Lecture notes, prepared by Dr. Jamal A. RASHID

Principles of Medical Genetics and Chromosomal DisordersAt present, practice of medicine depends upon knowledge of anatomy, physiology, biochemistry, etc…,. In the near future dealing with diseases will need understanding of the molecular anatomy, physiology, and biochemistry of the human genome.The greatest explosion had occurred in the field of genetics than in any other paediatric field during the previous decade.Genetically determined disorders, although 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.

Definitions of Terms Commonly Used in Genetics

Congenital Defect: only means that the defect is present at birth, it does not suggest genetic aetiology.

Genetic disorder: means that the condition is caused by abnormal genes or chromosomes.

The chromosome: chromosomes are rod-shaped bodies situated inside the cell nucleus. Each chromosome is composed of 2 strands called chromatids attached at centromere. Chromosomes are the bearer of the genes. The normal number of chromosomes is constant for each species, being 46 in man (23 pairs in each of somatic “body” cells). This number constitutes the “Diploid number” which is made of 22 pairs of “autosomes” and a pair of sex chromosomes designated XX in females and XY in males.

Denver classified chromosomes in human into 22 pairs, while Patau classified them into 7 groups from A to G as follows:

Medical Genetics:of disease.

Inheritance: means the passage of hereditary traits from one generation to another. It is the process by which, one acquires characteristics from his or her parents and then transmits these traits to his or her own children.

The gene: it is the basic unit of heredity; it is made up of DNA. Genes are ultramicroscopic structures. Each gene occupies a certain place on a chromosome called “locus”. Hereditary traits are controlled by pairs of genes on chromosome pairs.

The two alternative genes on the homlogous chromosome are called “allele”. If the alleles code for the same trait, these are said to be present in a homozygous state, while if they code for different forms they are in a “heterozygous state”. If a gene clinically manifests itself even in the heterozygous state, it is called a “Dominant” gene or character. A gene that cannot express itself clinically when present in heterozygous state, but only when in a homozygous state is called “Recessive” gene or character. Carrier State: individuals heterozygous for a

recessive trait. Mutation: means a permanent heritable

change in a gene, that causes it to have a different effect from that it had previously, this changed gene can be passed to the following generations. Mutation may occur spontaneously or be induced by mutagens as various medicines or chemicals, e.g., mustard gas, ionizing radiation (X-ray or UVL).

Deletion: means loss of part of a chromosome, mostly through breakage.

Karyotype: It is the description of the chromosomes of an individual. Thus the normal human male karyotype is 22 XY,

Patau classification

Denver classification

A 1-3B 4-6C 7-12 + X chromosome

D 13-15E 16-18F 19-20

G 21-22 + Y chromosome

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while the normal human female karyotype is 22XX.

Mitosis: the type of cell division which takes place in the somatic cells and in which each of the two daughter cells carries full compliment of 46 chromosomes as their mother cells.

Meiosis: the reduction division which occurs in the germ cells during the process of gametogenesis. This division in human reduces the number of chromosomes to 23 in the ova or sperm.

Lyon Hypothesis: says that one of the two X chromosomes in human female is mainly or completely inactivated early in embryonic life (before 16th day of gestation). This process takes place randomly, resulting in 2 populations of somatic cells, one population with the maternal and the other with the paternal X-chromosome inactivated. But once decision is made, all the descendants of that cell will have the same X-chromosome inactivated.

Mosaic: a karyotype state in which two or more cell lines are present in the same individual.

Phenotype: is the physical appearance or make up of an individual.

Alleles: are alternative forms of a gene at a given locus.

Sex chromatid “Barr Body”: it is a darkly stained body seen near the nuclear margin in a high percentage of the cells of normal female. The number of Barr bodies seen in a cell is equal to the number of X-chromosomes minus one, i.e., in a normal female there is one Barr body in each somatic cell, and there is no Barr body in male cells.

Gamete (ovum or sperm) FormationEach somatic (body) cell in human contains 46 chromosomes, 23 have come from each parent. Cell division in the somatic cells is mitosis (non-reduction division) and each daughter cell contains 46 chromosomes as the mother (original) cell.While in the germ cells of both sexes, the cell division is of reduction (meiosis) variety, the resulting cell (ovum or sperm) will contain only 23 chromosomes, i.e., the number of chromosomes is halved.The female gamete (ovum) has 22 autosomes and one X-chromosome, while the male gamete (sperm) can have 2 types of chromosomal pattern: 22+X or 22+ Y.

Fertilization of the ovum by an X-bearing sperm will result in a female offspring, while if fertilized by a Y-bearing sperm a male offspring will result. Thus each offspring (boy or girl) inherits half their chromosomes from their father and the other half from their mother. That is why they have some characteristics of both.

Genetics and DiseaseHuman diseases in general may have a purely genetic cause without any role of the environment in their causation. On the other hand some conditions are caused by pure environmental factors without any role of genetic predisposition as most infections and accidents.In-between these 2 extremes there are many childhood diseases, causation of which requires both genetic and environmental factors (polygenic or multifactorial). Another group of diseases, which is relatively more significant in young children than in adults, is the group of chromosomal disorders which are generally linked to the genetically determined diseases.

Chromosomal DisordersAlthough rare in clinical practice a large proportion of aborted fetuses are found to have chromosomal disorders. The younger the GA of the aborted foetus the higher the percentage of chromosomal abnormalities, thus the incidence decreases from 50% during the first 2 months to less than 5% by 7 months of gestation and 5% of stillborns have a chromosomal anomaly.It has been found that 65% of the fetuses with Down syndrome and 95% of those with Turner syndrome are spontaneously aborted. Chromosomes contain a large number of genes. Loss or gain of a whole chromosome due to abnormalities in cell division may cause so great disturbances in the genetic constitution of the foetus that it may result in abortion, stillbirth, death soon after birth, or survival with some malformations, mental retardation or infertility.Of all live born babies 0.5% has a chromosomal anomaly.Chromosomal abnormalities are in general sporadic and therefore the risk of recurrence in the offspring is low.

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Mechanisms of Chromosomal AnomaliesChromosomal disorders may be numerical or structural and generally arise by some of the following mechanisms:

1. Inversion: a break may occur along the length of the chromosome arm. The broken pieces may rearrange themselves in a new way. If there is neither loss nor gain of genetic material, there may be no significant clinical manifestations.

2. Isochromosome: Normally chromosomes divide longitudinally during mitosis. Rarely a transverse division may occur through the centromere, thus instead of making 2 normal chromosomes, two new types of chromosomes are formed, one having both the long arms and the other both the short arms, these are called isochromosomes. Features may occur as there will be some excess and some deficiency of genetic materials.

3. Nondisjunction: during meiosis both members of a pair of chromosomes may fail to separate and go jointly to either of the daughter cells. Thus one of the daughter cells will have 22, and the other 24 chromosomes. Then after fertilization by a normal gamete (having 23 chromosomes) the resultant zygote will either have 47 or 45 chromosomes.

4. Mosaicism: this state happens if the process of non-disjunction occurs in the first mitotic instead of the meiotic division, resulting in 2 cells, one with 47 and other with 45 chromosomes. As each one of these cells will reproduce similar cells by further normal mitosis, 2 cell lines will be observed, a line with 45 and another with 47 chromosomes. There may be more than 2 cell lines, one with normal and the others with abnormal chromosomes complements.

5. Translocation: one chromosome or a segment of it may translocate itself and join another chromosome. Thus one chromosome will be absent or shorter, while another chromosome appears longer. If no loss or gain of the genetic material occurs in this process the translocation is called balanced and the person is phenotypically normal. The translocated chromosome may be transmitted to either gamete during meiosis, and when this gamete (with translocated chromosome)

mates a normal gamete, the resulting zygote may either have excess or deficiency of the genetic material. Such an offspring will be abnormal in both karyotype and phenotype.

6. Deletion: break-off and loss of a fragment of a chromosome. If a large portion of a chromosome is lost, it would be lethal or causes a grave disability.

Classification of Chromosomal AbnormalitiesI. Numerical Abnormalities:

a. Excess of one or more autosome (autosomal trisomy): this may occur by non-disjunction or by translocation mechanism. Examples of autosomal trisomies include:

i. Trisomy 21 (Down syndrome)ii. Trisomy 18 (Edward syndrome)

iii. Trisomy 13 (Patau syndrome)b. Autosomal monosomy: means absence of one

of the autosomal chromosomes, this abnormality is incompatible with life.

c. Numerical sex chromosome anomalies:i. Extra-chromosomes:

1. XXY (Klinefelter syndrome)2. XYY3. XXX4. XXXY5. XXXXY

ii. Deficient chromosome: XO (Turner syndrome)

d. Triploidy: means presence of 3 haploid sets of chromosomes in one cell, i.e., presence of 69 chromosomes. This condition is not compatible with life.

e. Tetraploidy means presence of 4 haploid sets of chromosomes in one cell, i.e., 92 chromosomes, which is again incompatible with life.

f. MosaicismII. Structural Abnormalities

a. Translocation (balanced structural change)b. Deletion (unbalanced structural changes)

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Features of Some Chromosomal Disorders

Down Syndrome “Mongolism”, “Trisomy G”, “Trisomy 21”

It is the first autosomal trisomy described in man by John Down in 1966. The name mongolism is sometimes used as the patients look like those of Mongolian race. 21 and 22 trisomies can not clinically be differentiated. The incidence of Down syndrome is 1 in 700 in most parts of the world.Maternal age at pregnancy strongly contributes to the incidence, thus:

Maternal Age Incidence of Down syndrome

20 1 in 200030 1 in 100035 1 in 35040 1 in 10045 1 in 40>45 1 in 35

This increase of incidence in elderly mothers is attributed to the exposure of the maternal oocyte to the harmful environmental factors for a longer period of time, since Graffian follicles are present in the foetal life and remain throughout the reproductive life of the woman. On the other hand the sperm of man has a short life span and has therefore lesser chances for exposure to harmful influences. The age of the father has lesser effect on the incidence of Down syndrome.

Clinical Features

1. General: hypotonia during infancy and mental retardation throughout life are constant features

2. Short stature3. Craniofacies:

a. Brachycephalyb. Upward and outward slanting

palpebral fissuresc. Prominent epicanthic foldsd. Strabismuse. Speckled irides (Brushfield spots)f. Protruding tongue from a relatively

small mouth, furrowed tongue, small teeth

g. Prominent malformed ears

h. Small nose and flat nasal bridgei. Broad short neck

4. Hands and Feet: short broad hands, single palmer crease (Simian crease) in 85%, clinodactyly (short incurved little finger due to hypoplasia of its middle phalanx)& a gap between the first and second toe.

5. Greater liability to have:a. Associated CHD, most commonly the

AV canalb. Congenital intestinal obstruction

especially duodenal stenosis, or Hirschsprung disease

c. Leukaemiad. Frequent respiratory infection

6. Special non-aggressive forms of moderate to severe mental retardation

They are characteristically friendly individuals who show an unusual enjoyment of music. Babies with Down syndrome look all alike. Mosaic cases have less severe features. 95% result from non-disjunction, 3% from translocation, and 2% from mosaicism. None-mosaic cases can be clinically diagnosed at birth from the appearance and the striking hypotonia.

Management

Parents should be told about the illness on the second or third day after birth, or the husband is told so that he will then later on explain the condition to his wife.The fact that there is no curative treatment for Down syndrome must be explained to the parents. Children with Down syndrome have a shorter life span than the average in that community, even in the absence of associated severe congenital anomalies.Genetic counseling may be helpful if one of the parents is found to have translocation of chromosome 21.

Edward Syndrome (Trisomy 18 or “E” Trisomy)

Much less common than Down syndrome; it occurs at a frequency of 1: 6000 births, being more common in females. 90% are due to non-disjunction. As in Down syndrome, maternal age seems to be important.

Clinical characters include:

- Prominent occiput- CHD- Receding chin and triangular face- Short sternum and single umbilical artery

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- Flexion deformities of the fingers, which are rigidly fixed across the palm. The middle finger overriding the index.

- Characteristic “rocker-bottom” feet, the sole is convex and the heel is prominent, simulating a rocking chair

The majority of affected babies die during the first 3 months of life.

Patau Syndrome (Trisomy 13-15 or D Trisomy)

- It occurs at a frequency of 1 in 10,000 births. Characterized by gross deformities of the hand and face.

- There is microcephaly with a relatively large “onion-nose’ receding jaw, cleft lip and palate are common.

- The eyes may be absent, small or of normal size but with coloboma or cataract. The finger nails are narrow and hyperconvex.

- Capillary haemangioma- CHD is common- Flexion deformities of the fingers- There may be associated agenesis of corpus

callosum- The majority of affected babies die during

early infancy

75% of cases result from non-disjunction, 20% from translocation, and 5% from mosaicism. The risk for recurrence in other children is only high in the presence of parental translocation.

Cri-du-chat Syndrome

An extremely rare disorder caused by deletion of the short arm of chromosome 5. Clinically cri-du-chat syndrome is characterized by:

- Severe mental, motor, and growth retardation- Microcephaly with broad head- Prominent epicanthic folds, ocular

hypertelorism and antimongoloid slant (Downward and outward sloping palpebral fissures)

- Broad face, saddle nose and micrognathia- Low set, malformed and rotated ears with

accessory auricles- Simian crease in 50%- Characteristic cry similar to mewing cat or

kittleA variant of cri-du-chat is caused by deletion of the short arm of chromosome number 4, differentiated

from cri-du-chat by absence of the characteristic cry and by common presence of midline fusion defects (scalp, nose, lips, palate, and in males the penis).

Turner Syndrome (Ovarian Dysgenesis)

Occurs at a frequency of 1 in 2500 births and their chromosomal pattern is XO, i.e., they have 45 chromosomes and are chromatin negative females. Most of the XO fetuses are aborted during the first trimester. The cause is probably non-disjunction in spermatogenesis than in oogenesis.At birth diagnosis is suspected from lymphoedema of the feet and hands, and lax neck skin. Other features later in life include:

- Short stature- Shield-like chest, widely spaced nipples- Neck webbing and low posterior hairline- Cubitus valgus (increased carrying angle of

the arms)- Short fourth metacarpals and metatarsals- Mild mental retardation- The nails are small, narrow, and deeply set- Associated congenital anomalies especially

coarctation of the aorta and horse-shoe kidneys.

- The ovaries are either absent or severely hypoplastic

- Sexual infantilism becomes evidence at the time of expected puberty, thus there will be:

o Primary amenorrhoea and infertilityo Underdeveloped breasts, mostly

consisting of fato Appearance of pubic and axillary hair,

since these result from adrenal androgens (these are absent in hypopituitarism, since there is also lack of adrenal androgens)

o Infantile external genitaliao Severely hypoplastic uteruso Raised urinary gonadotrophins (FSH)

Patients with Turner syndrome, who are heterozygous for XLR disorders, may show the disease.

Treatment

No hormonal treatment is indicated in childhood, but at the usual age of puberty substitution therapy with oestrogen (daily orally for 6 months or until menstruation occurs, subsequently, cyclic oestrogen-progesterone therapy is administered).

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Klinefelter Syndrome “XXY Syndrome”

It occurs at a frequency of 1 in 500 male births. 80% have XXY, 10% mosaic, and 10% XXYY or XXXY karyotype, so they are chromatic +ve males.

Clinical features

They look like normal boy’s early in life and the condition is seldom diagnosed before adolescence, because the external genitalia are normal. The only clues to the diagnosis before puberty are unusually long legs, behavioral problems, and when investigated they are found to be chromatic positive. After pubertal age there will be:

- A long boy with sparse body (including axillary and pubic) hair, long limbs and knock knees

- Behavioral disorders: social inadequacy and immature personality. The degree of intellectual deficit is directly proportional to the number of the extra X chromosomes

- Microorchidism (small sized testes) occasionally with cryptorchidism

- Decreased androgen level in the blood, resulting in temporal recession of the hair

- Although they are capable of erection, performance of intercourse, and ejaculation of sperm fluid, they are sterile

- Raised urinary excretion of FSH- Gynaecomastia, broad pelvis, horizontal limit

of pubic hair, and feminine voice- Commonly they suffer chronic pulmonary

conditions as asthma, emphysema, and bronchiectasis

Patients with Klinefelter syndrome have normal survival and there is no increased risk to have other affected children.

Treatment

Replacement of testosterone since 11-12 years of age. 50mg every 3 weeks, slowly increased until a maintenance of 250 mg/3 weeks is reached.

XYY Syndrome

This occurs at a frequency of 1-2/1000 boys. They are reproductively functional and more or less normal in outlook, but they are more criminal in behavior and this is involved in the crimes against property. They generally do not commit any crimes against their siblings, and they do not respond to the corrective measures taken against their crimes.

Fragile X Syndrome

This is a familial (XLR) form of chromosomal disorder and is considered to be the second most common cause of mental retardation after Down syndrome. One third of female carriers may show mild affection. On the other hand between 20-50% of boys who have the fragile X are asymptomatic and transmit the chromosome to all of their daughters, who are also asymptomatic. However in the subsequent generation both male and female offspring of those daughters begin to show the illness.The following are some of the reported features:

- Mental retardation- Macrocephaly- Prognathia (prominent jaw)- Short stature- Large protruding ears- Macro-orchidism, especially after puberty- Rapid and repetetive speech- Generally they are pleasant and socially

engaging, although some of them avoid eye contact and simulate autism

They have a normal life span. No curative treatment is available, although it has been found that folic acid may improve the psychological state. Prenatal diagnosis is possible.

Single Gene InheritanceThe Mendelian laws of inheritance are applied to all living creatures including human beings. All of the 46 human chromosomes which are present in every single cell of the body carry genes. The autosomes arrange in pairs according to their shape, and the members contain the same gene loci and are known as homologous chromosomes.Every autosomal gene locus occurs twice in every cell of the body. If both loci possess the same genetic information, the individual is considered homozygous (i.e., identical), while if the gene loci carry different information (e.g., one normal gene with another abnormal one) the individual is considered heterozygous. Therefore, every individual can be considered as one of the following:

1. Homozygous for the normal gene2. Homozygous for the abnormal gene3. Heterozygous, i.e., he carries both normal and

abnormal gene on the homologous chromosome

During gamete formation, every gamete receives one chromosome from each pair and consequently carrys

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half of the “diploid” number of chromosomes. The 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 dominantAutosomal recessive.X-Linked recessive.X-Linked dominant.

Autosomal DominantIn 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 run a 75% risk of inheriting the anomaly within which figure 25% will be homozygous.

Examples of AD genetic diseases in human:

1. Achondroplasia2. Dubin-Johnson syndrome3. Congenital spherocytosis4. Marfan syndrome5. Neurofibromatosis6. Tuberous sclerosis7. A and B blood groups and Rh

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Autosomal RecessiveUp 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)

For obvious reasons, AR disorders are more common in consanguineous marriages, as the chance for the relatives of a heterozygous carrier individual to be similarly heterozygous is much higher in non-relatives.If one parent is homozygous (affected) for an AR disorder and the other parent is homozygous normal (free of abnormal gene), then all of their children will be heterozygous (carriers), and thus clinically normal. AR as AD disorders affect both sexes equally and the former is generally more severe, appears earlier in life and its pedigree is horizontal.Careful examination of the heterozygous states may show some variation from the normal homozygote in some AR conditions.

Examples of AR disorders

1. Albinism2. Phenylketoneurea3. Galactosaemia4. Thalassaemia5. Cystic fibrosis6. Crigler-Najjar syndrome7. Wilson disease8. Werdnig-Hoffmann syndrome9. O blood group

The heterozygous states of some AR disorders can be detected as in:

1. Beta thalassaemia: high HbA2

2. Calactossaemia: low galactose-1-PUT3. Glycogen storage disease: high glycogen4. Cystinosis; high cystine5. PKU: high s. phenylalanine

X-Linked DisordersThe 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.

XLRXLR 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

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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.X-linked disorders are similar to AD disorders in that 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.

Demonstrations1. Mother is carrier and father is normal (most

common situation)

2. Father affected and the mother is homozygous normal (free of abnormal gene)

3. Mother is homozygous affected (extremely rare) and father is normal

In XLR disorders, absence of family history indicates:1. New mutation in X chromosome2. No male children in the previous known

generations3. 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 affected father)

2. Heterozygous state in Turner syndrome3. 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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Clinical Examples of XLR disorders

1. Haemophilia A and B2. Color blindness3. Duchenne muscular dystrophy4. Hunter syndrome5. Nephrogenic diabetes insipidus6. Ocular albinism

XLDThis is the rarest form of singe gene Mendelian inheritance. XLD mode varies from XLR mode in that not only the heterozygous males, but also the heterozygous females manifest the disease. So LD 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 daughters of an affected father are heterozygous and clinically affected, as well as half of the sisters of the father. Heterozygous female (clinically affected) will pass the trait to 50% of her children regardless of their sex.Thus male patients affected by an XLD disorder must have inherited the disorder from their mothers, while female patients may have inherited the disease from either father or mother.

Clinical Examples of XLD Disorders

1. Vitamin D resistant rickets2. 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”.

Sex-Influenced GenesThere are 2 other modes of sex-related inheritance that have nothing to do with sex chromosomes, these are:

1. Sex-controlled inheritance: the same gene gives an effect in the male different from that in the female, e.g., the tone of the voice. One gene determines this character in both sexes, but it gives a high pitch in female and a low pitch in male

2. Sex-limited inheritance: this is an extreme degree of sex-controlled inheritance, e.g., the gene which determines a heavy beard in males has no effect in female, i.e., it expresses itself only in one sex

Genetic CounselingIt is the process by which patients or relatives at risk of a disorder which may be hereditary are advised of:

1. The consequences of the disorder2. The probability of developing the disorder3. The probability of transmitting the disorder4. The ways of prevention or at least minimizing

its incidence or effects

In order to make genetic counseling informative, accurate diagnosis of the proband is essential.

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