Chapter 2 Genetics Genetic disorders - Cairo of genetic disorders ... inheritance Mitochondria inheritance…

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  • Genetics Dr. Mohamed Ismail

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    Genetic disorders

    Karyotyping Definition: It is the study of number, size & shape of the chromosomes in a single human cell

    Human Chromosomal number

    46 chromosomes (diploid number) 44 autosomes & 2 sex chromosomes. Autosomal Chr. are arranged by size & position of centromere into groups (A-B-C-


    What is gene? : Part of DNA that code for synthesis of single polypeptide chain Each human has about 30.000 genes most are in pairs except those on the X chromosome in male

    Q: Indications or Karyotyping (when do we suspect chromosomal


    1- Abnormal features

    Odd face as mongloid look of down syndrome(discuss)

    Eye : mongloid or anti-mongloid look

    Ear: malformed ear

    Mouth: cleft lip and palate

    Hand and feet: syndactyly or clinodactyly 2- Mental retardation 3- Ambiguous genitalia 4- Delayed puberty: Turner & Klinefelter 5- Short stature in (female) 6- Spontaneous abortion (7% chromosomal abnormalities)

    Classification of genetic disorders

    Single gene disorders Multifactorial (polygenic) inheritance Mitochondria inheritance Chromosomal abnormalities (structural and numerical)




    Cleft palate

    Chapter 2 Genetics

  • Genetics Dr. Mohamed Ismail

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    Numerical chromosomal anomalies A. Autosomal

    Trisomies: Extrachromosome is present (trisomy 21, 13, 18). Monosomies: One chromosome is missing (as monosomy 21 and 22)

    B. Sex chromosomes Klinefelter syndrome Turner syndrome Super female Mention when do we suspect chromosomal abnormalities?

    Structural chromosomal abnormalities 1. Unbalanced Reciprocal Translocation: Exchange of unequal amount of genetic

    material between non-homologous chromosomes

    2. Deletion: Loss of portion of chromosome. Example1: Cri du chat syndrome:

    Loss of the tip of the short arm of chromosome 5 (5p)

    C.P.: High-pitched mewing cry (like a cat) +Mental retardation

    Example2: Prader-Willi syndrome: deletion of chromosome 15 C.P.: hypotonia Obesity- hypogonadism

    3. Ring chromosome: special deletion in which the broken ends reunite ring. 4. Inversion: Fragmentation of a chromosome then reconstitution in inverted manner. 5. Duplication: Presence of an extra piece of a chromosome. 6. Isochromosomes: Division of centrosome transversely instead of longitudinally 7. Fragile chromosomes:{fragile X chromosome}: in male it present with mental

    retardation face (prominent forehead , mandible ear and long face) large testes

    N.B.: Balanced reciprocal translocation: Exchange of equal amount of genetic material between homologous chromosomes asymptomatic

  • Genetics Dr. Mohamed Ismail

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    Examples on Numerical chromosomal anomalies

    Down syndrome (Trisomy 21 or Mongolism) 47 chromosomes: There are 3 chromosome No 21 instead of 2 (G trisomy)

    Incidence It is the most common autosomal trisomy. The incidence = 1/700

    The incidence rise with advanced maternal age Clinical picture A. Abnormal features:

    Head: Vault: Thin silky hair - small head - Flat occiput (brachycephaly) -delayed closure

    of the anterior fontanel

    Eye: Upward slanting palpebral fissure medial epicanthal folds- Brush field spots (white spots on the iris) - strabismus.

    Mouth: Delayed teething - protruded fissured tongue (scrotal tongue) - small mandible

    Ear: Low seated small ears overfolded helix underdeveloped ear lobule

    Nose: Flat nasal bridge

    Neck: short neck

  • Genetics Dr. Mohamed Ismail

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    Trunk:Hernia - Broad iliac bones - Abdominal distention

    Genitalia: Small penis -Undescended testes

    Hands: Simian crease (single transverse palmer crease) - Clinodactyly -Broad hand & fingers Feet: Big space between the first and second toes ( sandal sign)- Longitudinal planter


    B. Growth and development

    Most of measures of growth are delayed Delayed motor development (discuss) Delayed mental development (discuss)

    C. System involvement

    CVS: Congenital heart disease (in 40% of cases): Endocardial cushion defect- VSD - ASD - PDA - Fallot's tetralogy

    CNS: Hypotonia -laxity of ligaments (acrobatic maneuver) -Epilepsy

    GIT: Imperforate anus - duodenal atresia - hirsch sprung disease

    Renal: renal anomalies (detected by US) Endocrinal: High incidence of (diabetes- hypothyroidism ) Higher incidence of hearing & Visual impairment

    D. Complications

    Higher susceptibility for infection especially recurrent respiratory infections. Heart failure (the cause of death in infancy). Higher incidence of leukemia Accidents

    E. Prognosis

    In the absence of congenital heart and leukemia normal survival Usually happy and love music Down fertility and lipido but a female down may have a child (50%) down

  • Genetics Dr. Mohamed Ismail

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    Genetic types of Down syndrome

    1- Non disjunction 2- Translocation Incidence 94% 5%

    Number of chromosomes

    47 46 but with large abnormal chromosome (2 X 21)


    Non disjunction of the matted pair of chs. No: 21 in maternal meiosis

    It results in zygote with 47 chs. in which 3 chs. are 21

    Unbalanced Robertsonian translocation The extra chromosome No: 21 is

    translocated to one of the chs. of: D group (13,14,15) or G group (21,22)

    Risk factor Advanced age of the mother Familial

    Risk of recurrence

    with maternal age

    1/1000 at 30 years 1% at 40 years 1:10 at 50 years

    To the D group (calculated) 1/3 carrier 1/3 down syndrome 1/3 normal (run in family).

    To G (21) group:100 % Down syndrome

    3- Mosaic down syndrome

    Incidence: 1%

    Number of chromosomes: Some cells: 46 - Other cells : 47

    Mechanism: after fertilization and normal zygote formation Non disjunction in early mitotic division 2 cell lines one with 46 and the other with 47 chromosomes Risk factors: not dependent on Family history or the Age of mother Prognosis: less features and less mental affection

    Investigations Prenatal diagnosis

    Triple test :( fetoprotein - estradiol - HCG) Ultrasonography (thickness of the nuchal fold) Amniocentesis or Chorionic villous sampling (for karyotyping)

    Karyotyping (chromosomal study)

    For the infant to confirm the diagnosis and determine genetic type. Parental Karyotyping only in translocation type.

    Echocardiography congenital heart disease

    U/S intestinal anomalies.

    Hearing and vision testing

    Check thyroid profile & blood glucose.

    Management 1. Proper nutrition 2. Diagnose and manage possible complications. 3. Educational & social rehabilitation in specialized institutes like speech therapy aiming

    to make the child as independent as possible.

  • Genetics Dr. Mohamed Ismail


    Some sex chromosome abnormalities

    Klinefelter syndrome

    Cytogenetic: 47 (44 +XXY) male. Incidence : 1/1000 male Features

    1. Mild Mental retardation +Behavioral abnormalities 2. Tall stature 3. Gynecomastia 4. Hypogonadism with small testes & absent spermatogenesis 5. Infertility (most common presentation)

    Prognosis: Normal life expectancy Investigation

    1. karyotyping 2. FSH &LH 3. Gonadal biopsy: dysgenesis

    Treatment: Testosterone at time of puberty

    N.B. Trisomy 18(Edward's Syndrome) Hypertonia- Prominent occiput - overlapping finger Rocker bottom feet

    N.B. Trisomy 13 (Patau syndrome) Small eyes (microphthalmia) and other eye defects - Cleft lip and palate - Polydactyly

    N.B. both numerical chromosomal abnormalities show mental retardation Microcephaly

    congenital heart prognosis: death before the age of 1 year

  • Genetics Dr. Mohamed Ismail


    Turner syndrome

    Cytogenetics: 45 (44 +XO) Female. Incidence : 1/5000 (Recurrence risk 1%). Features Newborn: Lymph edema of hands and feet.

    Childhood: (see the photo)

    Investigation 1. Hormonal profile (high FSH and LH but low estradiol). 2. Gonadal biopsy: dysgenesis (streak ovary).

    Treatment Hormonal replacement: growth hormone till puberty then cyclic estrogen and

    progesterone 2ry sexual charchters only, but still infertile.

    Super female

    Cytogenetic: 47 [44 +XXX] female Features Impaired mentality &reproductive problems

  • Genetics Dr. Mohamed Ismail


    Single gene disorders

    1. Autosomal dominant inheritance

    2. Autosomal recessive inheritance

    definition Appears even if a single copy of an abnormal gene located on one of the autosomes.

    Appears if only 2 copies of an abnormal gene located on 2 of the autosomes.

    Affected individuals

    Homozygous (have 2 copies) or heterozygous(have only one copy).

    only homozygous (i.e. they have 2 abnormal genes, one from each parent)

    Unaffected individuals

    Normal (no carrier state) Normal or carriers (heterozygous)

    Recurrence risk

    Heterozygous 50% Homozygous 100%

    When parents have one affected child, the risk to each subsequent offspring is 25%

    Distribution Equal distribution to males & females Equal distribution to males & females

    Consanguinity No relation Strong relation

    Disease Usually structural defect Usually enzymatic defect


    Hematology: C. spherocytosis - Von Willebrand disease

    Skeletal disorders: Achondroplasia- osteogenesis imperfect- Ehlers Danlos $- Marfan $- Otosclerosis

    Neuro: Tuberous sclerosis, neurofibromatosis- Huntington's disease myotonic dystrophy

    Renal: AD polycystic kidney

    Hematology: Thalassemia -sickle cell anemia.

    Endocrinal :Adrenogenital $ - goitrous cretinism

    Metabolic: Phenyl ketonuria-cystic fibrosis- galactosemia Glycogen storage disease

    Neuro.: Werding Hoffman-

    N.B. Some carriers of AR diseases are biologically fitter than normal (sickle cell carrier are resistant to infection with malaria)

  • Genetics Dr. Mohamed Ismail


    3. Sex-linked inheritance Sex-linked disorders are those, which are caused by abnormal genes on the X or Y chromosome.

    X-linked recessive inheritance

    Female Females may be affected if:

    She has inherited 2 copies of the abnormal gene She has Turner syndrome (45,X) Lyonization


    The carrier female transmits the abnormal gene to 50 % for each son (to be affected) & to 50% of her daughters (carriers).

    Carrier female may show mild symptoms or abnormal laboratory finding (Discuss)

    Male Male will be affected from carrier or affected mother only (not from father).

    No carrier in males

    Recurrence: The affected male will transmit the abnormal gene to all of his daughters who will be carriers and to none of his sons

    Examples 1. Agammaglobulinemia 2. Blood diseases: G6PD deficiency, hemophilia A & B 3. Color blindness( green red) 4. Duchenne muscle dystrophy & Beckers muscle dystrophy 5. Errors of metabolism MPS II (Hunter syndrome)

    X-linked dominant inheritance The affected female transmits the disorder to half of her daughters & half of her sons. The affected male transmits the disorder to all of his daughters & to none of his sons

    Examples: Pseudohypoparathyroidism - Vitamin D resistant rickets.

    Y-linked inheritance Y chromosome carries genes that determine sexual differentiation

    and spermatogenesis (if affected infertility) Genes on the Y chromosome show holandric inheritance (passed

    exclusively from an affected man to all his sons and to none of his daughters)

  • Genetics Dr. Mohamed Ismail


    Multifactorial (polygenic) inheritance Definition

    Interaction of a genetic predisposition with adverse environmental factors The genetic susceptibility is determined by the effects of many genes

    Characteristic features

    1. These disorders are much commoner than single gene disorders. 2. The prevalence is (2-5%) & may be more in some diseases). 3. The risk Declines sharply with more distant relationship with the affected individual 4. The risk increase with more than one affected individual in the family or affected

    person of the less risky sex


    1. Congenital malformations of infancy:

    Cleft lip/palate. Pyloric stenosis Congenital heart disease. Congenital dislocation of the hip Neural tube defects

    (spina bifida anencephaly). talipus equinoverus Hypospadius

    2. Acquired disorders of childhood

    Atopy and Bronchial asthma. Type I DM Epilepsy.

    3. Acquired disorders of adult

    Diabetes mellitus (type I and type II) Alzeheimer's Hypertension. Atherosclerosis and coronary heart disease

    4. Normal criteria : height intelligence

  • Genetics Dr. Mohamed Ismail


    Mitochondrial gene inheretance Mitochondria contain small amount of DNA that code for enzymes involved in energy

    production Mitochondria are transmitted to the embryo from his mother only Mitochondrial diseases include mitochondrial myopathy & mitochondrial


    Genetic counseling Definition: Providing information about inherited disorders in the family and how to avoid it (by prenatal diagnosis and carrier detection).

    Genetic counseling should provide the Recurrence risk Very low (1%) in chromosomal abnormalities. Discuss recurrence in down syndrome (25-50%) in single gene inheritance (2-5%) in Multifactorial inheritance.

    Indications Consanguineous marriage ( of AR diseases) indicate screening based on

    diseases prominent in the population (SCA in black Africans/ thalassemia in Mediterranean area)

    Mention indication of Karyotyping + Microcephaly/ Macrocephaly Bleeding tendency Metabolic disorders

    Early diagnosis of single gene disorders by DNA

    Prenatal diagnosis: beta thalassemia cystic fibrosis Duchenne muscle dystrophy

    Presymptomatic diagnosis: in some AD diseases (Huntington's disease)

    Carrier detection X linked recessive diseases: (Duchenne muscle destrophy hemophilia)

    This could be done with 2 methods

    Biochemical assay not reliable

    DNA markers accurate Autosomal recessive disease (cystic fibrosis)


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