1.
Molecular and cellular basis
of genetic disorders.

2.
OUTLINE:
Patterns of inheritance
O 1. Mendelian;
• Autosomal Dominant
• Autosomal Recessive
• X-linked Recessive
• X-linked Dominant
• Y-linked
O 2. Non mendelian;
• Modifiers to monogenic
inheritence.
• Complex/Polygenic
inheritence
O 3. Chromosomal
disorders.

3.
Important terms.
O Genes: Segments of the DNA on
chromosomes that code for a specific protein.
O Allele; The different forms of the same gene
found on the different chromosomes.
O Homozygous Vs Heterozygous.
O Genotype Vs Phenotype.

4.
Mendelian
1. First discovered and
postulated by Gregor
Mendel.
2. Monogenic
3. Classic type with
predictable
inherittence patterns;
punnet squares,
pedigree charts.

5.
Autosomal Dorminance
O Single mutation on one copy of a gene.
O Autosomes involved.
O Affected individuals are heterozygous for a disease
mutation.
O Males & females affected equally.
O Does not skip generations
O 50 percent risk that an affected parent will pass a
mutated allele to the child.)
O As a rule; carriers don’t exist!!
O Mostly affects structural and regulator/membrane
proteins.

6.
Autosomal Recessive
O Mutation on both alleles.
O Autosomes involved.
O Compound heterozygous mutations (two different mutations
affecting the same gene)
O Or one homozygous mutation (the same mutation on both
alleles of a gene).
O Both males and females are equally affected.
O Carriers of autosomal recessive mutations have one allele with a
mutation and one normal allele, and are usually unaffected.
O 25 percent of the couple's children will be affected, and 75
percent will be unaffected. Two-thirds of unaffected offspring
will be heterozygous carriers and one-third homozygous.
O Usually affect enzyme proteins.

7.
X-linked
O X or Y chromosome.
O X-linked recessive inheritance is most common.
O More prevalent in males.
O Females, however, would only manifest the phenotype if they
were homozygous for the gene (which would only occur in the
rare event that both the father and mother are carriers)
O e.g X-linked recessive diseases are Hemophilia VIII and IX.
O X-linked dominant traits occur in both sexes.
O More severe among males due to the absence of a normal X
chromosome
O F:M= 2:1
O Y-linked; Males only. sexual dysfunction; no other
confirmed examples of other types of Y-linked diseases.

8.
Variations;
1. Penetrance; phenotypic expression of
mutation.
O Incomplete penetrance skips variation e.g
O Variable expressivity e.g NF Type 1.
2. Age (adult onset conditions)
O Huntington’s symptoms typically become worse
as one ages.
O MEN1, 7% at age 10, 100% at 60yrs

9.
5. New mutations skip generations.
6. Sex limited/influenced mutations; eg male pattern
boldness. *How do you tell this apart from X-
linked recessive?
7. Pleiotropy e.g SCD
8. Mosaicism;. E,g Turner’s syndrome, Down’s
syndrome
9. Anticipation; eg Myotonic dystrophy, Huntington’s.

10.
9. Codominance; ABO blood grouping
10. Incomplete dorminance eg in SCD
11. Heterogeneity e.g in DM type 1
12. Environmental modification. E.g in PKU with dietary
modification, Emphysema and smoking regulation.
13. Imprinting. E.g PWS (paternal) and Angelman Syndrome
(maternal)

11.
Enzyme disorders
O Accumulation of tissue damaging substrate e.g
lack of phenyl hydroxylase= no breakdown of
phenyl alanine= PKU
O Metabolic block and deficiency of end product
e.g lack of tyrosinase= no melanin= albinism
O Failure to inactivate tissue-damaging substrate
e.g alpha1 antitrypsin deficiency(protease)=
unchecked pulmonary neutrophil activity=
destruction of alveolar elastin= emphysema
O Genetically determined adverse reactions to
drugs e.g G-6PD deff.

12.
Receptor and transport protein
disorders
O Familial hypercholesterolemia;
deficient LDL receptor
O Hemoglobinopathies
SCD
Thalasemias
Osteogenesis imperfecta

13.
Non classic monogenic
inheritence
O Trinucleotide repeat mutations;
Expansion of trinucleotides sharing G&C, unstable
DNA
Might exist in coding or non coding regions
Parental origin predisposes to varying types of expansion
Most neurogenic disorders; Fragile X syndrome,
Huntington’s
O Genomic imprinting; e.g Prader Willi Syndrome
and Angelman syndrome.

14.
……continued
O Mitochondrial Inheritance;
• Purely maternal origin.
• Affects both males and females but females transmit
• mtDNA encodes enzymes involved in oxidative
phosphorylation
• Affects organs most dependent above metabolism; CNS,
Skeletal & cardiac muscle, Kidneys.
• e.g Leber hereditary optic neuropathy.
O Gonadal mosaicism;
• Mutations in early embryonic dev’t
• Affects cells destined to form gonads, somatic cells normal
• Phenotypically normal parent, affected offspring.

15.
Complex/Polygenic disease/Non-
mendelian
O Polygenic involvement with continuous phenotypic
variations in affected populations.
O Normal phenotypic characteristics under this; skin
color, height, intelligence, curling of hair.
O Often modified(amplified) by environmental factors
O Classic example; DM
O Incomplete penetrance and variable expressivity of
monogenic trait can overlap so in essence diseases in this
category are classified by elimination

16.
Chromosomal disorders.

17.
Karyotyping….
O Cytogenetic method.
O Normally diploidy with 22 homologous autosomal
pairs and 1 sex chromosome pair= 46XX/46XY.
O Mitotic Inhibitor(N-diacetyl-N-methylcolchicine)
applied to cell in metaphase.
O Stained by Giemsa(G-banding)
O Pairs arranged according to length followed by sex
chromosome.
O Shorthand; 47,XY, +21; Xp21.2

18.
Polyploidy
O Addition of complete haploid sets of DNA
O 2n + n =3n (triploidy), tetratploidy.
O Occur at fertilization or cleavage errors during
mitosis
O Incompatible with life and often lead to
abortions or IUFD

19.
Aneuploidy
1. Non disjunction;
O Gametogenesis
O n+1 or n-1
O Offspring; Trisomy(2n+1) and Monosomy(2n-1)
2. Anaphase Lag;
O Whole Xsome in meiosis or chromatid in mitosis
left out
O Normal cell + monosomic cell.

20.
O When x-linked; compatible with life
O When autosomal usually= intrauterine demise.
O E.g
Edward’s 47, XX+18 47, XY+18
Down’s 47,XX+21 or 47,XY+21
Turner 45,X

21.
Balanced structural
Inversion;
O Paracentric and
pericentric.
O Phenotypically
normal

22.
Translocation

23.
Types of translocation..
O Reciprocal; 46,XX,t(2;5)(q13;p14)
O Insertions
O Robertsonian; e.g Down’s, Edward’s.

24.
Unbalanced structural
Deletions
O Chromosomal tearing or
unequal cross-over.
O Terminal or interstitial.
O 46, XY, del(16)(p11.2p13.1)
O Ring deletion; 46,XY,r(14)
O Di-George, Velocardiofacial
syndromes and schizophrenia

25.
Duplication
O Unequal cross over or
abnormal segregation.

26.
Isochrome…..
O Deletion-duplication
mutation.
O Centromere cleavage;
joining of short arms
and long arms

27.
Sex chromosomal disorders

28.
Referrences
Up-to-date;
O Benjamin A Raby, MD, MPHSection
Editor:Anne Slavotinek, MBBS, PhDDeputy
Editor:Jennifer S Tirnauer, MD Basic principles
of genetic disease
O Benjamin A Raby, MD, MPHSection
Editor:Anne Slavotinek, MBBS, PhDDeputy
Editor:Jennifer S Tirnauer, MD Non-Mendelian
inheritance patterns of monogenic diseases .
http://ghr.nlm.nih.gov/handbook/illustrations/