PATTERNS OF INHERITANCE dr. R. Sutomo, Sp.A, Ph.D

Pattern of inheritance Why concerns? Genetic counseling Impact of genetic counseling Not for reducing the incidence Option for therapy frequently unavailable

Why genetic counseling? Recurrence risk assessment Well-informed-based decision Psychological impacts Adjustment Predicting prognosis

Studying pattern of inheritance How to investigate? Family studies Drawing a pedigree

Family studies A particular trait or disorder  genetic and hereditary? observation of the way in which it is transmitted from one generation to another, or on study of its frequency among relatives Taking a family history can, in itself, provide a diagnosis

Family tree A family tree is a shorthand system of recording the pertinent information about a family Begins with the person through whom the family came to the attention of the investigator index case, proband or propositus, or proposita (for female)

Mendelian character Its presence and absence depends on the genotype at a single locus A certain genotype at one locus is necessary and sufficient for the character to be expressed Does not mean that the character is programmed by only one pair of genes ±10.000 mendelian characters

Mendelian inheritance Remind: dominance and recessiveness are properties of characters, not genes Character: Dominant  manifest in heterozygote Recessive  not manifest in heterozygote

Symbols in pedigree Individuals

Symbols in pedigree Individuals

Symbols in pedigree Relationships

Symbols in pedigree Assisted reproductive scenarios

Mendelian inheritance Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Y-linked

Basic Mendelian inheritance Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant Y-linked

Autosomal dominant inheritance

Pedigree of autosomal dominant inheritance

Features of AD inheritance An affected person usually has at least one affected parent No skipping of generation Affects either sex Transmitted by either sex Affected x unaffected mating  child: 50% chance of being affected (assuming that the affected parent is heterozygous)

RISK CALCULATION Dd x dd Dd x Dd ?????? d D Dd dd D d DD Dd dd Affected : unaffected 1 : 1

Autosomal dominant disorders Achondroplasia Myotonic dystrophy Neurofibromatosis Osteogenesis imperfecta Tuberous sclerosis Facioscapulohumeral dystrophy Acute intermittent porphyria Acute intermittent porphyria Familial breast cancer (BRCA 1, BRCA 2 Familial hypercholesterolemia Familial adenomatous polyposis Charcot-Marie-Tooth disease Huntington disease

Unusual autosomal dominant inheritance Non-penetrance Variable expression Anticipation De novo mutation Genetic imprinting

Non-penetrance Penetrance: the probability that a person with a certain genotype will manifest the character Non-penetrance  failure of a dominant character to manifest Theoretically, dominant character 100% penetrance In fact  continuum characters: Fully penetrant mendelian   multifactorials Complicating the genetic counseling

Variable expression Different family members  different features of the disease/syndrome Waardenberg syndrome Hearing loss Different color eyes White forelock Premature graying of hair

Genetic anticipation The phenotype is more severe in successive generation Unclear mechanism Examples: Myotonic dystrophy Huntington disease

Genetic imprinting Normally, genes are equally express either from paternal or maternal copies Genetic imprinting: expression depends on the origin of the gene/genes paternal or maternal Paternal imprinting Prader-Willi syndrome Maternal imprinting  Angelman syndrome

Genetic imprinting The disorder manifests only when the gene is inherited from the mother

Genetic imprinting The disorder manifests only when the gene is inherited from the father

Prader Willy Syndrome Angelman Syndrome Prevalence: 1/10.000-15.000 Chromosome 15q11-q13 Genotipe Paternal/maternal deletion of 5q11-q13 (70%) Uniparental disomy (UPD) (25-30%) Maternal UPD (PWS) Paternal UPD (AS) Defect of imprinting center in 15q11-q13 paternal  (-)  PWS maternal  (-)  AS

PRADER-WILLI SYNDROME Obesity Short stature Peeled skin Almond-shaped eyes Hypotonicity Small hands and feet Narrowed nasal bridge Down-turned mouth Narrowed bitemporal Hypogonadism Mental reterd Dysartria Sticky saliva

(Happy puppet syndrome) ANGELMAN SYNDROME (Happy puppet syndrome) Flat occiput Prominent mandible Microcephaly(~2 yo) Hypopigmentation Strabismus Contracture Happy face Hyperactivity Ataxic gait Hand flapping Puppet-like movement Wide mouth Spaced teeth Chewing/ mouthing >> Severe MR Epilepsy Severe speech imp

De novo mutation Newly occured mutation Autosomal recessive? X-linked recessive?

Complicated AD pattern Be familiar with common AD disorders What’s the shortcut...? Be familiar with common AD disorders

Autosomal recessive inheritance

Pedigree of AR inheritance

Features of AR inheritance Affected people are usually born to unaffected parents  WHY? Parent of affected people are usually asymptomatic carrier Increased incidence of parental consanguinity  WHY? Affect either sex After the birth of an affected child, each subsequent child has a 25% chance of being affected

Segregation of AR alleles

AR inheritance affected carrier

Effect of consanguinity on AR inheritance

Autosomal recessive disorders

Complication to AR inheritance Pseudo-dominant Common recessive conditions can give a pseudo dominant pedigree pattern Blood group O may be seen in successive generation because of repeated marriages of group O people with heterozygotes

Complication to AR inheritance Pseudo-dominant A individual who is homozygous for an autosomal recessive disorder marries a carrier of the same disorder, their children have a 1 in 2 (50%) chance of being affected

Complication to AR inheritance Complementation Two affected parents may give unaffected child The disorder is associated with defect in several genes The children will be normal whenever the parents carry mutation in different genes AR congenital profound hearing loss Usher syndrome: hearing loss + retinitis pigmentosa Associated with defects in 8 different genes

Complementation Locus heterogeneity Mutational heterogeneity

Genocopy Disorders with the same phenotype due to different genetic loci Phenocopy Disorders with the same phenotype being the result of environmental causes

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