Objectives  Pattern of inheritance  Chromosomal Abnormalities  Polygenic or multifactorial inheritance  DNA analysis  Pre-symptomatic testing  Gene therapy  Genetic counselling

ABC of Genetics Dr.AbdulRahman Alnemri, MD

Genetic vs Familial Disorders: A genetic disorder Mendelian inheritance Altered genetic material could be sporadic/familial A familial disorder Either genetic / enviromental more common in relatives of an affected individual. PATTERN OF INHERITANCE

The Pedigree  The diagram of a family history  3 generation  Propand PATTERN OF INHERITANCE

 Single mutant gene  Genotype / phenotype  Homozygous / Heterozygous  Compound  Mutation  Recessive / Dominant  Autosomal / X-linked PATTERN OF SINGEL GENE INHERITANCE

 > ½ of known mendelian phenotype.  The incidence of some autosomal dominant disorder is quite high at least in specific geographic area.  An individual carries the abnormal gene in hetrozygous state on one of a pair autosomes (1 -22 chromosomes)  Male and female offspring have 50% chance of inheriting the abnormal gene from affected parent  Variable expressivity  Reduced Penterance non-penetrance (asymptomatic) eg Otosclerosis 40% of gene carriers have deffness  Low – grade mosaicism, germ-line mosaicism. No family history eg. Achondroplasia 80% have normal parents PATTERN OF AUTOSOMAL DOMINAT INHERITANCE

 Rare situation where both parents are affected  much severe than heterozygous e.g. Achondroplasia and familial hypercholesteremia, exception is Huntington disease.  What is the risk for the child to be homozygous?  A- 50% B- 25% C.100% D. Non risk HOMOZYGOTES FOR AD TRAITS

 Depend on fitness  Sever disorder – reduce reproductive capacity ƒ  new mutation NEW MUTATIO IN AD TRAITS

1.The pheotype appears in every generation “Vertical Pattern”, exception: ofresh mutation onon-penrterant disease 2.Any child of an affected parent has a 50% risk of inheriting the traits, each pregnancy is “independent event” 3.Phenotypically normal family member do not transmit the phenotype to their children. 4.Male and Female are equally likely to transmit the phenotype to children of either sex. 5.A significant proportion of cases are due to new mutations. CRITERIA FOR AUTOSOMAL DOMINANT INHERITANCE

 Less common than autosomal dominant conditions.  Expressed only in homozygotes.  Affected offspring inherited an abnormal alele from each parent, both are unaffected hetrozygous carrier  The risk of each child male or female being affected is 1 in 4 (25%) PATTERN OF AUTOSOMAL RECESSIVE INHERITANCE

 Baseline risk figures for any abnormality are up to 3% for any child for any parents and = 4.5 – 5% for the offspring of the first cousins.  Risk of recurrences is 25% CONSANGUINITY IN AUTOSOMAL RECESSIVE INHERITANCE

1.Seen only in the sibship of the proband “Horizontal Pattern” 2.Recurrence risk for siblings of an affected child is 25% 3.Males and Females are equally affected. 4.Parents of an affected child are a symptomatic carriers of the genes. CRITERIA FOR AUTOSOMAL RECESSIVE INHERITANCE

ParentsProgeny r/rR/RR/r r/rR/r½ R/r ½ r/r r/rr/rall r/r THE OFFSPRING OF HOMOZYGOUS RECESSIVE

MPS1

True or False  Autosomal recessive disorders often affect metabolic pathways  Autosomal dominant disorders usually affect structural proteins

 More than 250 disorders have been described  X – inactivation (Lyon Hypothesis)  Males are hemizygous affected  Female can be carrier, occasionally shows mild sings of the disease  Risk for sun % ?  Daughters of affected males will all be carriers  Sun of affected father ? X – LINKED recessive INHERITANCE

 The incidence of the trait is much higher in males than in females.  The gene is transferred from an affected man to all of his daughters. Any of his daughter’s sons has a 50% chance of inheriting the gene.  The gene may be transmitted through a series of carrier females.  The gene is never transmitted from father to son.  Heterozygous female are usually unaffected  Sporadic cases are ? Consequence of new gene mutations. X – LINKED INHERITANCE

 If both parents carry an x-linked recessive allele “consanguineous”  Turnur Syndrome – hemizygous for X chromosome genes.  Skewed X inactivation pattern. FEMALES AFFECTED WITH X-LINKED RECESSIVE CONDITIONS

HEMOPHILIA

 Affected males with normal mates have no affected sons and no normal daughters.  Both males and females offspring of carrier have a 50% risk of inheriting the phenotype.  For rare phenotype, affected females are about twice as common as affected males.  E.g. Vitamin D- resistant rickets PATTERN OF X-LINKED DOMINANT INHERITANCE

 Normal traits (e.g. Ht, IQ) and developmental disorders and many common disorders of adult life.  Liability genes [has a normal distribution curve] AND Environmental factors. MULTIFACTIONAL INHERITANCE

1.Although the disorder is obviously familial there is no distinctive pattern of inheritance within a single family. 2.The recurrence risk is higher when more than one family member is affected. 3.The more sever the malformation, the greater the recurrence risk. CHARACTERISTICS INCLUDES

4.There is a similar rate of recurrence (typically 3 – 5%) among all first degree relatives, And risk is much higher for first degree relatives compared to second degree relatives and so on. 5.If a multifactorial trait is more frequent in one sex than in the other, the risk is higher for relatives of patient of the less susceptible sex. 6.The risk of recurrence is related to the incidence of the disease. 7.Increased recurrence risk when the parents are consanguineous. 8.The frequency of concordance for identical twins ranges from 21% - 63%. CHARACTERISTICS INCLUDES (Cont.)

INCIDENCE IN SIBS Unilateral CL, no CP 4 Unilateral CLP 4.9% Bilateral CL, no CP 6.7% Bilateral CLP 8.0%

Mitochondrial Inheritance:  MDNA encodes 13 proteins in respiratory chain of the organelle.  Mitochondrial DNA mutations (deletion), always shown maternal transmission though Paternal Inheritance may occur!  High mutation rate.  Heteroplasmy  variable expression. NON-TRADITIONAL PATTERN OF INHERITANCE

Sex–limited AND Sex ---influenced traits  Sex- Limited  due to anatomic difference e.g. uterine or testicular defects.  Sex- Influence  more in one sex.

Y – LINKED INHERITANCE

 Genomic Imprinting – phenotype expression depends on the parents of origin for certain genes. And chromosomes segments are inactivated (imprinted) during gamete formation and remain so in the resulting zygote.  Parader – willi syndrome and Angleman syndrome. IMPRINTING

 Inheriting both homologous chromosomes from a single parent.  Three types of phenotypic effects are seen. 1)Imprinted Genes 2)Autosomal Recessive 3)Mosaicism UNIPARENTAL DISOMY (UPD)

 Estimated in 0.7% of live births  In ≈ 2% of all pregnancies in woman over 35yrs. of age.  And In 50% of all spontaneous first trimester abortion.  Numerical / Structural. CHROMOSOMEAL DISORDERS

1)Problems of early growth and development, FTT developmental delay, dysmorphic features, short stature, ambiguous genetilia and mental retardation. 2)Recurrent abortions 3)Fertility problems 4)Family history of translocations. CLINICAL INDICATION FOR CHROMOSOMAL ANALYSIS

Gathering information: 1.Constructing the pedigree and analysis of the pedigree. 2.Reviewing Past records and Prenatal history. 3.Clinical assessment a. Visual assessment b. Measurement c. Extended Family 4. Counselling 5. Follow-up APPROACH TO THE DYSMORPHIC CHILD

Counselling: 1.Counsel the parents together 2.Remove distractions 3.Be prepared to repeat 4.Use visual aids 5.Ascertain what the family needs APPROCH TO THE DYSMORPHIC CHILD

Follow – up: Lack of diagnosis Counselling other family members New diagnostic technique Natural history APPROACH TO THE DYSMORPHIC CHILD