1. Hereditary pathology Department of Pathophysiology
The State Education Institution of Higher Professional Training
The First Sechenov Moscow State Medical University
under Ministry of Health of the Russian Federation
 Department of Pathophysiology
Hereditary pathology
Lecture presentation
Professor Pirozhkov S.V.
education year

2. Single base or point mutations
CLASSIFICATION OF MUTATIONS
Single base or point mutations
Chromosome mutations
Genome mutations
● Substitution
- synonimous
- missense
- nonsense
● Insertion
● Deletion
● Amplification of trinucleotide repeats
● Translocation
● Deletion
● Inversion
● Duplication
● Monosomy
● Trisomy
Frameshift
mutations

3. TYPES OF CHROMOSOMAL REARRANGEMENTS
TRANSLOCATIONS
ISOCHROMOSOMES
DELETIONS
INVERSIONS
RING CHROMOSOMES

4. ● Complex disease traits ● Chromosomal disorders
CATEGORIES OF GENETIC DISORDERS
● Monogenic
● Complex disease traits
● Chromosomal disorders

5. MENDELIAN TYPE DISEASES AUTOSOMAL DOMINANT DISORDERS
● Manifest in heterozygous state
● Each affected individual has an affected parent (unless the condition arise by a new mutation in the sperm or ovum)
● Both males and females can be affected
● There is a 50% probability that the offspring of an affected heterozygote will inherit the mutant allele

6. EXAMPLES OF AUTOSOMAL DOMINANT DISORDERS
■ Familial hypercholesterolemia
■ Amyloidosis
■ Hereditary spherocytosis
■ Osteogenesis imperfecta
■ Hereditary retinoblastoma
■ Neurofibromatosis
■ Marfan’s syndrome
■ Polydactily

7. Penetrance is the proportion of individuals with a given genotype who present with any phenotypic features of the disorder
Expressivity, or variability in clinical expression, describes the range of phenotypic effects in individuals carrying a given mutation

8. AUTOSOMAL RECESSIVE DISORDERS
● Clinically apparent only in the homozygous state
● The parents are clinically normal
● Males and females are affected in equal proportions
● Consanguinity can be a contributing factor
● If both parents are carriers for the same abnormal allele, the probability of disease in offspring is 25%, for a heterozygous (carrier) it is 50%, for a normal (noncarrier) offspring it is 25%

9. EXAMPLES OF AUTOSOMAL RECESSIVE DISORDERS
■ Fenylketonuria
■ Alkaptonuria
■ Lysosomal storage diseases
■ Glycogenoses
■ Hemochromatosis
■ α1-Antitrypsin deficiency
■ Galactosemia
■ Sickle cell anemia

10. X-LINKED DISORDERS
● Males usually display the full phenotype, regardless of whether the mutation produces a recessive or dominant allele in the female
● An affected male does not transmit the disorder to his son, but all daughters are carriers
● Sons of heterozygous women have one chance in two of receiving the mutant gene
● Expression of disease in females is often variable and influenced by random X- chromosome inactivation

11. EXAMPLES OF X-LINKED RECESSIVE DISORDERS
■ Hemophylia A and B
■ Glucose-6-phosphate dehydrogenase deficiency
■ Color blindness
■ Bruton agammaglobulinemia
■ Wiscott-Aldrich syndrome
■ Chronic granulomatous disease
■ Diabetes insipidus

12. COMPLEX DISEASE TRAITS (MULTIFACTORIAL DISEASES)
Multiple genes and nongenetic factors interact to contribute to the presence or absence of disease in a single individual
Examples:
● Diabetes mellitus type I
● Coronary heart disease
● Cleft lip
● Peptic ulcer
● Essential hypertension
● Schizophrenia
● Gout

13. KARYOTYPE OF A MALE WITH TRISOMY 21

14. Trisomy 21 – Down syndrome
Clinical features:
● Moderate-to-severe mental retardation
● A flat nose or absent bridge, oblique palpebral fissures
● Sloping forehead
● Short broad hands with a single palmar crease (simian crease)
● Generally dwarfed physique
● Approximately 40% of patients have congenital heart disease (atrial or ventricular septal defect, atrioventricular valve malformation)
● 10-fold to 20-fold increased risk of leukemia
● Abnormal immune responses that predispose to infection

15. TRISOMY 18: EDWARDS SYNDROME
Prominent occiput
Karyotype:
47,XX,+18
Mental retardation
Micrognathia
Incidence: 1 in 8,000 births
Low set ears
Short neck
Overlapping fingers
Congenital heart defects
Renal malformations
Limited hip abduction
Rocker-bottom feet

16. MONOSOMY OF THE X CHROMOSOME: TURNER SYNDROME
Karyotype:
45, X
Short stature
Low posterior hairline
Webbing neck
Incidence: 1 in 3,000 female births
Coarctation of aorta
Broad chest and widely spaced nipples
Cubitus valgus
Streak overies, infertility, amenorrhea
Pigmented nevi
Peripheral lymphedema at birth

17. MOSAICISM – the presence in the same individual of two or more populations of cells that differ in karyotype due to mitotic errors in early development
Examples:
46,XY/47,XY,+21 – mosaic Down type; 45,X/46,XX – mosaic Turner type;
46,XY/47,XXY or 47,XXY/48,XXXY – mosaic Klinefelter type