The lecture has been given on Dec. 12th & 23rd, 2010 - Feb. 6th, 2011 by Dr. Jamal.

1. Lecture notes, prepared by Dr. Jamal A. RASHID
Principles of Medical Genetics
Patau Denver
and Chromosomal Disorders classificatio classification
At present, practice of medicine depends upon n
knowledge of anatomy, physiology, biochemistry, A 1-3
etc…,. In the near future dealing with diseases will B 4-6
need understanding of the molecular anatomy, C 7-12 + X chromosome
physiology, and biochemistry of the human genome.
The greatest explosion had occurred in the field of D 13-15
genetics than in any other paediatric field during the E 16-18
previous decade. F 19-20
Genetically determined disorders, although G 21-22 + Y chromosome
individually rare (some occur at a frequency of one in
200,000 – 300,000), the sum of all genetic disorders
makes a significant contribution to the morbidity and
mortality among children.
The field of medical genetics is new. It was for the
first time in 1956 when the normal number of human
chromosomes was found to be 46.
In the USA, among different categories of genetic
diseases in neonates, it was found that 0.5% had a
non-lethal chromosomal disorder, 0.4% had single
gene Mendelian inheritance conditions and 1% had
mutlifactorial (polygenic) disorders.
• Medical Genetics: is the study of the
inheritance of disease.
Definitions of Terms Commonly Used • Inheritance: means the passage of hereditary
in Genetics traits from one generation to another. It is the
process by which, one acquires characteristics
• Congenital Defect: only means that the from his or her parents and then transmits
defect is present at birth, it does not suggest these traits to his or her own children.
genetic aetiology. • The gene: it is the basic unit of heredity; it is
• Genetic disorder: means that the condition is made up of DNA. Genes are ultramicroscopic
caused by abnormal genes or chromosomes. structures. Each gene occupies a certain place
• The chromosome: chromosomes are rod- on a chromosome called “locus”. Hereditary
shaped bodies situated inside the cell nucleus. traits are controlled by pairs of genes on
Each chromosome is composed of 2 strands chromosome pairs.
called chromatids attached at centromere. The two alternative genes on the homlogous
Chromosomes are the bearer of the genes. chromosome are called “allele”. If the alleles code
The normal number of chromosomes is for the same trait, these are said to be present in a
constant for each species, being 46 in man homozygous state, while if they code for different
(23 pairs in each of somatic “body” cells). forms they are in a “heterozygous state”.
This number constitutes the “Diploid If a gene clinically manifests itself even in the
number” which is made of 22 pairs of heterozygous state, it is called a “Dominant” gene
“autosomes” and a pair of sex chromosomes or character. A gene that cannot express itself
designated XX in females and XY in males. clinically when present in heterozygous state, but
Denver classified chromosomes in human only when in a homozygous state is called
into 22 pairs, while Patau classified them into 7 “Recessive” gene or character.
groups from A to G as follows: • Carrier State: individuals heterozygous for a
recessive trait.
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2. • Mutation: means a permanent heritable Gamete (ovum or sperm) Formation
change in a gene, that causes it to have a Each somatic (body) cell in human contains 46
different effect from that it had previously, chromosomes, 23 have come from each parent. Cell
this changed gene can be passed to the division in the somatic cells is mitosis (non-reduction
following generations. Mutation may occur division) and each daughter cell contains 46
spontaneously or be induced by mutagens as chromosomes as the mother (original) cell.
various medicines or chemicals, e.g., mustard While in the germ cells of both sexes, the cell division
gas, ionizing radiation (X-ray or UVL). is of reduction (meiosis) variety, the resulting cell
• Deletion: means loss of part of a (ovum or sperm) will contain only 23 chromosomes,
chromosome, mostly through breakage. i.e., the number of chromosomes is halved.
• Karyotype: It is the description of the The female gamete (ovum) has 22 autosomes and one
chromosomes of an individual. Thus the X-chromosome, while the male gamete (sperm) can
normal human male karyotype is 22 XY, have 2 types of chromosomal pattern: 22+X or 22+ Y.
while the normal human female karyotype is Fertilization of the ovum by an X-bearing sperm will
22XX. result in a female offspring, while if fertilized by a Y-
• Mitosis: the type of cell division which takes bearing sperm a male offspring will result. Thus each
place in the somatic cells and in which each offspring (boy or girl) inherits half their chromosomes
of the two daughter cells carries full from their father and the other half from their mother.
compliment of 46 chromosomes as their That is why they have some characteristics of both.
mother cells.
• Meiosis: the reduction division which occurs Genetics and Disease
in the germ cells during the process of
Human diseases in general may have a purely genetic
gametogenesis. This division in human
cause without any role of the environment in their
reduces the number of chromosomes to 23 in
causation. On the other hand some conditions are
the ova or sperm.
caused by pure environmental factors without any role
• Lyon Hypothesis: says that one of the two X of genetic predisposition as most infections and
chromosomes in human female is mainly or accidents.
completely inactivated early in embryonic life In-between these 2 extremes there are many childhood
(before 16th day of gestation). This process diseases, causation of which requires both genetic and
takes place randomly, resulting in 2 environmental factors (polygenic or multifactorial).
populations of somatic cells, one population Another group of diseases, which is relatively more
with the maternal and the other with the significant in young children than in adults, is the
paternal X-chromosome inactivated. But once group of chromosomal disorders which are generally
decision is made, all the descendants of that linked to the genetically determined diseases.
cell will have the same X-chromosome
inactivated.
• Mosaic: a karyotype state in which two or Chromosomal Disorders
more cell lines are present in the same Although rare in clinical practice a large proportion of
individual. aborted fetuses are found to have chromosomal
• Phenotype: is the physical appearance or disorders. The younger the GA of the aborted foetus
make up of an individual. the higher the percentage of chromosomal
• Alleles: are alternative forms of a gene at a abnormalities, thus the incidence decreases from 50%
given locus. during the first 2 months to less than 5% by 7 months
• Sex chromatid “Barr Body”: it is a darkly of gestation and 5% of stillborns have a chromosomal
stained body seen near the nuclear margin in anomaly.
a high percentage of the cells of normal It has been found that 65% of the fetuses with Down
female. The number of Barr bodies seen in a syndrome and 95% of those with Turner syndrome are
cell is equal to the number of X- spontaneously aborted.
chromosomes minus one, i.e., in a normal Chromosomes contain a large number of genes. Loss
female there is one Barr body in each somatic or gain of a whole chromosome due to abnormalities
cell, and there is no Barr body in male cells. in cell division may cause so great disturbances in the
genetic constitution of the foetus that it may result in
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3. abortion, stillbirth, death soon after birth, or survival 5. Translocation: one chromosome or a segment
with some malformations, mental retardation or of it may translocate itself and join another
infertility. chromosome. Thus one chromosome will be
Of all live born babies 0.5% has a chromosomal absent or shorter, while another chromosome
anomaly. appears longer. If no loss or gain of the
Chromosomal abnormalities are in general sporadic genetic material occurs in this process the
and therefore the risk of recurrence in the offspring is translocation is called balanced and the person
low. is phenotypically normal. The translocated
chromosome may be transmitted to either
gamete during meiosis, and when this gamete
Mechanisms of Chromosomal (with translocated chromosome) mates a
Anomalies normal gamete, the resulting zygote may
Chromosomal disorders may be numerical or either have excess or deficiency of the genetic
structural and generally arise by some of the material. Such an offspring will be abnormal
following mechanisms: in both karyotype and phenotype.
1. Inversion: a break may occur along the 6. Deletion: break-off and loss of a fragment of
length of the chromosome arm. The broken a chromosome. If a large portion of a
pieces may rearrange themselves in a new chromosome is lost, it would be lethal or
way. If there is neither loss nor gain of causes a grave disability.
genetic material, there may be no significant
clinical manifestations.
2. Isochromosome: Normally chromosomes Classification of Chromosomal
divide longitudinally during mitosis. Rarely a Abnormalities
transverse division may occur through the I. Numerical Abnormalities:
centromere, thus instead of making 2 normal a. Excess of one or more autosome (autosomal
chromosomes, two new types of trisomy): this may occur by non-disjunction
chromosomes are formed, one having both or by translocation mechanism. Examples of
the long arms and the other both the short autosomal trisomies include:
arms, these are called isochromosomes. i. Trisomy 21 (Down syndrome)
Features may occur as there will be some ii. Trisomy 18 (Edward syndrome)
excess and some deficiency of genetic iii. Trisomy 13 (Patau syndrome)
materials. b. Autosomal monosomy: means absence of one
3. Nondisjunction: during meiosis both of the autosomal chromosomes, this
members of a pair of chromosomes may fail abnormality is incompatible with life.
to separate and go jointly to either of the c. Numerical sex chromosome anomalies:
daughter cells. Thus one of the daughter cells i. Extra-chromosomes:
will have 22, and the other 24 chromosomes. 1. XXY (Klinefelter syndrome)
Then after fertilization by a normal gamete 2. XYY
(having 23 chromosomes) the resultant 3. XXX
zygote will either have 47 or 45 4. XXXY
chromosomes. 5. XXXXY
4. Mosaicism: this state happens if the process ii. Deficient chromosome: XO (Turner
of non-disjunction occurs in the first mitotic syndrome)
instead of the meiotic division, resulting in 2 d. Triploidy: means presence of 3 haploid sets of
cells, one with 47 and other with 45 chromosomes in one cell, i.e., presence of 69
chromosomes. As each one of these cells will chromosomes. This condition is not
reproduce similar cells by further normal compatible with life.
mitosis, 2 cell lines will be observed, a line e. Tetraploidy means presence of 4 haploid sets
with 45 and another with 47 chromosomes. of chromosomes in one cell, i.e., 92
There may be more than 2 cell lines, one with chromosomes, which is again incompatible
normal and the others with abnormal with life.
chromosomes complements. f. Mosaicism
II. Structural Abnormalities
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4. a. Translocation (balanced structural change) f. Protruding tongue from a relatively
b. Deletion (unbalanced structural changes) small mouth, furrowed tongue, small
teeth
g. Prominent malformed ears
Features of Some Chromosomal h. Small nose and flat nasal bridge
Disorders i. Broad short neck
Down Syndrome “Mongolism”, “Trisomy G”,
4. Hands and Feet: short broad hands, single
palmer crease (Simian crease) in 85%,
“Trisomy 21”
clinodactyly (short incurved little finger due
It is the first autosomal trisomy described in man by to hypoplasia of its middle phalanx)& a gap
John Down in 1966. The name mongolism is between the first and second toe.
sometimes used as the patients look like those of 5. Greater liability to have:
Mongolian race. a. Associated CHD, most commonly the
21 and 22 trisomies can not clinically be AV canal
differentiated. b. Congenital intestinal obstruction
The incidence of Down syndrome is 1 in 700 in most especially duodenal stenosis, or
parts of the world. Hirschsprung disease
Maternal age at pregnancy strongly contributes to the c. Leukaemia
incidence, thus: d. Frequent respiratory infection
6. Special non-aggressive forms of moderate to
Maternal Age Incidence of Down severe mental retardation
syndrome
20 1 in 2000 They are characteristically friendly individuals who
30 1 in 1000 show an unusual enjoyment of music. Babies with
35 1 in 350 Down syndrome look all alike. Mosaic cases have less
40 1 in 100 severe features. 95% result from non-disjunction, 3%
45 1 in 40 from translocation, and 2% from mosaicism. None-
>45 1 in 35 mosaic cases can be clinically diagnosed at birth from
the appearance and the striking hypotonia.
This increase of incidence in elderly mothers is
attributed to the exposure of the maternal oocyte to Management
the harmful environmental factors for a longer period Parents should be told about the illness on the second
of time, since Graffian follicles are present in the or third day after birth, or the husband is told so that
foetal life and remain throughout the reproductive life he will then later on explain the condition to his wife.
of the woman. On the other hand the sperm of man The fact that there is no curative treatment for Down
has a short life span and has therefore lesser chances syndrome must be explained to the parents. Children
for exposure to harmful influences. with Down syndrome have a shorter life span than the
The age of the father has lesser effect on the average in that community, even in the absence of
incidence of Down syndrome. associated severe congenital anomalies.
Genetic counseling may be helpful if one of the
Clinical Features parents is found to have translocation of chromosome
1. General: hypotonia during infancy and mental 21.
retardation throughout life are constant
features Edward Syndrome (Trisomy 18 or “E”
2. Short stature Trisomy)
3. Craniofacies: Much less common than Down syndrome; it occurs at
a. Brachycephaly a frequency of 1: 6000 births, being more common in
b. Upward and outward slanting females. 90% are due to non-disjunction. As in Down
palpebral fissures syndrome, maternal age seems to be important.
c. Prominent epicanthic folds
Clinical characters include:
d. Strabismus
e. Speckled irides (Brushfield spots) - Prominent occiput
- CHD
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5. - Receding chin and triangular face A variant of cri-du-chat is caused by deletion of the
- Short sternum and single umbilical artery short arm of chromosome number 4, differentiated
- Flexion deformities of the fingers, which are from cri-du-chat by absence of the characteristic cry
rigidly fixed across the palm. The middle and by common presence of midline fusion defects
finger overriding the index. (scalp, nose, lips, palate, and in males the penis).
- Characteristic “rocker-bottom” feet, the sole
is convex and the heel is prominent, Turner Syndrome (Ovarian Dysgenesis)
simulating a rocking chair Occurs at a frequency of 1 in 2500 births and their
chromosomal pattern is XO, i.e., they have 45
The majority of affected babies die during the first 3 chromosomes and are chromatin negative females.
months of life. Most of the XO fetuses are aborted during the first
trimester. The cause is probably non-disjunction in
Patau Syndrome (Trisomy 13-15 or D spermatogenesis than in oogenesis.
Trisomy) At birth diagnosis is suspected from lymphoedema of
- It occurs at a frequency of 1 in 10,000 births. the feet and hands, and lax neck skin. Other features
Characterized by gross deformities of the later in life include:
hand and face. - Short stature
- There is microcephaly with a relatively large - Shield-like chest, widely spaced nipples
“onion-nose’ receding jaw, cleft lip and - Neck webbing and low posterior hairline
palate are common. - Cubitus valgus (increased carrying angle of
- The eyes may be absent, small or of normal the arms)
size but with coloboma or cataract. The finger - Short fourth metacarpals and metatarsals
nails are narrow and hyperconvex. - Mild mental retardation
- Capillary haemangioma - The nails are small, narrow, and deeply set
- CHD is common - Associated congenital anomalies especially
- Flexion deformities of the fingers coarctation of the aorta and horse-shoe
- There may be associated agenesis of corpus kidneys.
callosum - The ovaries are either absent or severely
- The majority of affected babies die during hypoplastic
early infancy - Sexual infantilism becomes evidence at the
time of expected puberty, thus there will be:
75% of cases result from non-disjunction, 20% from o Primary amenorrhoea and infertility
translocation, and 5% from mosaicism. The risk for o Underdeveloped breasts, mostly
recurrence in other children is only high in the consisting of fat
presence of parental translocation. o Appearance of pubic and axillary hair,
since these result from adrenal
Cri-du-chat Syndrome androgens (these are absent in
An extremely rare disorder caused by deletion of the hypopituitarism, since there is also
short arm of chromosome 5. Clinically cri-du-chat lack of adrenal androgens)
syndrome is characterized by: o Infantile external genitalia
- Severe mental, motor, and growth retardation o Severely hypoplastic uterus
- Microcephaly with broad head o Raised urinary gonadotrophins (FSH)
- Prominent epicanthic folds, ocular
hypertelorism and antimongoloid slant Patients with Turner syndrome, who are heterozygous
(Downward and outward sloping palpebral for XLR disorders, may show the disease.
fissures)
- Broad face, saddle nose and micrognathia Treatment
- Low set, malformed and rotated ears with
No hormonal treatment is indicated in childhood, but
accessory auricles
at the usual age of puberty substitution therapy with
- Simian crease in 50%
oestrogen (daily orally for 6 months or until
- Characteristic cry similar to mewing cat or
menstruation occurs, subsequently, cyclic oestrogen-
kittle
progesterone therapy is administered).
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6. Fragile X Syndrome
Klinefelter Syndrome “XXY Syndrome” This is a familial (XLR) form of chromosomal
It occurs at a frequency of 1 in 500 male births. 80% disorder and is considered to be the second most
have XXY, 10% mosaic, and 10% XXYY or XXXY common cause of mental retardation after Down
karyotype, so they are chromatic +ve males. syndrome. One third of female carriers may show mild
Clinical features affection. On the other hand between 20-50% of boys
who have the fragile X are asymptomatic and transmit
They look like normal boy’s early in life and the
the chromosome to all of their daughters, who are also
condition is seldom diagnosed before adolescence,
asymptomatic. However in the subsequent generation
because the external genitalia are normal. The only
both male and female offspring of those daughters
clues to the diagnosis before puberty are unusually
begin to show the illness.
long legs, behavioral problems, and when investigated
The following are some of the reported features:
they are found to be chromatic positive. After
- Mental retardation
pubertal age there will be:
- Macrocephaly
- A long boy with sparse body (including
- Prognathia (prominent jaw)
axillary and pubic) hair, long limbs and knock
- Short stature
knees
- Large protruding ears
- Behavioral disorders: social inadequacy and
- Macro-orchidism, especially after puberty
immature personality. The degree of
- Rapid and repetetive speech
intellectual deficit is directly proportional to
- Generally they are pleasant and socially
the number of the extra X chromosomes
engaging, although some of them avoid eye
- Microorchidism (small sized testes)
contact and simulate autism
occasionally with cryptorchidism
- Decreased androgen level in the blood,
They have a normal life span. No curative treatment is
resulting in temporal recession of the hair
available, although it has been found that folic acid
- Although they are capable of erection,
may improve the psychological state. Prenatal
performance of intercourse, and ejaculation of
diagnosis is possible.
sperm fluid, they are sterile
- Raised urinary excretion of FSH
- Gynaecomastia, broad pelvis, horizontal limit Single Gene Inheritance
of pubic hair, and feminine voice
The Mendelian laws of inheritance are applied to all
- Commonly they suffer chronic pulmonary
living creatures including human beings.
conditions as asthma, emphysema, and
All of the 46 human chromosomes which are present
bronchiectasis
in every single cell of the body carry genes. The
autosomes arrange in pairs according to their shape,
Patients with Klinefelter syndrome have normal
and the members contain the same gene loci and are
survival and there is no increased risk to have other
known as homologous chromosomes.
affected children.
Every autosomal gene locus occurs twice in every cell
of the body. If both loci possess the same genetic
Treatment information, the individual is considered homozygous
Replacement of testosterone since 11-12 years of age. (i.e., identical), while if the gene loci carry different
50mg every 3 weeks, slowly increased until a information (e.g., one normal gene with another
maintenance of 250 mg/3 weeks is reached. abnormal one) the individual is considered
heterozygous. Therefore, every individual can be
XYY Syndrome considered as one of the following:
This occurs at a frequency of 1-2/1000 boys. They are 1. Homozygous for the normal gene
reproductively functional and more or less normal in 2. Homozygous for the abnormal gene
outlook, but they are more criminal in behavior and 3. Heterozygous, i.e., he carries both normal and
this is involved in the crimes against property. They abnormal gene on the homologous
generally do not commit any crimes against their chromosome
siblings, and they do not respond to the corrective During gamete formation, every gamete receives one
measures taken against their crimes. chromosome from each pair and consequently carrys
half of the “diploid” number of chromosomes. The
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7. distribution of the genes to the gametes and the
mating process by the sperm follows the laws of
probability. The four known forms of Mendelian
single gene inheritance are:
Autosomal dominant
Autosomal recessive.
X-Linked recessive.
X-Linked dominant.
Autosomal Dominant
In which a single gene is quite sufficient to make the
trait or the disease to express itself clinically. It is
usually not possible to differentiate between hetero
and homozygous cases clinically. The most common
situation is when one parent is affected; there will be
affection of 50% of their children, regardless of their
sex. Homozygous cases of AD inherited disorders
may rarely be so severely affected that they die early
in life, or even prenatally.
In many families, AD conditions arise as a result of
new mutation, followed by its inheritance to the
following generations. Another explanation, apart
from new mutation, to the absence of the disease in
the parents is that AD conditions may skip a
generation to appear again in another generation.
Expression of AD conditions may to various degrees
be sex influenced or sex limited. The degree of
expression of these conditions are extremely variable
even in the members of the same family. AD
dominant conditions are generally less severe than the
AR ones and the pedigrees of the former are vertical
while in AR they are horizontal.
Some AD conditions are characterized by delayed age
of onset. The phenomena of being phenotypically
normal in spite of carrying the defective AD trait gene
and passing it on, is known as “incomplete
penetrance”.
Children who results from two heterozygous parents Examples of AD genetic diseases in human:
run a 75% risk of inheriting the anomaly within which 1. Achondroplasia
figure 25% will be homozygous. 2. Dubin-Johnson syndrome
3. Congenital spherocytosis
4. Marfan syndrome
5. Neurofibromatosis
6. Tuberous sclerosis
7. A and B blood groups and Rh
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8. Autosomal Recessive
Up to date now there are 950 AR diseases. AR
disorders manifest only in homozygous state, i.e., in
the presence of 2 defective genes on the homlogous
autosomal chromosomes. Most of the IEM are
inherited by AR mode, and the commonest situation
is when both parents are clinically normal but
heterozygous for the abnormal gene (carriers), such
mating will result in:
- ¼ of their offspring are affected (homozygous
for the gene)
- ¼ are normal (do not carry any abnormal
gene)
- ½ are clinically normal like their parent
(heterozygous carriers) Examples of AR disorders
1. Albinism
For obvious reasons, AR disorders are more common
2. Phenylketoneurea
in consanguineous marriages, as the chance for the
3. Galactosaemia
relatives of a heterozygous carrier individual to be
4. Thalassaemia
similarly heterozygous is much higher in non-
5. Cystic fibrosis
relatives.
6. Crigler-Najjar syndrome
If one parent is homozygous (affected) for an AR
7. Wilson disease
disorder and the other parent is homozygous normal
8. Werdnig-Hoffmann syndrome
(free of abnormal gene), then all of their children will
9. O blood group
be heterozygous (carriers), and thus clinically normal.
AR as AD disorders affect both sexes equally and the The heterozygous states of some AR
former is generally more severe, appears earlier in life disorders can be detected as in:
and its pedigree is horizontal. 1. Beta thalassaemia: high HbA2
Careful examination of the heterozygous states may 2. Calactossaemia: low galactose-1-PUT
show some variation from the normal homozygote in 3. Glycogen storage disease: high glycogen
some AR conditions. 4. Cystinosis; high cystine
5. PKU: high s. phenylalanine
X-Linked Disorders
The genotypic difference between man and woman is
that the two sex chromosomes of male are X and Y,
and those of female are two X chromosomes.
Practically there is no such ting as Y chromosomal
mode of inheritance, with few exceptions which are so
far unimportant.
Therefore, sex chromosome-linked modes are
generally termed X-linked, of which X-linked
recessive is the one with the greatest practical
importance. Up till now about 170 XL-disorders are
known.
XLR
XLR disorders nearly always are confined to male
individuals as the mutant recessive gene on the only X
chromosome in males is not suppressed by a normal
8

9. allele. While in females, these disorders are not
manifest clinically as the mutant gene is suppressed
by a normal allele and thus these heterozygous
females act as carriers of mutant gene, half of their
male children will inherit the mutant gene and express
the condition clinically, while half of heir female
children (who inherit the mutant gene) become
carriers like their mothers.
There is no father-to-sun transmission in both XL
recessive and dominant forms of disorders, as the
only X chromosome of the male (father) goes to the
daughters and not the sun, who receives the Y from
his father. All of the daughters of an affected father
obligatorily are carriers. 3. Mother is homozygous affected (extremely
X-linked disorders are similar to AD disorders in that rare) and father is normal
they show variation in clinical expression. Not all
affected males with XLR disorders have carrier
mothers, the abnormal gene might have originated by
new mutation. In fact in diseases in which the affected
male does not survive long enough to reproduce, the
chance of new mutations to maintain the disease is
high.
Demonstrations
1. Mother is carrier and father is normal (most
common situation)
In XLR disorders, absence of family history indicates:
1. New mutation in X chromosome
2. No male children in the previous known
generations
3. No transmission to male by chance
On rare occasions females are clinically affected by
XLR disorders, these situations may be due to:
1. A homozygous female (received an X from
her carrier mother and other X from her
2. Father affected and the mother is affected father)
homozygous normal (free of abnormal gene) 2. Heterozygous state in Turner syndrome
3. Random inactivation of the normal X
chromosome of a heterozygous female (Lyon
hypothesis).
The carrier state can be identified in some of the XLR
disorders as:
- Haemophilia A: ↓ Factor VIII
- Haemophilia B: ↓ Factor IX
- G6PDD: ↓ RBC G6PD
- Duchenne Muscular Dystrophy: ↑ s. CPK
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10. Clinical Examples of XLR disorders Sex-Influenced Genes
1. Haemophilia A and B There are 2 other modes of sex-related inheritance that
2. Color blindness have nothing to do with sex chromosomes, these are:
3. Duchenne muscular dystrophy 1. Sex-controlled inheritance: the same gene
4. Hunter syndrome gives an effect in the male different from that
5. Nephrogenic diabetes insipidus in the female, e.g., the tone of the voice. One
6. Ocular albinism gene determines this character in both sexes,
but it gives a high pitch in female and a low
XLD pitch in male
2. Sex-limited inheritance: this is an extreme
This is the rarest form of singe gene Mendelian degree of sex-controlled inheritance, e.g., the
inheritance. XLD mode varies from XLR mode in gene which determines a heavy beard in males
that not only the heterozygous males, but also the has no effect in female, i.e., it expresses itself
heterozygous females manifest the disease. So LD only in one sex
disorders affect both sexes equally, although males
are more severely affected than females. As in XLR,
there is no father to son transmission, but all Genetic Counseling
daughters of an affected father are heterozygous and It is the process by which patients or relatives at risk
clinically affected, as well as half of the sisters of the of a disorder which may be hereditary are advised of:
father. Heterozygous female (clinically affected) will 1. The consequences of the disorder
pass the trait to 50% of her children regardless of their 2. The probability of developing the disorder
sex. 3. The probability of transmitting the disorder
Thus male patients affected by an XLD disorder must 4. The ways of prevention or at least minimizing
have inherited the disorder from their mothers, while its incidence or effects
female patients may have inherited the disease from
either father or mother. In order to make genetic counseling informative,
accurate diagnosis of the proband is essential.
Clinical Examples of XLD Disorders
1. Vitamin D resistant rickets
2. Oro-facio-digital syndrome
Y-Linked Mode of Inheritance:
As Y chromosome is only one and in males, the gene
on it has no corresponding locus on the X
chromosome, the mode of Y-lined transmission is
quite simple. As a female has no Y chromosome, she
cannot exhibit the condition. If the male Y
chromosome carries the abnormal gene the condition
will be clinically expressed, so the question of
dominant or recessive cannot arise. The gene simply
follows the path of the Y chromosome, i.e., it is
handed on from the affected father to all his sons.
The gene which is present on Y chromosome is
known as “holandric gene” and the best known
example of Y-linked disorder in human is the growth
of hair on the outer rim of the external ear (trichosis).
Another example is the gene of histocompatibility
“H-Y gene”.
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