Types Of Genetic Disease

Single gene disorders

Chromosomal disorders

Multifactorial/Polygenic disorders Complex/Common diseases

Terminology Hereditary = derived from parents Familial = transmitted in the gametes

through generations Congenital = present at birth (not

always genetically determined - e.g. congenital syphilis, toxoplasmosis)

! not all genetical diseases are congenital - e.g. Huntington disease - 3rd to 4th decade of life

McKusick began his career by studying heart defects, but rapidly developed an interest in the inherited components of disease. In 1957 McKusick founded the Division of Medical Genetics at Johns Hopkins, and in 1966, created the first edition of the genetic reference "Mendelian Inheritance in Man," a compilation of inherited disease genes that continues to grow. Both a scientist and a prominent clinician, McKusick was the William Osler Professor of Medicine and Physician-in-Chief of The Johns Hopkins Hospital from 1973 until 1985.

McKusick, "Father of Genetic Medicine,"

1921-2008

Twelve print editions of MIM, the first published in 1966 and the most recent, in three volumes, published in 1998

Most common signs and

symbols used in pedigree

analysis

Types of Mendelian Inheritance

1- Autosomal inheritance 2- Sex linked inheritance

Autsomal inheritance refers to Genes located on autosome chromosomes

Sex linked inheritance refers to Genes located on

sex-chromosomes

MODE OF INHERITANCE

Autosomal recessive Autosomal dominant Sex-linked Maternal Inheritance - Mitochondrial DNA

Mendelian Pedigree Patterns

• 5 archetypal mendelian pedigree patterns:

- Autosomal Dominant (AD)- Autosomal Recessive (AR)- X-linked Dominant (XLD)- X-linked Recessive (XLR)- Y-linked

AUTOSOMAL DOMINANT DISORDERS

Achondroplasia – dwarfism Marfan Syndrome Familial (early-onset) Alzheimer Disease Huntington Disease Familial Hypercholesterolemia Familial Breast Cancer (BRCA1 or BRCA2 mutations) Osteogenesis Imperfecta- Bone Disease Myotonic Dystrophy

Autosomal Dominant pedigree

The affected gene which is located on chromosome 19 codes for the LDL receptor. The pedigree shows the following characteristics of an autosomal dominant mode of inheritance:

direct transmission from an affected parent to an affected child (does not skip generations) transmission from affected male to affected male about a 1:1 ratio of affected:unaffected among progeny with one affected parent (7:5)

Familial Hypercholesterolemia - FHC

Familial Hypercholesterolemia

Severity of Symptoms

Homozygous

Cutaneous Xanthomas

Heterozygous

Tendon Xanthomas

A.D. trait: Progressive Sensorineural Deafness

(DFNA1)

5q31.3 Human homologue of Drosophila diaphanous gene (DIAPH1)Low frequency hearing loss, Konigsmark syndrome

Autosomal Dominant

Autosomal Dominant critical point

Variable expression

Reduced penetrance / non-penetrance

New mutations

Expressivity

The expressivity of a gene is the degree to which a phenotype

is expressed in an individual Many autosomal dominant diseases show

variable expressivity

NeurofibromatosisCafe’ O leut Spots

Variable Expressivity

Penetrance – Age dependent, 100% in Adults

Pleiotropic

Variable expressivity - NF

Neurofibromatosis type I, A New Mutation in

Proband

Penetrance proportion of individuals with the mutation

who exhibit clinical symptoms

 e.g, 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not.

- Complete penetrance - Incomplete penetrance or reduced penetrance (when penetrance is less than 100%)

Penetrance Person who inherits the gene does not

develop the disorder

Reduce penetrance

Chorea Huntington

A.D. trait:Split-hand deformity

A type of Ectrodactyly

70% Penetrance

Split-hand deformity

Failure of penetrance in the mother of the consultant

Achondroplasia:A.D. with New Mutation- 80-90 %

Fitness=?1:15000 to 1:40000 live births Small Stature with short limbs, Large head, low nasal bridge, prominent forehead, lumbar lordosis.FGFR3 mutationsGain of Function Mutations

New MutationDiseases %Apert-Syndrome >95Achondroplasia 80Tuberöse Sclerosis 33–66 Neurofibromatosis 20–40 Marfan-Syndrome 30Myotonic Dystrophy 25Chorea Huntington <3AdultepolyzystischeNieren 1Familial Hypercholesterolemia <1

Haploinsufficiency

 A diploid organism only has a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy of the gene does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state.

Haplosufficiency is opposite of Haploinsufficiency

Phenotype in hetrozygous is different from that seen in both homozygous genotypes and its severity is intermediate between them

(e,g Red flower, Pink flower, White flower)

Incomplete dominance

- If expression of each allele can be detected even in presence of the other (e,g ABO Blood group)

Codominant alleles

Co-dominance

Sex-limited phenotype in A.D. disorder:

Male-limited Precocious Puberty (familial testotoxicosis) Expressed exclusively in males, due to mutations in LH R. R

4.75 yrs boy

Male-limited Precocious Puberty

Transmitted by affected males or by unaffected carrier females. Male to male transmission shows that the inheritance is autosomal, not X-linked. And not Y-linked because trait is transmitted through unaffected carrier females.

Sex-influence traits

Sex-influence traits Males and females can show different

phenotypes even with same genotypes

Autosomal Type of Baldness

Dominant in males (BB,Bb) Recessive in females (bb)

Characteristics of A.D.

Inheritance

AUTOSOMAL RECESSIVE DISORDERS

Consanguinity Thalassemia Cystic Fibrosis Glycogen Storage disease type 1a Phenylketone Urea

Autosomal Recessive Inheritance

Autosomal Recessive Inheritance

Two sisters, each of whom was homozygous for PKU, gave birth to children who are heterozygous for PKU but they have mental retardation characteristic of individuals affected with PKU. This happened because during fetal development there was a high concentration of phenylalanine in the blood of the mother which affected fetal brain development.

Pedigree of Maternal PKU

A pedigree with a woman (I-2) homozygous for an autosomal recessive disorder whose husband is heterozygous for the same disorder. They have a homozygous affected daughter so that the pedigree shows pseudodominant inheritance.

Pseudodominant inheritance

In fact Autosomal Recessive

Pseudoautosomal inheritance

Pseudoautosomal regions: PAR1 and PAR2 * homologous sequences of nucleotides on the X and Y chromosomes

PAR1 comprises 2.6 Mbp of the short-arm tips of both X and Y chromosomes PAR2 is located at the tips of the long arms, spanning 320 kbp

pseudoautosomal PAR1ASMT, ASMTL, CD99, CRLF2, CSF2RA, SFRS17A, DHRSXY, GTPBP6, IL3RAP2RY8, PLCXD1, PPP2R3B, SHOX, SLC25A6, XG, ZBED1, pseudoautosomal PAR2SPRY3, SYBL1, IL9R, CXYorf1

Pseudoautosomal regions

Léri-Weill dyschondrosteosis or LWD

 Rare genetic disorder  Dwarfism with short forearms and

legs (mesomelic dwarfism)

mutations in the SHOX gene found in the pseudoautosomal region PAR1 of the X and Y chromosomes"short stature homeobox" gene

Characteristics of Autosomal Recessive Inheritance

SEX-LINKED DISORDERS

Color Blindness Duchenne Muscular Dystrophy Hemophilia A Sex linked male lethal

X-linked Recessive DisorderHemophilia A

X-linked Recessive Inheritance

X-Linked Genes: Colorblindness and G6PD

Linked Genes: Secretor and Myotonic Dystrophy

Lyon hypothesis:

Random X-inactivation in female somatic cells. Adult tissues are a mosaic.

Functional Mosaicism:Immunostaining of Dystrophin in muscle biopsy.Females are mosaics with respect to their X-linked genes.

A Classic X-linked disorder

½ affected

X-linked Homozygous female

Punnett Squares for X-Linkage

                                               

   

3. Male w/Mutant X4. Female HeterozygousMale w/Mutant X

                                               

2 heterozygous females;2 normal males

1 heterozygous female;1 normal male; 2 affected both sexes

Two females; two males 3 unaffected; 1 affected male

1. No Mutant Alleles 2. Female Heterozygous

X-linked recessive:Color blindness, Homozygous

female

X-linked Recessive Inheritance

X-linked Dominant inheritance

X-linked Dominant DisorderMale Lethal during prenatal period

X-linked Homozygous female, Lethal in hemizygous male

Incontinentia pigmenti type 2 (IP2)

-Skin rash begins in infancy

-Swirling pattern of skin erythema, vesicles, pustules to thickening & hyperpigmentation scarring and thinning.

-Microcephaly

-Mental Retardation

-Small & absent teeth

-Loss of hair

Characteristics of X-linked dominant inheritance

1. Both males and females may be affected, but approximately twice as common in women

2. No male to male transmission (same as X-LR)

3. All daughters of affected man will be affected (different from AD)

4. Both sons and daughters of affected women have 50% risk of being affected (same as AD)

5. Affected women often have milder and more variable phenotype than affected men

Punnet's square for gametes and offspring of a female affected with an

X·linked dominant disorder

Punnett's square for gametes and offspring of a male affected with an X-linked dominant disorder.

Y-linked (holandric gene)

Caused by mutations on the Y chromosome

Males inherit a Y chromosome from their fathers, every son of an affected father will be affected

Female offspring of affected fathers are never affected There are relatively few Y-linked disorders, Why? (male infertility and hypertrichosis)

Total Genes On Chromosome: 397

Y- Chromosome Infertility

Types of Non Mendelian Inheritance

Triplet repeat disordersGenomic imprinting and

uniparental disomy Triallelic inheritanceGermline and somatic mosaicism Mitochondrial DNA mutations

Triplet Repeats Definition:

An expansion of a segment of DNA that contains a repeat of 3 nucleotides (triplet repeat) such as CAGCAGCAG . . . CAG.

Huntington disease: CAG

FraGile X: CGG

Myotonic Dystrophy: CTG

Freidrich Ataxia: AAG

Triplet Repeat: Features

The triplet repeat expansion is sometimes called a dynamic or unstable mutation because it exhibits anticipation:

As the gene is passed from parent to offspring, the number of triplet repeats may increase.

In this way, the condition may be more severe or have an earlier onset from generation to generation.

Imprinting Most genes are expressed equally from both

paternal and maternal alleles Genomic imprinting is the epigenetic marking of a

gene based on its parental origin that results in monoallelic expression

Genomic imprinting differs from classical genetics in that the maternal and paternal complement of imprinted genes are not equivalent

The mechanism of imprinting appears to involve a parental specific methylation of CpG-rich domains, that is reset during gametogenesis

Maternal Imprinting Paternal Imprinting

Conversion of maternal & paternal imprinting

*erasure of uniparental imprint on one chromosome & conversion to imprint of the other sex

Prader-Willi Syndrome15q11-q13 deletion-paternal (70%)

9-year-old affected boy

Hallmarks:

Obesity

Hypogonadism

Small hands & feet

Short stature

Developmental delay

Mental retardation

Angelman Syndrome15q11-q13 deletion-Maternal

(70%)

Unusual facial appearance

Short stature

Severe mental retardation

Spasticity

Seizures

3-6% E6-AP ubiquitin-protein ligase

7-9% imprinting center mutation

4-year-old affected girl

Genomic Imprinting

Mosaicism: Mutation during cell

proliferation, Somatic or gametogenesis

Germline Mosaicism

Pedigree of Mitochondrial Inheritance

Affected males do not transmit the trait to any of their children

Affected females transmit the trait to all of their children

The hallmark characteristics of mitochondrial inheritance in humans:

1. affected males do not transmit the trait to any of their children

2. affected females transmit the trait to all of their children

The pedigree shows the inheritance of a Hae II restriction enzyme polymorphism. The filled symbols indicate individuals who have lost a Hae II site which converts the 4.5 and 4.1 kb fragments into an 8.6kb fragment.

The three affected, related individuals in Generation I must have had an affected mother (not shown). The affected male in Generation I did not pass the trait on to any of his children. The two affected females

in Generation I passed the trait on to all of their children.

Mitochondrial DNA is passed down through the maternal line and can be nearly identical within the same family for up to 30 generations.   

Forensic Use of Mitochondrial DNA

MELAS(Mitochondrial Encephalomyopathy Lacticacidosis and storke-like Episodes)

MERF(Myoclonic Epilepsy and Ragged Red Fiber Disease)

Parental ConsanguinityAutosomal Recessive Inheritance

A cousin marriage, F = Coefficient of

inbreeding

Types of Consanguineous Mating

Examples of Coefficient of Inbreeding (F) for some Human Populations

Consanguineous Mating