2. OUTLINE:
Patterns of inheritance
O 1. Mendelian;
ā¢ Autosomal Dominant
ā¢ Autosomal Recessive
ā¢ X-linked Recessive
ā¢ X-linked Dominant
ā¢ Y-linked
O 2. Non mendelian;
ā¢ Modifiers to monogenic
inheritence.
ā¢ 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.
5. Mendelian
1. First discovered and
postulated by Gregor
Mendel.
2. Monogenic
3. Classic type with
predictable
inherittence patterns;
punnet squares,
pedigree charts.
6. 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 donāt exist!!
O Mostly affects structural and regulator/membrane
proteins.
7.
8. 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.
9.
10. 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.
11. 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 Huntingtonās symptoms typically become worse
as one ages.
O MEN1, 7% at age 10, 100% at 60yrs
12. 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 Turnerās syndrome, Downās
syndrome
9. Anticipation; eg Myotonic dystrophy, Huntingtonās.
13. 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)
14. 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.
15. Receptor and transport protein
disorders
O Familial hypercholesterolemia;
deficient LDL receptor
O Hemoglobinopathies
SCD
Thalasemias
Osteogenesis imperfecta
16. 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,
Huntingtonās
O Genomic imprinting; e.g Prader Willi Syndrome
and Angelman syndrome.
17. ā¦ā¦continued
O Mitochondrial Inheritance;
ā¢ Purely maternal origin.
ā¢ Affects both males and females but females transmit
ā¢ mtDNA encodes enzymes involved in oxidative
phosphorylation
ā¢ Affects organs most dependent above metabolism; CNS,
Skeletal & cardiac muscle, Kidneys.
ā¢ e.g Leber hereditary optic neuropathy.
O Gonadal mosaicism;
ā¢ Mutations in early embryonic devāt
ā¢ Affects cells destined to form gonads, somatic cells normal
ā¢ Phenotypically normal parent, affected offspring.
18. 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
20. Karyotypingā¦.
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
21.
22.
23. 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
24. 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.
25. O When x-linked; compatible with life
O When autosomal usually= intrauterine demise.
O E.g
Edwardās 47, XX+18 47, XY+18
Downās 47,XX+21 or 47,XY+21
Turner 45,X
29. Types of translocation..
O Reciprocal; 46,XX,t(2;5)(q13;p14)
O Insertions
O Robertsonian; e.g Downās, Edwardās.
30. 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
35. 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/
Editor's Notes
7. Pleiotropy is the term used to describe a constellation of varying clinical effects, usually in different organ systems, which can arise due to mutations in a single gene
8. some cells carrying the mutation, while others do not
9. severity of some diseases increases as the disease is passed on through generations
9. Equal expressivity of dorminant alleles in offspring.
Shared expressivity in offspring.
several genes code for a single mutation
is the differential expression of genetic material depending on whether it was inherited from the male(paternally imprinted=silenced =only maternal genes expressed) or female (vice versa)parent
MtDNA has 37 genes, 22 transcribed into tRNA, 2 into Rrna, the rest encode subunits of respiratory chain enzymes.
Heteroplasmy
Threshold effect