Lecture 1 - Inheritance patterns 23-24 full.pdf

Inheritance patterns MD210 – GGE – Genetics Lesson 1 Semester 2.1 1 Essential Learning Outcomes By the end of this lesson you should be able to: • Distinguish between hereditary and congenital disorders • Recognise and understand Mendelian inheritance patterns and apply this knowledge to solve pr...

Inheritance patterns MD210 – GGE – Genetics Lesson 1 Semester 2.1 1 Essential Learning Outcomes By the end of this lesson you should be able to: • Distinguish between hereditary and congenital disorders • Recognise and understand Mendelian inheritance patterns and apply this knowledge to solve problems and interpret pedigrees • Demonstrate understanding of the concepts of penetrance and expressivity • Demonstrate understanding of the concept of incomplete dominance 2 A Story of 2 Women…Clinical Case 1 • Helen 64 y/o single female • Estimated life expectancy at birth < 3 • Normal development, schooling, work • Lives alone, fully independent Activities of Daily Living (ADLs) •Well until February 2014 - admitted May 2014 with SOB on minimal exertion, and acute kidney injury •Thoracic aortic aneurysm and thoracoabdominal aneurysm, dilation of aortic arch •Bilateral pulmonary hyperinflation (lungs otherwise clear) ?Obstructive airways disease • History of sudden death on mother’s side • Mother RIP 4 years ago – Known Aortic Stenosis • Referred to Endocrinology OPD by Cardiothoracic surgeon with congenital deformity of her spine and ? Syndrome 3 Physical Examination • Short stature (141cm) • BMI 19.6 • Poor dentition • Webbed neck • High Arched Palate • Normal carrying angle • Low set hairline – mid thoracic spine • Protrusion from skullcongenital • Pectus excavatum • No organomegaly • Spine: • Kyphoscoliosis • Significantly restricted range of movement cervical and thoracic spine 4 Klippel-Feil Syndrome • A complex syndrome of osseous and visceral anomalies which was described for the first time in 1912 by Maurice Klippel and Andre Feil • They described patients who had: 1. short, webbed neck 2. decreased range of motion in the cervical spine 3. low-set hairline • Characterised by congenital fusion of any 2 of the 7 cervical vertebrae • Rare – incidence estimated 1 in 42,000 births (true incidence unknown) • Mutations in the GDF6, GDF3, or MEOX1 genes (bone development) • Inheritance pattern can be autosomal dominant or recessive (depends on gene involved) 5 A Story of 2 Women… Clinical Case 2 • Karen, 45 Year Old Female • Married with 2 children • Previously well all her life • Depressed and forgetful (getting worse) • Referred to a psychiatrist • Noted involuntary movements (fingers & face) • Mother died young of a brain disease 6 Suspect Diagnosis • Huntington Disease • Affects 3-7 per 100,000 people of European Ancestry • Inherited in an autosomal dominant pattern • Progressive neuronal loss - disease onset usually occurs in 30’s or 40’s • Survival for 15-20 years after 1st symptoms Woody Guthrie (RIP 1967) 7 Genetics of Huntington Disease • Caused by a mutation in the HTT gene • Anticipation – offspring may have earlier onset/more severe phenotype than parent due to further expansion of the repeat • 27-35 premutation (risk for children) • 36-39 at risk (incomplete penetrance) • 40+ = HD • Preimplantation and prenatal diagnosis possible – ethical and legal (insurance) considerations 8 Question Go to www.menti.com • Select the non-hereditary, congenital diseases from the following list: • Cystic Fibrosis • Toxoplasmosis • Sickle Cell Anaemia • Cerebral Palsy • Type 1 Diabetes 9 Menti Question • Rank these concepts in order of first appearance • The concept of DNA • The concept of genes • The concept of inheritance 10 Which Came First ? 1. Inheritance: recognised for millennia 2. The Concept of Gene: developed as the “unit” of inheritance (19th Century) 3. The Concept of DNA: chemical entity that encodes the units of inheritance (20th Century) 11 Autosomal / X-Linked Inheritance • • Autosomal inheritance – not sex dependent • Allele located on one of the 22 autosomes X-linked inheritance – clear pattern of sex dependent inheritance • Allele located on the X chromosome 12 Pedigree Interpretation Pedigree chart: • Shows the occurrence of phenotypes of a particular gene in a family tree • A family history showing the phenotypes of ancestors in chart form • Used to infer the pattern of inheritance and calculate the risk for future offspring 13 Menti Question - What’s the Pattern of Mendelian Inheritance? 14 Mendelian Inheritance X Linked Recessive Pattern Character is typically manifest in male offspring of unaffected females Not in offspring of affected males Female X Linked Recessive: Basis Genetic locus is on an X chromosome Female has 2 X chromosomes XX Hh Non-functional allele on one X chromosome means –one functional allele for a woman - no functional allele for a man Male XY h H = dominant allele (normal) h = recessive allele (haemophilia) 15 What Mendelian Pattern do you See with X Linked Dominant? e.g. vitamin D resistant rickets, a.k.a. X-linked hypophosphatemic rickets (XLH) 16 Mendelian Inheritance Y Linked What is the only know Y linked character ? The Only Know Character is Maleness 50% Chance that each Child of an Affected Male Will Manifest the Character 17 Menti Questions – Pedigree Interpretation 18 Example of a Dichotomous Trait: Cleft Chin Did my parents have cleft or smooth chins? Will my children have cleft or smooth chins ? Dominant or recessive? 19 Polygenic/Multifactorial Character is determined by a large number of genes and the interaction of expression of those genes with the environment (not Mendelian) Height Shoe size Eye colour Intelligence 20 Environmental influence • An environmental factor may impact on all members of the population will little variation in effect related to genotype (for example a high velocity projectile) • In some cases the genetic property is almost always associated with an expressed trait (relatively independent of environmental factors) e.g. Huntington Disease • In some cases the genetic property is associated with an expressed trait only under very specific environmental conditions • In medicine; genetic predisposition to develop a specific disease (e.g. type 2 diabetes) 21 Incomplete Penetrance vs Variable Expressivity Incomplete penetrance Variable expressivity • Penetrance = probability of a genotype/trait being expressed • Variation in phenotypic expression when penetrance is complete • Incomplete = phenotype only expressed in a fraction (%) of the population with the genotype • A range of symptoms displayed in individuals with the same fully penetrant genotype BB x bb BB x bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Incomplete penetrance for blue phenotype Variable expressivity for blue phenotype 22 Penetrance and Expressivity • Variable expressivity is the norm among genetic diseases and is particularly common for disorders that affect multiple organ systems Factors that Influence Penetrance and Expressivity: • Age, Gender, Environmental risk factors, Lifestyle risk factors, Modifier genes, Parent of origin (epigenetic) effects 23 Clinical Case • Osteogenesis imperfecta (OI) • Rachel’s mother had 10 leg bone fractures as a child, is 4ft 11 inches tall, is very double-jointed and has had blue/grey sclera since birth • Rachel is 26, 5 ft 7, has never had a fracture and has normal colour eyes • Rachel’s daughter is 4, has already had 2 fractures, is slightly double-jointed and has normal colour eyes COL1A1 genotype of all 3 females • All three females are heterozygous for the same dominant mutation in the COL1A1 gene Cc 24 Menti Questions • What phenomenon best explains the genotype phenotype correlation seen in Rachel? • What phenomenon best explains the genotype-phenotype correlation seen between Rachel’s child and her grandmother? 25 Rachel • Rachel is 26, 5 ft 7, has never had a fracture and has normal colour eyes • Not expressing the phenotype at all – incomplete penetrance COL1A1 genotype of Rachel Cc 26 Rachel’s mother and Rachel’s daughter • Rachel’s mother had 10 leg bone fractures as a child, is 4ft 11 inches tall, is very double-jointed and has had blue/grey sclera since birth • Expression of the OI phenotype • Rachel’s daughter is 4, has already had 2 fractures, is slightly double-jointed and has normal colour eyes • Same genotype but less severe phenotype expressed • Variable expressivity COL1A1 genotype of Rachel’s mother Cc COL1A1 genotype of Rachel’s daughter Cc 27 Clinical Case • Familial Hypercholesterolemia, is a genetic disorder with a dominant pattern of inheritance that is associated with mutations in the LDLR gene on Chr 19 • Roberto 35 - Heterozygous for LDLR mutation • Elevated LDL cholesterol 350mg/dL • Skin lesions (xanthelasmata) present on eyelids and under the eyes • Recently had a mild MI • His twin sons (age 2) have symmetrical xanthomas on their knees and elbows • Blood LDL cholesterol level 1.2g/dL • Homozygous for LDLR mutation 28 Menti Question • What phenomenon of inheritance explains the phenotype of Roberto’s condition? 29 Incomplete Dominance Roberto - Heterozygous for LDLR mutation Intermediate phenotype of hypercholesterolemia Ll Roberto’s sons - Homozygous for LDLR mutation Severe phenotype of hypercholesterolemia LL 30 Things to Remember 1. A gene can be considered in different ways: • A unit of inheritance that passes from one generation to another and is responsible for a trait/character • or a DNA sequence associated with a particular property / encoding for a particular protein 2. Hereditary disease is not always congenital (present at birth) and congenital disease is not always hereditary (determined by genetic factors and therefore capable of being passed on) 3. Huntington Disease is an important autosomal dominant hereditary disease that is not congenital. It associated with an expanded trinucleotide repeat and the phenomenon of anticipation. 4. A Mendelian character/trait is one with a generally clear cut pattern of inheritance (a.k.a. monogenic character) 5. There are exceptions/qualifications to almost anything that I can say about genetics (or actually the world in general I suppose) Try to get broad general principles but don’t get too confident Uncertainty is the business of medicine (some people struggle with that) 31