MS523.L12.Autosomal Dominant and Recessive Inheritance.Q3.23.pptx

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Course: MS523 Human Genetics Lecture: Autosomal Dominant and Recessive Inheritance Presenter: Dr. Darl Swartz Date: 2/6/23 11/21/ Dr. Darl Ray. Swartz 1 Objectives: 1. Explain how a disease-causing allele/gene is not easily defined. 2. Define locus, autosomes, haploid, diploid, gametes, zygote,...

Course: MS523 Human Genetics Lecture: Autosomal Dominant and Recessive Inheritance Presenter: Dr. Darl Swartz Date: 2/6/23 11/21/ Dr. Darl Ray. Swartz 1 Objectives: 1. Explain how a disease-causing allele/gene is not easily defined. 2. Define locus, autosomes, haploid, diploid, gametes, zygote, and somatic cells. 3. Explain how Mendel’s laws relate to meiosis. 4. Describe autosomal dominant and recessive monogenic disease and predict their inheritance pattern/probabilities using Punnett’s square. 5. Define consanguinity, what populations it manifests, how it influences inheritance of monogenic diseases, and example coefficients of consanguinity for different reproductive unions. 6. Explain why Mendelian genetics does not easily apply to many diseases considering de novo mutations, multiple loci, penetrance, expressivity, multiple alleles at a locus, and pleiotropy. 11/21/2 Dr. Darl Ray. Swartz 2 Outline: I. II. III. IV. V. VI. 11/21/2 Concepts Mendel’s Laws and Meiosis Autosomal Dominant Autosomal Recessive Consanguinity Variants Upon Variants Dr. Darl Ray. Swartz 3 ) Concepts A) Disease-causing genes can be anywhere in the genome, not just in protein coding genes, and a disease can be caused by a constellation of causative alleles ruling out the one gene one disease hypothesis. B) Terms used to describe genes and inheritance in sexually-reproducing organisms include alleles, loci, autosomal, haploid, diploid, gametes, zygote, and somatic cells. C) Mendel studied the inheritance of dominant and recessive alleles and from these studies developed the law of segregation and law of independent assortment that result from events in meiosis I. D) Reginald Punnett, working with William Bateson, developed the Punnett’s Square to predict the probabilities of inheritance (recurrence risk). E) Autosomal dominant and autosomal recessive diseases have distinguishing inheritance patterns (transmittance) and recurrence risks making differentiating between the two relatively straight forward. F) Consanguinity is reproductive unions of related individuals that results in a higher proportion of autosomal recessive inheritance than predicted by population genetics. G) Many biological processes result inDr.variations on classical Mendelian genetics such4 Darl Ray. Swartz 11/21/2 Mendel’s Laws and Meiosis 11/21/2 Dr. Darl Ray. Swartz 5 Mendel’s Laws and Meiosis A) Genes 1) Mendel’s alleles that are contained within gametes 2) Segment of DNA that is involved in determining phenotype (a) Can be anywhere in the genome (b) Coding regions (i) Exons (ii)5’ UTR, intron, 3’ UTR (c)Non-coding regions (i) Promoter/enhancer (ii)Regulatory RNAs (lnc, mi, sn, e) (d)Structural regions of chromosomes B) Locus 1) Location of gene on the chromosome 11/21/2 Dr. Darl Ray. Swartz 6 Mendel’s Laws and Meiosis C) Autosomes 1) Humans are diploid (2n) 2) 22 pairs (44 total) in humans (2n = 44, n = 22) (a)22 paternal chromatids (b) 22 maternal chromatids (c)22 homologous pairs (i) Not exactly the same DNA sequence (d) X and Y are not homologous (for the most part) 3) Chromosomes numbered 1 – 22 4) Locus of gene the same for paternal and maternal chromosome 5) Pair of genes is the genotype 6) Can determine parental origin of gene via via haplotyping (a)Determine DNA sequence of parents and offspring for locus 11/21/2 Dr. Darl Ray. Swartz 7 Mendel’s Laws and Meiosis D) Sex chromosomes 1) 1 pair 2) Female XX 3) Male XY (a)Is theoretically hemizygous for X and Y 4) Greater than 2 sex chromosomes (aneuploidy) or just 1 X is found in the human population (a)XXX and higher females > extra X syndrome (b) XXY in males > Klinefelter syndrome (c)X in females > Turner syndrome E) Total chromosome count = autosome + sex chromosomes 1) 22 pairs of autosome + 1 pair of sex chromosomes = 23 pairs (46 total) 11/21/2 Dr. Darl Ray. Swartz 8 Mendel’s Laws and Meiosis F) Human life cycle 1) Haploid gametes fuse during fertilization to give diploid zygote (a)Sperm (1n) + egg (1n) > zygote (2n) 2) Zygote develops via mitosis to give somatic cells and gametogenic cells 3) Gametogenic cells segregate to gonads (testes and ovary) develop and contain diploid cells capable of meiosis 4) Spermatogonia and oogonia go through reductive division to produce gametes (a)1 spermatogonia > 4 spermatozoa (b) 1 oogonia > 1 egg + 3 polar bodies 11/21/2 Dr. Darl Ray. Swartz 9 Mendel’s Laws and Meiosis G) Mendel developed the concept of dominant and recessive alleles (genes) 1) He selected pea cultivars that demonstrated true breeding (homozygous for character of interest) and crossbred them (the simplest genetic model) (a)Single copy genes (peas are unique amongst plants in that they have many single copy genes) 2) Inherit one allele from sperm and one from egg thus 2 copies of the gene 3) If copies the same = homozygous 4) If copies different = heterozygous 5) Dominant gene can mask/hide the phenotype of the recessive gene in the heterozygote 6) Theoretical example of genes for eye color (eye color is actually multigenic) (a)B is the gene for brown eyes and dominant (b)b is the gene for blue eyes and recessive (c) Homozygous genotype of BB = brown eyes (d)Heterozygous genotype of Bb = brown eyes (e)Homozygous genotype of bb = blue eyes 7) Generally dominant alleles only require one good copy of the gene to give phenotype 10 11/21/2 Dr. Darl Ray. Swartz Mendel’s Laws and Meiosis H) Mendel’s first law 1) Law of segregation > the pair of genes segregate such that only one of the genes from each parent is transmitted to the offspring and random union of gametes during fertilization (a) Meiosis I > separation of homologs/reductive division during MEIOSIS I: Separates homologous chromosomes anaphase I NOTE: Interphase precedes mitosis and meiosis where chromosomes are replicated to give sister chromatids that are exactly the same 11/21/2 Dr. Darl Ray. Swartz 11 Mendel’s Laws and Meiosis H) Mendel’s first law 2) Developed from mono-hybrid crosses of homozygous peas for various characters (a) Pea color (green or yellow traits) (b) Pea shape (wrinkled or smooth traits) (c)Plant height (tall or short traits) 3) Traits determined by alleles at one locus for the character and are thus monogenic 4) Many human diseases are monogenic and cataloged in OMIM as well as other nonmonogenic diseases 11/21/2 Dr. Darl Ray. Swartz 12 Mendel’s Laws and Meiosis I) Mendel’s second law 1) Law of independent assortment (of alleles for multiple characters) > genes at different loci are transmitted to the offspring independently (a) Meiosis I > random segregation of autosomal chromosomes or distant loci on the same chromosome (i) Crossing over to “unlink” genes at distant loci on the same chromosome 2) Developed from di-hybrid crosses of homozygous peas for two characters (a) Pea color (b) Plant height 11/21/2 Dr. Darl Ray. Swartz (c)Resulted in unique combination of 13 Mendel’s Laws and Meiosis J) Mendel’s laws are explained by meiotic processes 1) Replicate DNA during interphase to give 2X DNA and sister chromatids for each autosome and sex chromosome (2n) 2) Meiosis I > reductive division giving 2 cells with 1X DNA and 1n chromosomes (a) Prophase I (i) Alignment of bivalents (sister chromatids) to form tetrads (maternal and paternal chromatids) (ii)Synapsis between one paternal chromatid and one maternal chromatid  Crossing over of segments between homologs  Mixes up genes between maternal and paternal homologs at specific loci and thus part of Law 2 (un-links genes on a chromatid)  Occurs at 1 – 3 sites per tetrad using one sister or from each 11/21/2 Dr. Darl Ray. Swartz homolog 14 Mendel’s Laws and Meiosis J) Mendel’s laws are explained by meiotic processes 2) Meiosis I > reductive division giving 2 cells with 1X DNA and 1n chromosomes (b) Metaphase (i) Loss of nuclear membrane (ii)Attachment of kinetochore microtubules to fused kinetochore of each bivalent (not each chromatid) (iii) Alignment of tetrads along metaphase plate (c)Anaphase I (i) Separation of bivalents at chiasma of tetrad (ii)Random segregation of different bivalents (autosomes and sex chromosome)  Explains Laws 1 and 2 (iii) Bivalents migrate towards opposite poles (d) Telophase I 11/21/2 Darl Ray. Swartz (i) Formation of nuclei andDr. nuclear membrane 15 Mendel’s Laws and Meiosis J) Mendel’s laws are explained by meiotic processes 2) Meiosis I > reductive division giving 2 cells with 1X DNA and 1n chromosomes MEIOSIS I: Separates homologous chromosomes 11/21/2 Dr. Darl Ray. Swartz 16 Mendel’s Laws and Meiosis J) Mendel’s laws are explained by meiotic processes 4) Interkinesis > phase between meiosis I and meiosis II (a) Do not replicate DNA (b) Do replicate centrioles (c)Do re-organize centromere/kinetochore to allow for each sister chromatids to get linked to kinetochore microtubules Mol Cell Biol. 2015 Feb; 35(4): 634–648. 11/21/2 Dr. Darl Ray. Swartz 17 Mendel’s Laws and Meiosis J) Mendel’s laws are explained by meiotic processes 5) Meiosis II > division giving 4 cells with 0.5X DNA and one sister of each chromatid (1n) (a) Prophase II (i) Akin to prophase of mitosis but relatively rapid (b) Metaphase II (i) Attachment of kinetochore microtubules to kinetochore of each chromatid (ii)Alignment of sister chromatids at metaphase plate (c)Anaphase II (i) Separation of sister chromatids (ii)Chromatids migrate to opposite poles (d) Telophase II (i) Formation of nuclei and nuclear membrane 11/21/2 Dr. Darl Ray. Swartz 18 Mendel’s Laws and Meiosis J) Mendel’s laws are explained by meiotic processes 4) Meiosis II > division giving 4 cells with 0.5X DNA and one sister of each chromatid (1n) MEIOSIS II: Separates sister chromatids 11/21/2 Dr. Darl Ray. Swartz 19 Mendel’s Laws and Meiosis J) Mendel’s laws are explained by meiotic processes 5) Cytokinesis (a) In oogenesis, not equal and functionally is ejection of one of the nuclei (polar body) per meiotic division (b) In spermatogenesis, retain cytoplasmic linkages (incomplete) until much later in development (spermiogenesis stage) 6) Errors in meiosis I (bivalent separation) and meiosis II (sister chromatid) 20 11/21/2 Dr. Darl Ray. Swartz result in aneuploidies as presented earlier Mendel’s Laws and Meiosis K) Punnett’s square is used to determine genotype probabilities (recurrence risk) 1) Developed by Reginald Punnett hence it is Punnett’s square 2) Diagrammatic method of calculating probabilities of zygote (offspring) genotypes based upon gametes (parental genotypes) (a)Recurrence risk probability in human genetics 3) For a monogenic character, make a 3 X 3 table (a)Need (or model) genotypes of parents (i) Meiosis/gametogenesis gives the gamete genotype (ii) Code genes with uppercase (generally dominant) and lowercase (generally recessive) letter (iii) Bb > B with an 0.5 probability and b with an 0.5 probability (b)Upper right 2 cells are gamete probabilities from one parent (c) Lower left 2 cells are gamete probabilities from other parent (d)Zygote genotypes are determined by combining gamete genotypes down columns and across rows (random union of gametes) (i) Zygote genotype probability is the product of the gamete X gamete probability (rule of multiplication) 4) Can use software to determine Dr. genotype and phenotype probabilities 11/21/2 Darl Ray. Swartz 21 Mendel’s Laws and Meiosis K) Punnett’s square is used to determine genotype probabilities (recurrence risk) PP (diploid) > Meiosis Gamete genotypes P, P (haploid) pp (diploid) > Meiosis Gamete genotypes p, p (haploid) Pp (diploid) > Meiosis Gamete genotypes P, p (haploid Maternal Gamete Genotypes (Haploid) Paternal Gamete Genotyp es (Haploid) P (0.5) 11/21/2 p (0.5) Zygote Genotype (diploid) Zygote Genotype (diploid) Zygote Genotype (diploid) P (0.5) p Zygote Genotype (diploid) (0.5) PP (0.25) Pp (0.25) Dr. Darl Pp Ray. Swartzpp Pp X Pp Offspring genotype probabilities: PP = 0.25, ¼, Pp = 0.50, ½, pp = 0.25, ¼ Offspring phenotype probabilities (assuming P dominant): 22 Mendel’s Laws and Meiosis L) Monogenic character (disease) 1) Genes for disease are at one locus and have 2 possible alleles (a) Disease gene can be dominant or recessive (b) Can be heterozygous (variant & normal) or homozygous (variant & variant or normal & normal) (b) Disease can have multiple variants within the gene (multiple alleles at a locus) (i) ABO blood type alleles M) Polygenic character (disease) 1) Genes for disease are at multiple loci with each loci having 2 (or morel) possible alleles (a)Disease genes can be dominant or recessive (b)Disease phenotype dependent upon the combination of alleles N) Mendelian genetics assumes that the relationship between genotype and phenotype is binary 1) Dominant or recessive trait for a character O) Gene dosage effects for monogenic disease may give three possible phenotypes from the genotypes 23 11/21/2 Dr. Darl Ray. Swartz ) Autosomal Dominant Postaxial polydactyly (mostly autosomal dominant but not in this exa 11/21/2 Dr. Darl Ray. Swartz 24 ) Autosomal Dominant A) Frequency of about 5/1000 (0.5% or 1/200) for all types of human autosomal dominant disease genes 1) Specific diseases have low frequency in the population 2) Disease present when 1 variant copy is present (heterozygous) B) Inheritance pattern features 1) Transmission pattern: Observed in every generation > vertical transmission in a pedigree 2) Observed in equal proportion in male and female offspring 3) Recurrence risk: (a) D = disease-causing gene, d = non-disease-causing gene (b) Genotype DD or Dd > disease phenotype (c)DD x dd > 100% chance for disease/0% chance no disease (d) Dd x Dd > 75% chance for disease/25% chance no disease (e) Dd x dd > 50% chance for disease/50% chance no disease 11/21/2 Dr. Darl Ray. Swartz 25 ) Autosomal Dominant C) Variant gene product can be: 1) Gain of function such that it stimulates disease development (a) Proto-oncogene > oncogene (gain of function) 2) Dominant negative gene product that inhibits the function of normal allele gene product 3) Non-functional for a gene that requires two good copies for normal function (results in haploinsuficiency) 4) Non-functional with non-disease form being inhibitor of disease development (a) Some tumor suppressor genes with haploinsufficiency D) Can occur through spontaneous germline mutations (gametogenesis error) 1) More frequent in autosomal dominant than autosomal recessive diseases E) Homozygote disease phenotype generally more severe than heterozygote 11/21/2 Dr. Darl Ray. Swartz 26 ) Autosomal Dominant F) Achondroplasia as an example 1) Clinical phenotype is short limb dwarfism with macrocephaly, kyphosis, midfacial retrusion (a)Diagnosis via infant/pediatric phenomics 2) Genetics (a)>90% associated with a point mutation in FGF3R gene resulting in altered protein aa sequence (i) FGFR c.1138G>C Aa AA (p.Gly380Arg) (ii) Gain of function mutation resulting in increased Pauli Orphanet Journal of Rare Diseases (2019) 14: sensitivity of receptor to ligand (over active/gain of function) (b)Fully penetrant (if have the variant will show the phenotype) 27 11/21/2 Dr. Darl Ray. Swartz ) Autosomal Dominant F) Achondroplasia as an example 2) Genetics 11/21/2 (e)> 80% of cases via spontaneous germline mutations (somatic cells from parents do not have the mutation) (f) Recurrence rate (for next offspring) from germline mutations much higher than predicted from frequency of spontaneous germline mutations observed in other diseases/variants (g) Nearly all germline mutations of paternal origin with probability increasing with paternal age (anticipation?) (i) Variant likely clonally selected in germline cells (spermatogonia) and expanded to give higher proportion of mutant sperm  FGF3R variant has moderate proliferative advantage > population genetics and natural selection in spermatogonia (ii)Paternal age effect mutation (akin to trisomy 21 for maternal origin effects) 28 Dr. Darl Ray. Swartz ) Autosomal Dominant F) Achondroplasia as an example 3) Cellular and molecular mechanisms of phenotype (a)FGF3R overactive signaling inhibits chondrocyte proliferation and hypertrophy resulting in reduced endochondral bone formation (i) Phenotype readily demonstrates locations of intramembranous vs endochondral bone formation (b) FGF3R is a tyrosine kinase (growth factor) receptor and acts via multiple signaling pathways in chondrocytes akin to insulin signaling (c)Major pathway involved is not resolved but somehow blocks chondrocyte differentiation into 11/21/2 Dr. Darl Ray. Swartz Science's STKE 13 Apr 2004: Vol. 2004, Issue 228, pp. pe17 DOI: 10.1126/stke.2282004pe17 29 ) Autosomal Dominant F) Achondroplasia as an example 4) Treatment (a)Environmental adaptations to stature early during development (b) Growth hormone treatment results in a 2.8 to 3.5 cm increase in height (c)Limb extension using osteomy and gradual distraction via external fixators can increase height by 25 cm (d) FGF3R inhibition (i) FGF3R extracellular domain to compete for ligand with chondrocyte FGF3R (ii)C-type natriuretic peptide analogues (iii) Various pathway inhibitors 11/21/2 Dr. Darl Ray. Swartz 30 ) Autosomal Recessive 11/21/2 Dr. Darl Ray. Swartz 31 ) Autosomal Recessive A) Frequency of about 2/1000 (0.2% or 1/500) for all types of human autosomal recessive genes 1) Specific diseases have low frequency in the population 2) Patient has two copies of a variant (homozyogous) B) Classic type of inheritance pattern in biology textbooks C) Inheritance pattern features 1) Transmission pattern: Skips generations/not observed in prior generation, can be observed in multiple siblings of same generation 2) Observed in equal proportion in male and female offspring 3) Recurrence risk: (a)N = non-disease-causing gene, n = disease causing gene (b)Genotype nn > disease phenotype (c) Nn x nn > 50% chance for disease/50% chance no disease (d) Nn x Nn > 25% chance for disease/75% chance no disease (e)NN x nn > 0% chance for disease/100% chance no disease D) High frequency within a family pedigree may involve consanguinity E) Carriers (heterozygotes) may have less severe form of disease 1) Gene dosage effects (2 goods are better than 1 good) 32 11/21/2 Dr. Darl Ray. Swartz ) Autosomal Recessive F) Alpha-1 anti-trypsin deficiency as an example 1) Clinical features of emphysema onset after 40 (accelerated by smoking), liver disease (cirrhosis, cancer) and liver failure (a)Diagnosis via metabolomic measure of alpha-1 anti-trypsin in blood (b)Early onset emphysema in absence of environmental factors 2) Genetics (a)Numerous variants in the gene coding for a protease inhibitor produced by the liver (b)Disease most prevalent in European descendants, especially northern Europe (i) Allelic (gene) frequency of 1 to 2% in US Caucasians from population genetics (c) Most common variant is PI Z (proteinase inhibitor Z allele) (i) SERPINA1 c1096G>A (p.Glu342Lys), SNV 11/21/2 Dr. Darl Ray. Swartz 33 ) Autosomal Recessive F) Alpha-1 anti-trypsin deficiency as an example 3) Cellular mechanism of disease (a) Normal protein is synthesized by the liver and secreted into blood (b) Inhibits elastase (and other proteases) secreted by neutrophils in the lung to prevent excessive degradation of elastin (c)Variant results in protein aggregation by forming salt bridges and thus accumulates in liver instead of being secreted (i) Excessive accumulation in ER results in hepatic effects (hepatotoxicity followed by fibrosis) (ii)Lack of protease inhibition results in excessive degradation of elastin in alveoli and loss of elasticity > emphysema 4) Treatment (a) Transfusion with functional enzyme (b) Bronchodilators (c) Gene therapy (i) Adeno-associated virus mediated gene therapy > in clinical trials 34 11/21/2 Dr. Darl Ray. Swartz (ii) mRNA of corrected sequence > pre-clinical trials ) Consanguinity 11/21/2 Dr. Darl Ray. Swartz 35 ) Consanguinity A) Reproductive unions between related persons B) A small population effect in terms of population genetics 1) Founder and Bottleneck effect taught in Biology C) Not common in current Western populations 1) Was common in European rulers in the 16th – 19th century 2) Can be a problem in assisted reproductive technology (a) Common sperm donor or egg donor (b) Is an issue in domesticated animals (livestock and pets) D) More common in Middle East and some regions in India 1) Most often first cousin or uncle/niece unions 2) Populations being assessed genomically/bio-informatically for loss of function mutations and phenotypic effect of – function of the gene in 11/21/2 Dr. Darl Ray. Swartz humans 36 ) Consanguinity E) Increases probability of autosomal recessive diseases 1) Higher probability of heterozygotes for disease than normal population 2) Higher mortality rate observed in 1st cousin offspring 3) About 2-fold higher incidence of genetic disease in 1st cousin offspring F) Can calculate coefficient of consanguinity 1) 2) 3) 4) 11/21/2 Siblings share 1/2 genetic identity Uncles and nieces share ¼ genetic identity 1st cousins share 1/8 genetic identity 2nd cousins share 1/16 genetic identity Dr. Darl Ray. Swartz 37 ) Consanguinity G) Calculate via: 1) Develop a truncated pedigree just considering the common ancestor carrier of the disease (1st cousin example) (a) Grandpa > mother > son (b) Grandpa > father > daughter 2) Begin with the one of the individuals in the union (son or daughter) and proceed to the common ancestor (Grandpa) then to the other individual (son or daughter). 3) The coefficient of relationship is calculated by (1/2)n-1 where n = number of individuals in the path (multiplication rule) (a) 1/16 for Grandpa as common ancestor for 1st cousins 4) If there are multiple routes (multiple common ancestors) then add the probabilities for each path together (addition rule) (a) 1/16 for Grandpa and 1/16 for Grandma as common ancestors of 1/8 11/21/2 Dr. Darl Ray. Swartz 38 ) Consanguinity G) Calculate via: 1st Cousin Union Grandma Grandpa 1/2 Father Mother 1/1 6 Father 1/2 1/2 Daughter Son 1/2 Mother 1/2 1/2 11/21/2 1/2 1/2 Daughter Son 1/16 1/16 + 1/16 = 1/8 Dr. Darl Ray. Swartz 39 ) Variant Upon Variants Somatic Mosaicism De Novo Mutations Pleiotropy Locus Heterogeneity 11/21/2 Penetrance Germline Mosaicism Dr. Darl Ray. Swartz Expressivity Multiple Alleles at a locus 40 ) Variants Upon Variants A) Most genetic disease do not follow Gospel Mendelian genetics and result from numerous variant biological factors B) De Novo Mutations 1) Observe presence of disease without any family history of disease (a)Low recurrence risk in siblings if not in progenitor germline cells 2) Mostly observed for autosomal dominant variants 3) Occurs in germline cells > can be inherited in offspring (a)Spontaneous mutations in spermatozoa or oocyte (b)Can be chromosomal (aneuploidy) or at the single gene level 4) Increase in frequency with increasing age (maternal and paternal age effects) (a)Females > trisomy 21 > chromosomal segregation aberration (b)Males > positive selection for germ cell clones carrying developmental advantage 5) Overall rate of occurrence of de novo mutations in the zygotes that survive to term is low (a)Most lost during development 6) Recurrence risk is low for offspring from young parents 7) Recurrence risk is likely higher for older parents (both male and female) 41 11/21/2 Dr. Darl Ray. Swartz ) Variants Upon Variants B) De Novo mutations 9) Observed in: (a) Hemophilia A (up to 20%) (b) Duchenne muscular dystrophy (up to 20%) (c)Osteogenesis imperfecta type II (< 1%) 10) Germline mosaicism (a) Parent may have variant in somatic cells (b) Multiple offspring with the variant in offspring not likely via multiple de novo mutations during meiosis (c)De novo mutation that occurs early in gonad development such that progenitor cells (mitotic 11/21/2 Dr. Darl Ray. Swartz spermatogonia or oogonia) contain 42 ) Variants Upon Variants C) Locus heterogeneity 1) Multiple loci variants (not alleles) of the disease-causing genes 2) Example of adult polycystic kidney disease (APKD) (a)Autosomal dominant (b)Progressive development of renal cysts (c) Frequency of 1/1000 persons of European decent (d)Caused by two different genes on different chromosomes (i) PKD1 gene on chromosome 16 that code for polycystin 1 protein (78%) (ii) PKD2 gene on chromosome 4 that codes for polycystin 2 protein (15%) (e)Polycystins are transmembrane proteins thought to be involved in kidney development and found on primary cilia 11/21/2 Dr. Darl Ray. Swartz 43 ) Variants Upon Variants D) Penetrance 1) Proportion of individuals with the disease-causing variant that have the disease phenotype 2) A binary metric (have or do not have the disease) 3) Observe family history where grandparents and children have the disease but not the parents for an autosomal dominant disease (a)Likely another variant in the parent that “corrects” the disease or/and environmental factor (aka epigenetics) (i) i.e. need to find out WHY they do not have the disease 4) Example of autosomal dominant diseases (a)Achondroplasia > 100% penetrance > complete penetrance (b) Retinoblastoma > 90% penetrance > reduced penetrance (i) 10% of heterozygotes do not have the disease 44 11/21/2 Dr. Darl Ray. Swartz ) Variants Upon Variants D) Penetrance 5) Age-dependent penetrance (a) Phenotype not observed until into adulthood (b) Typically an accumulation of damage over time that results in disease (c)Classic example of Huntington’s disease (d) Other examples: (i) APKD (ii)Alpha-1 anti-trypsin (iii) And many more chronic diseases such as cancer 11/21/2 Dr. Darl Ray. Swartz Endocrine-Related Cancer (2008) 15 1035–1041 45 ) Variants Upon Variants E) Expressivity (Variable Expression) 1) The degree of severity of the disease phenotype 2) A scalar metric (shades of grey for disease phenotype) 3) Expression of disease can be influenced by: (a) Environment > diet, epigenetics (b) Allelic heterogeneity > numerous different variants of gene that cause disease (e.g. of CFTR variants from Brown Case Study) (c)Modifier genes > inhibit or enhance diseases progression 11/21/2 Dr. Darl Ray. Swartz 46 ) Variants Upon Variants F) Pleiotropy 1) Variant has multiple effects on phenotype (a) Syndromic 2) Variants involved in embryogenesis and early development (a) Dysmorphias 3) Variant expressed in many organs or involved in critical processes of specific tissue types 4) Many examples Baylor center Isaiah Austin, right, poses for a (a) Sickle cell disease > blood vessels photo with NBA Commissioner Adam Silver after being granted ceremonial first round pick during become occluded the 2014 NBA draft, Thursday, June 26, 2014, in New York. Austin, who was projected to be a first (b) Cystic fibrosis > lungs and other round selection was diagnosed with Marfan just four days before the draft. (Jason secretory organs (pancreas, sweat glands)syndrome DeCrow/AP) (c)Marfan’s syndrome > fibrillin variants that affect elastin development and modify 47 11/21/2 growth factor signaling Dr. Darl Ray. Swartz Copyright Notice All materials found on Geisinger Commonwealth School of Medicine’s course and project sites may be subject to copyright protection, and may be restricted from further dissemination, retention or copying. Disclosure I have no financial relationship with a commercial entity producing health-care related products and/or services.

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