Single Gene Disorders

(1)

The concept of heredity

Inheritance of single gene disorders Polygenic and multifactorial inheritance

Molecular pathology in genetic diseases deviating from classic inheritance

Functional importance of epigenetic mechanisms in genome, and the role in development and disease etiopathogenesis

(2)

Aristotle and Hippocrates concluded:

important human characteristics were determined by semen, using menstrual blood as a culture medium and the uterus as an incubator.

Leeuwenhoek and de Graaf recognized the existence of sperm and ova, thus explaining how the female could also transmit characteristics to her offspring.

Pierre de Maupertuis, a French naturalist, studied hereditary traits such as extra digits (polydactyly) and lack of pigmentation (albinism), and showed from pedigree studies that these two conditions were inherited in different ways.

Joseph Adams (1756–1818), a British doctor, also recognized that different mechanisms of inheritance existed.

(3)

The Law of Uniformity

When two homozygotes with different alleles are crossed, all of the offspring in the F1 generation are identical and heterozygous. In other words, the characteristics do not blend, as had been believed previously, and can reappear in later generations.

The Law of Segregation

Each person possesses two genes for a particular characteristic, only one of which can be transmitted at any one time. Rare exceptions to this rule can occur when two allelic genes fail to separate because of chromosome non-disjunction at the first meiotic division.

The Law of Independent Assortment

Members of different gene pairs segregate to offspring independently of one another. In reality, this is not always true, as genes that are close together on the same chromosomeanother tend to be inherited together, because they are ‘linked’ (p. 136). There are a number of other ways by which the laws of mendelian inheritance are breached but, overall, they remain foundational to our understanding of the science.

Gregor Mendel (1822-1884)

(4)

Human mitotic figures were observed from the late 1880s, and it was in 1902 that Walter Sutton, an American medical student, and Theodour Boveri, a German biologist, independently proposed that chromosomes could be the bearers of heredity (chromosome theory).

Thomas Morgan transformed Sutton’s chromosome theory into the theory of the gene, and Alfons Janssens observed the formation of chiasmata between homologous chromosomes at meiosis.

The connection between mendelian inheritance and chromosomes.

DNA as the Basis of Inheritance

Unraveling the genetic code

(5)

Patterns of Inheritance

• Chromosomal

• Single gene (Mendelian)

• Multifactorial

• Non-Mendelian

– Mitochondrial inheritance – Imprinting

– Uniparental disomy

• Somatic cell genetic disorders

(6)

Chromosome Abnormalities

• Numerical

– Aneuploidy – Polyploidy

• Structural

– Translocation – Deletion

– Inversion – Duplication – Ring

– Isochromosome

(7)

Single Gene Disorders

• Autosomal dominant

• Autosomal recessive

• X-linked dominant

• X-linked recessive

• Y-linked ?

(8)

Multifactorial Disorders

both genetic and environmental factors are involved in causing the disorder

• congenital malformations

• common (complex) disorders

(9)

mitochondrial disorders

(maternal inheritance)

(10)

somatic cell

genetic disorders

(11)

Number of Entries

(Updated February 17th, 2017) Autosomal X-Linked Y-Linked Mitochondria

l Total

* Gene description 15347 734 49 37 16167

+ Gene and phenotype, combined 39 0 0 0 39

# Phenotype description,

molecular basis known 5257 339 5 33 5634

% Phenotype description or locus,

molecular basis unknown 1434 119 4 0 1557

Other, mainly phenotypes with

suspected mendelian basis 1642 105 3 0 1750

Total 23719 1297 61 70 25147

OMIM* Statistics

*: Online Mendelian Inheritance in Man https://www.omim.org/statistics/entry

Updated September 13th, 2019

(12)

Frequency of Different Types of Genetic Disease

Type Incidence at Birth

(per 1000)

Prevalence at Age 25 Years (per

1000)

Population

Prevalence (per 1000)

Disorders due to genome and chromosome mutations

6 1.8 3.8

Disorders due to

single-gene mutations 10 3.6 20

Disorders with multifactorial inheritance

50 50 600

(13)

• 50% of all conceptions are lost before implantation or shortly afterwards

(before the woman realizes she is pregnant)

• 15% of recognized pregnancies end in spontaneous miscarriage before 12 weeks’

gestation

Chromosomal abnormalities are found in about 50% of all spontaneous abortions

This rises to 60% if a gross structural abnormality is present

(14)

Incidence of Chromosome Abnormalities at Different Stages of Fetal or Postnatal Life

Abnormal Karyotype

First-Trimester Abortuses

Fetuses of Mothers > 35 Years*

Live Births

Total incidence 1/2 1/50 1/160

Percentage of abnormalities Numerical

abnormalities 96% 85% 60%

Structural abnormalities

Balanced 0% 10% 30%

Unbalanced 4% 5% 10%

(15)

• 25-30% of all perinatal deaths

(after 28 weeks’ gestation plus the first week of life)

occur as a result of structural anomaly

• and genetic factors are responsible for about 80% of these cases

(16)

2-3 % of all newborns have at least one major malformation (adverse outcome on the function or social acceptability of the

individual)

10 % of all newborns have at least one minor malformation if someone has 2 or more minor malformation, there is a risk of

having major malformation with a probability of 10-20 % 25 % death in early infancy

25 % mental and physical problems of all newborns;

0.5 % chromosomal anomaly 1 % single gene disorder

(17)

Causes of congenital malformations

(18)

Adulthood:

common diseases

(19)

genetic basis of common disorders:

genetic susceptibility

(20)

Risk Ratios λ_r for Siblings of Probands with Diseases with Familial Aggregation and Complex Inheritance

Disease Relationship λ_r

Schizophrenia Siblings 12

Autism Siblings 150

Manic-depressive (bipolar) disorder Siblings 7

Type 1 diabetes mellitus Siblings 35

Crohn's disease Siblings 25

Multiple sclerosis Siblings 24

(21)

Empirical Risks for Counseling in Type 1 Diabetes

Relationship to

Affected Individual Risk for Development of Type 1 Diabetes

MZ twin 40%

Sibling 7%

Sibling with no DR

haplotypes in common 1%

Sibling with 1 DR

haplotype in common 5%

Sibling with 2 DR

haplotypes in common 17% (20%-25% if shared haplotype is DR3/DR4)

Child 4%

Child of affected

mother 3%

Child of affected father 5%

(22)

(23)

Disease Race Frequency Porphyria

variegata South african

(white) 3.0

Caucasians (general) 0.01 Cystic fibrosis N. Europeans 0.4-0.5

Afro-americans,

orientals 0.01

(24)

(25)

(26)

Disease Frequency

per 10000 Unimpaired

life İmpaired

life Lost life years Familial

hypercholesterolemia 20 55 10 5

Congenital deafness 1 0 70 0

Cystic fibrosis

(untreated) 5 2 8 60

Muscular dystrophy (X-linked)

2 4 16 50