders resu
1 It i.e. made inact
Type ischaracterized by large expansions of of CGG
CuU
trinucleotides, leading to fragile site in chromosone butes two hom
e.g. fragile X syndrome. Contribute the
Type 2 It involves the relatively small CAG
expansion of an CA
repeat within coding region of the genes. All disorders o
 GENE ABNORMALITIES AND HUMAN HEALTH 47
this type are
dominantly inherited, i.e.
disease. Huntington
e3It
Type 3 involves expansion of CTG
lated region of the gene, e.g. repeat in the 3
untrans
myotonic dystrophy.
RETROTRANSPOSONS
Retrotransposon is another example of the dynamism within the
denome that can lead to either harmless
and thus usualy unrecognized) or to a polymorphic variation
disease. The transposons
mobilize via RNA form which is reverse
an
transcribed into DNA.
The "new DNA" thus formed is inserted at a
novel site in the
genome (Fig. 4.6). Although only single case of this of
mutation in humans (hemophilia A) has been attributed type
to this
mechanism till now, retrotransposons
are to likely be recognized
more frequently as
investigation at the molecular level continues.
The pedigree symnbols that used in
are depicted in
are
taking family history
Figure 4.7.
Retrotransposons mobilize via an RNA
jormback into DNA at distant site
SUMMARY
Not
everything in family is genetic. Environmental factors, such
s iniection and teratogens may also simulate genetic conditions.
so, it is incorrect to visualize
genetic disorders as always
Ongenital. Huntington disease, keratoconus and Fabry disease
Ve a variable age of onset-the patient may even wait for 40
yea r symptoms to appear. Occasionally two or more children
a t h y parents may be affected. Data from a small number of
fa ly annot
cannot establish a pattern of inheritance. However, large
families are
re suggestive of a possible mode of inheritance of
ger els which can be autosomal or X-linked. Every type of
inheritance
Notab
has some features which mark it apart from others.
the absence of male-to-
mote X-linked inheritance is
male among
whilansmission. Autosomal dominant disorders appear late
while recesssi disorders appear early. Even if all the genes are
norm
d i s , still because of some unknown cellular processes genetic
iisorders res
ers
(.e. mad result. This happens when genes are imprinted
contr-
bute e inactive). It has been found that if one parent
utes chromosomes and other parent does not
o homologous
con u t e the same chromosome, it can lead to a genetic
Cont