This document discusses genetic disorders and their causes at various levels including single gene mutations, chromosomal abnormalities, and multifactorial inheritance. It covers different types of genetic mutations and their implications for resulting proteins and diseases. Various modes of inheritance for genetic disorders are described including autosomal dominant, autosomal recessive, and sex-linked inheritance patterns. Specific examples of genetic disorders are provided for each category. The document also discusses cytogenetic disorders involving abnormalities in chromosome number or structure.

1. Genetic Disorders
Dr. Umme Kulsum Munmun
Assistant Professor
Department of Pathology
Cumilla Medical College

2. Genome
• The genome is the entire set of DNA instructions
found in a cell.
• In humans, the genome consists of 23 pairs of
chromosomes located in the cell's nucleus, as well
as a small chromosome in the cell's mitochondria.
• A genome contains all the information needed for
an individual to develop and function.

6. • An exon is a region of the genome that ends up
within an mRNA molecule.
• Some exons are coding, in that they contain
information for making a protein,
• whereas others are non-coding. Genes in the
genome consist of exons and introns.

7. • An intron is a region that resides within a gene but
does not remain in the final mature mRNA
molecule following transcription of that gene
• does not code for amino acids that make up the
protein encoded by that gene.

8. Genetic Diseases
• Genetic disorders encountered in medical practice
represent only the tip of iceberg
• 50% of spontaneous abortuses during early months
of gestation have a demonstrable chromosomal
abnormality

9. Genetic Disorders
• Broadly classified in three categories:
- Disorders related to single gene mutations with
large effects (Mendelian disorders)
- Chromosomal disorders
- Complex multigenic disorders (interactions of
multiple variant forms of genes and environmental
factors)

11. Two major categories of
mutations
• Germline mutations occur in gametes. They can be
transmitted to offspring and every cell in the
offspring will have the mutation.
• Somatic mutations occur in other cells of the body,
are confined to just one cell and its daughter cells.
Somatic mutations cannot be passed on to
offspring.(Cancer and other congenital
malformations)
• Mutations may change the structure of a
chromosome or just change a single nucleotide.

12. GENE MUTATION
• POINT MUTATION (single base substitution) within
a coding sequence: VAL-GLU
• MUTATIONS in NON-coding sequences defective
transcription, regulation
• DELETIONS/INSERTIONS frameshift mutation,
involvement is NOT a multiple of 3
• Tri-nucleotide REPEATS, e.g., CGG repeats many
times in fragile X syndrome

14. Frameshift mutation

15. GENE MUTATIONS
• INTERFERE with protein synthesis
• SUPPRESS transcription, DNARNA
• PRODUCE abnormal mRNA
• DEFECTS carried over into TRANSLATION
• ABNORMAL proteins WITHOUT impairing
syntheses

16. GENETIC DISORDERS
•SINGLE gene mutations, following classical
MENDELIAN inheritance patterns the most
•MULTIFACTORIAL inheritance
•CHROMOSOMAL disorders

17. MENDELIAN inheritance patterns
• AUTOSOMAL DOMINANT
• AUTOSOMAL RECESSIVE
• SEX-LINKED (recessive), involving “X” chromosome

18. AUTOSOMAL DOMINANT
• Disease is in HETEROZYGOTES
• NEITHER parent may have the disease (NEW mut.)
• Both male and female are affected , both can transmit
• If an affected person marries an unaffected one, every
conception has 50% chance of having the disease
• Variation in PENETRANCE (environment?, other genes?)
• VARIABLE EXPRESSIVITY (environment?, other genes?)
• May have a DELAYED ONSET
• Usually result in a REDUCED PRODUCTION or INACTIVE
protein

19. AUTOSOMAL DOMINANT
• HUNTINGTON DISEASE
• NEUROFIBROMATOSIS
• MYOTONIC DYSTROPHY
• TUBEROUS SCLEROSIS
• POLYCYSTIC KIDNEY
• HEREDITARY SPHEROCYTOSIS
• VON WILLEBRAND DISEASE
• MARFAN SYNDROME
• EHLERS-DANLOS SYNDROMES (some)
• OSTEOGENESIS IMPERFECTA
• ACHONDROPLASIA
• FAMILIAL HYPERCHOLESTEROLEMIA
• ACUTE INTERMITTENT PORPHYRIA

20. AUTOSOMAL DOMINANT
PEDIGREE
1) BOTH SEXES INVOLVED
2) GENERATIONS NOT SKIPPED

21. AUTOSOMAL RECESSIVE
• Disease is in HOMOZYGOTES
• More UNIFORM expression than AD
• The trait usually does not affect the parent of the individual but siblings may
have the disease
• 25% chance of being affected in each birth
• Often COMPLETE PENETRANCE
• Onset usually EARLY in life
• Affected individual is most likely the product of
consanguineous marrage
• NEW mutations rarely detected clinically
• Proteins show LOSS of FUNCTION
• Include ALL inborn errors of metabolism
• MUCH more common that autosomal dominant

22. AUTOSOMAL RECESSIVE
• CF
• PKU
• GALACTOSEMIA
• HOMOCYSTINURIA
• LYSOSOMAL STORAGE
• Α-1 ANTITRYPSIN
• WILSON DISEASE
• HEMOCHROMATOSIS
• GLYCOGEN STORAGE
DISEASES
• Hgb S
• THALASSEMIAS
• CONG. ADRENAL
HYPERPLASIA
• EHLERS-DANLOS (some)
• ALKAPTONURIA
• NEUROGENIC MUSC.
ATROPHIES
• FRIEDREICH ATAXIA
• SPINAL MUSCULAR
ATROPHY

23. AUTOSOMAL RECESSIVE PEDIGREE
1) BOTH SEXES
INVOLVED
2) GENERATIONS
SKIPPED

24. SEX (“X”) LINKED
• MALES ONLY
• HIS SONS are healthy
• ALL his DAUGHTERS are CARRIERS
• The “Y” chromosome is NOT homologous to the
“X”, i.e., the concept of dominant/recessive has no
meaning here
• HETEROZYGOUS FEMALES have no phenotypic
expression (carriers)….usually, this means
autosomal “recessive”

25. SEX (“X”) LINKED
• DUCHENNE MUSCULAR DYSTROPHY
• HEMOPHILIA , A and B
• G6PD DEFICIENCY
• AGAMMAGLOBULINEMIA
• WISKOTT-ALDRICH SYNDROME
• DIABETES INSIPIDUS
• LESCH-NYHAN SYNDROME
• FRAGILE-X SYNDROME

26. SEX LINKED PEDIGREE
• MALES ONLY, sons of affected males are
OK

27. SINGLE GENE DISORDERS
• ENZYME DEFECT (Most of them, e.g., PKU)
• Accumulation of substrate
• Lack of product
• Failure to inactivate a protein which causes damage
• RECEPTOR/TRANSPORT PROTEIN DEFECT (Familial
Hypercholesterolemia)
• STRUCTURAL PROTEIN DEFECT (Marfan, Ehl-Dan)
• Structure
• Function
• Quantity
• ENZYME DEFECT WHICH INCREASES DRUG
SUSCEPTIBILITY: G6PDPrimaquine

28. STRUCTURAL PROTEIN DEFECTS
• Marfan Syndrome
• Fibrillin-1 defect (not -2 or -3)
• Tall, dislocated lens, aortic arch aneurysms, etc.
• Ehlers-Danlos Syndromes)
• Multiple (6?) different types
• Various collagen defects
• Hyperelastic skin, hyperextensible joints

29. RECEPTOR PROTEIN DEFECTS
• FAMILIAL HYPERCHOLESTEROLEMIA
• LDL RECEPTOR defect
• Cholesterol TRANSPORT across liver cell impaired
• CHOLESTEROL BUILDUP IN BLOOD
• “Scavenger System” for CHOL kicks in, i.e.,
MACROPHAGES
• YOU NOW KNOW WHY MACROPHAGES are
“FOAMY”

30. ENZYME DEFICIENCIES
•BY FAR, THE LARGEST KNOWN
CATEGORY
• SUBSTRATE BUILDUP
• PRODUCT LACK
• SUBSTRATE could be HARMFUL
•LYSOSOMAL STORAGE DISEASES
comprise MOST of them

31. LYSOSOMAL STORAGE DISEASES
• GLYCOGEN STORAGE DISEASES
• SPHINGOLIPIDOSES (Gangliosides)
• SULFATIDOSES
• MUCOPOLYSACCHARIDOSES
• MUCOLIPIDOSES

32. GLYCOGEN STORAGE DISEASES
• MANY TYPES
• Storage sites: Liver, Muscle, Heart

33. SPHINGOLIPIDOSES
• MANY types, Tay-Sachs most often referred to
• GANGLIOSIDES are ACCUMULATED, due to a
hexoseaminidase A deficiency
• Ashkenazi Jews (1/30 are carriers)
• CNS neurons a site of accumulation
• CHERRY RED spot in Macula

34. SULFATIDOSES
• MANY types, but the
• metachromatic leukodystrophies (CNS),
• Krabbe,
• Fabry,
• Gaucher, and
• Niemann-Pick (A and B) are most common

35. ALKAPTONURIA
•HOMOGENTISIC ACID
•HOMOGENTISIC ACID OXIDASE
•BLACK URINE
•BLACK NAILS (OCHRONOSIS), SKIN
•BLACK JOINT CARTILAGE (SEVERE
ARTHRITIS)

37. NEUROFIBROMATOSIS
• NF1 and NF2
• Neurofibromas, café-au-lait, Lisch nodules

38. MULTIFACTORIAL INHERITANCE
• Multi-”FACTORIAL”, not just multi-GENIC
• Common phenotypic expressions governed by
“multifactorial” inheritance
• Hair color
• Eye color
• Skin color
• Height
• Intelligence
• Diabetes, type II

39. FEATURES of
multifactorial inheritance
• Expression determined by NUMBER of variant
genes (polymorphism)
• Each variant genes confers a small increase in
disease risk
• Low penetrance
• Environmental interactions are important in the
pathogenesis of disease
• Expression of CONTINUOUStraits (e.g.,
height) vs. DISCONTINUOUS traits (e.g., Diabetes I)

40. “MULTIFACTORIAL” DISORDERS
•Cleft lip, palate
•Congenital heart disease
•Coronary heart disease
•Hypertension
•Gout
•Diabetes
•Pyloric stenosis
•MANY, MANY, MANY MORE, perhaps MOST!

41. Cytogenetic/ Chromosomal
disorders (structural)

42. COMMON CYTOGENETIC DISEASES
(numerical)
•AUTOSOMES
• TRISOMY-21 (DOWN SYNDROME)
• 13 (Patau), 18 (Edwards),
• 22q.11.2 deletion
• SEX CHROMOSOMES
•KLINEFELTER: 47XXY etc.
•TURNER: 45XO

43. Down Syndrome
• Flattened face.
• Small head.
• Short neck.
• Protruding tongue.
• Upward slanting eye lids (palpebral fissures)
• Unusually shaped or small ears.
• Poor muscle tone.
• Broad, short hands with a single crease in the palm.

45. SEX CHROMOSOME DISORDERS
• Problems related to sexual development and
fertility
• Discovered at time of puberty
• Retardation related to the number of X
chromosomes
• If you have at least ONE “Y” chromosome, you are
male

46. KLINEFELTER (XXY, XXXY, etc.)
•Hypogonadism found at puberty
•#1 cause of male infertility
•NO retardation unless more X’s
•47, XXY 82% of the time
•L----O----N----G legs, atrophic testes,
small penis

47. TURNER (XO)
•45, X is the “proper” designation
•Often, the WHOLE chromosome is not
missing, but just part
•NECK “WEBBING”, “STREAK “ OVARIES
•EDEMA of HAND DORSUM
•CONGENITAL HEART DEFECTS most FEARED

48. HERMAPHRODITES
• GENETIC SEX is determined by the PRESENCE or ABSENCE
of a “Y” chromosome, but there is also, GONADAL
(phenotypic), and DUCTAL sex
• TRUE HERMAPHRODITE: OVARIES AND TESTES, often on
opposite sides (VERY RARE)
• PSEUDO-HERMAPHRODITE:
• MALE: TESTES with female characteristics (XY)
• FEMALE: OVARIES with male characteristics (XX)

49. Ovotestis (True hermaphroditism)

50. SINGLE GENE, NON-Mendelian
•Triplet repeats
•Fragile X (CGG) syndrome
•Others: ataxias, myotonic dystrophy
•Mitochondrial Mutations: (maternal)
(LEBER HEREDITARY OPTIC NEUROPATHY)
•Genomic “IMPRINTING”: (Inactivation of
maternal or paternal allele, contradicts Mendel)
•Gonadal “MOSAICISM”: (only gametes have
mutated cells)

51. KARYOTYPING
•Defined as the study of CHROMOSOMES
•46 = (22x2) + X + Y
•Conventional notation is “46,XY” or “46,XX”
•Short arm = p, long arm = q

53. F.I.S.H. (gene “probes”)
•Fluorescent In-
Situ Hybridization
• Uses fluorescent labelled
DNA fragments, ~10,000
base pairs, to bind (or not
bind) to its complement

54. SPECTRAL KARYOTYPING