PATTERNS OF SINGLE GENE INHERITANCE Chapter 7 Genetics in Medicine

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1 PATTERNS OF SINGLE GENE INHERITANCE Chapter 7 Genetics in Medicine
08/21/2018 Le Poole

2 KEY CONCEPTS 1. Genetic variation originates from heritable DNA mutations. 2. Recessive disorders manifest themselves only when no healthy allele is present 3. The risk of a recessive genetic disease is affected by consanguinity. 4. Dominant disorders exhibit a phenotype despite the presence of a healthy allele. 5. Sex linked diseases affect males and females differently. 6. Non-mendelian inheritance patterns exist for some single gene disorders.

3 1. Genetic variation originates from heritable DNA mutations.
Sex linked: encoded on the X (or the Y) chromosome, thus conferred together with gender Autosomal: encoded on numeric chromosomes Recessive: both alleles must be affected for the trait to be displayed Dominant: a single mutant allele confers a phenotype

4 Pedigree Symbols

5 Definitions Genotype genetic constitution of an individual or locus
Phenotype outward characteristics of an individual or gene product Allele one of the alternative versions of a gene or DNA sequence at a given locus Locus position occupied by a gene on a chromosome Homozygote genotype with identical alleles at a given locus Heterozygote genotype with different alleles at a given locus Hemizygous genotype with a single allele for a given chromosome segment Compound heterozygote genotype with 2 different mutant alleles at one locus Polymorphism alternate genotypes present in a population at >1% Penetrance the proportion of individuals manifesting disease Expressivity the extent to which a mutation exhibits a phenotype Genetic heterogeneity can result from different mutations at 1 locus (allelic), or from mutations at different loci (locus). Phenotypic heterogeneity occurs when the same mutations manifests itself differently among individuals.

6 2. Recessive disorders For single gene disorders, a phenotype is considered recessive if manifest in the homozygote. Image nhlbi.nih.gov Vaso-occlusion Infarcted spleen Fatigue Dactylitis (inflamed finger) Sickle cell crises Illustration only

7 Autosomal recessive inheritance
Appears in more than one sibling of the proband, but not in parents , offspring or other relatives Males and females equally affected Parents are asymptomatic carriers Parents may be consanguineous The risk to each siblings of the proband is 25%

8 3. Consanguinity The risk of a recessive genetic disease for a given mating depends on the population carrier frequency and on partner consanguinity. Families carrying the same disease-associated mutation in Notch-3 in Finland

9 Consanguinity Degree of relationship to the proband is indicated in the symbols III-8 and III-9 are consanguinous and are doubly related to the proband

10 Proportion of alleles in common
Consanguinity continued Proportion of alleles in common (sibs) Degree of relationship (n) corresponds to the number of uninterrupted line segments connecting two blood relatives in a pedigree chart. The proportion of alleles two related individuals have in common = (½)n Coefficient of inbreeding (F) is the proportion of loci at which a person is homozygous by descent =½  coefficient of relationship

11 Coefficient of Inbreeding F
Degree of relationship III-1 and III-2= Proportion of alleles that they have in common= 1/2x1/2x1/2= Coefficient of inbreeding F for child IV-1= odds of inheriting the same allele from both= (can be A1, A2, A3 or A4) Odds of inheriting a given, diseased allele from both (example: A3)= 1/4x 1/16= 3rd 1/8 1/16 1/64

12 ‘Whiteboard’ calculation
A1A2 A3A4 Sam in generation I carries a recessive allele for CF. What are the odds that his great-great grandchild will develop cystic fibrosis? Degree of relationship parents Proportion of alleles parents have in common Coefficient of inbreeding (proportion of alleles in child homozygous by descent) 5 ½ (5)= 1/32 ½ (6)= 1/64 To calculate odds of disease A2A2 in child: Odds dad is a carrier? Odds mom is a carrier? Odds of diseased allele passed on to child from either parent? 1/8x1/2x1/8x1/2= 1/256 1/8 for either ½ for either

13 Coefficient of Inbreeding* for Some Human Populations
Canada Roman Catholic United States Hutterites Dunkers (Pennsylvania) Latin America Southern Europe Japan India (Andhra Pradesh) Samaritans .02 .03 .005 .04 *= proportion of alleles that are homozygous by decent

14 4. dominant disorders For single gene disorders, a phenotype is con-sidered dominant if manifest in the heterozygote. incomplete dominance In humans: hair texture codominance in humans: bloodgroups A& B Illustration only

15 Pedigree showing typical inheritance of a form of progressive sensorineural deafness (DFNAI) inherited as an autosomal dominant trait. disease phenotype is usually seen in every generation. A child of an affected parent has a 1 in 2 risk of inheriting the disease trait. Unaffected family members are unlikely to transmit the disease to their offspring. Males and females are usually equally affected.

16 Dominant disorder: Familial hypercholesterolemia
Dominant disorders are hardly ever purely dominant. Patients with mutations in one allelle of the LDL receptor gene display elevated blood cholesterol and premature hear disease. Manifestations are more severe/ earlier onset in homozygote mutant patients. Haploinsufficiency: Gene product from a single healthy allele is not enough to prevent disease.

17 Reduced penetrance Ectrodactyly Most common mode of inheritance: autosomal dominant with reduced penetrance Various changes to 7q Pedigree of split-hand deformity demonstrating failure of penetrance in the mother of the consultand (arrow). Reduced penetrance must be taken into account in genetic counseling.

18 5. sex-linked diseases Mutations in genes on the X-chromosome can affect males and females differently; the disease frequency equals the frequency of the defining allele in males. Illustration only

19 X-linked recessive inheritance
Image: X-linked recessive inheritance Affected fathers transmit the disease to their grandsons through their daughters but not through their sons All daughters of affected fathers are carriers and have a 50% chance of transmitting the gene to their children. The affected females are carriers and the affected males express the disease

20 X-linked dominant inheritance
Affected fathers always transmit the disease to their daughters but never to their sons Affected mothers have a 50% chance of transmitting the disease to all their children

21 6. Non-Mendelian inheritance
somatic or germline mosaicism A mutation occurring during cell proliferation, in somatic cells or during gametogenesis, leads to a proportion of cells carrying the mutation. Mosaic FGFR3 mutation J Clin Invest. 2006; 116(8):2201 When non-mosaic: Achondroplasia

22 X inactivation Duchenne’s muscular dystrophy
Progressive muscle weakness Fibrosis 1:3,600 boys Life expectancy ~25 y Mutations in dystrophin gene X inactivation Immunostaining for dystrophin in muscle specimens. A, A normal female. B, A male with Duchenne muscular dystrophy. C, A carrier female. Staining creates the bright lines seen here encircling individual muscle fibers. Muscle from DMD patients lacks dystrophin staining. Muscle from DMD carriers exhibits both positive and negative patches of dystrophin immunostaining, reflecting X inactivation. (Courtesy of K. Arahata, National Institute of Neuroscience, Tokyo.)

23 Prader-Willi Syndrome
7. Imprinting/parent of origin effects PWS region AS gene Deletion active inactive Prader-Willi Syndrome Angelman Syndrome An example is shown here for Angelman and Prader-Willi syndromes: Both syndromes most commonly result from a deletion in the long arm of chromosome 15 (15q11-q13)

24 pedigree for paraganglioma syndrome 1, caused by a mutation in the SDHD gene, which demonstrates a ‘parent of origin’ effect. The gene is imprinted active in male gametes. Pedigree for a dominant disorder that demonstrates a parent of origin effect due to genomic imprinting

25 8. Repeat disorders Huntington’s disease
Images dianenet.com Huntington’s disease Uncontrolled limb movements Mood alterations Decline in reasoning skills Obsessive-compulsive behaviour Autosomal dominant inheritance Maps to chromosome 4 Pedigree and electrophoresis of PCR products containing the CAG repeat region

26 severity increases in subsequent generations
Anticipation: severity increases in subsequent generations Myotonic dystrophy Illustration only

27 Relationship between age of onset and # of repeats
Example: myotonic dystrophy

28 Anticipation in a three generation family with myotonic dystrophy
Grandmother has had bilateral cataracts; mother has moderate facial weakness with myotonia and cataracts. The child has congenital myotonic dystrophy: Autosomal dominant Muscle wasting Cataracts Myotonia Hypersomnia Insulin resistance

29 Factors defining inheritance of mitochondrial DNA
9. Mitochondrial inheritance Factors defining inheritance of mitochondrial DNA Mitochondrial DNA can be heteroplasmic: more than one type of mitochondrial DNA may be present in cells from a single individual Mitochondrial DNA is inherited maternally. A small and random sample of mitochondrial DNA is selected for inclusion in the oocyte during oogenesis Mitochondrial DNA undergoes random segregation through multiple rounds of mitosis during embryogenesis.

30 Maternal inheritance Replicative segregation of a heteroplasmic mitochondrial mutation during embryogenesis:

31 mitochondrial DNA disorders
Pedigree of Leber hereditary optic neuropathy, a form of spontaneous blindness caused by a defect (point mutations) in mitochondrial DNA. © 2005 Elsevier

32 complications to the basic pedigree patterns that may impact diagnosis and/or counseling
New mutations – especially for autosomal dominant disorders Genomic imprinting – different phenotypes depending on the parental source of the mutation Reduced penetrance – not all patients with the disease genotype express symptoms Variable expressivity – the severity of the disease differs in patients with the same genotype Phenotypic variability – disorders that affect multiple organs can produce different symptoms in related family members (pleiotropy) due to effects of environment or other genes Delayed onset – e.g triplet repeat expansion disorders (Huntington disease, myotonic dystrophy, etc.) Small family size - limited pedigree information on which to base a counseling recommendations

33 Questions?