Medical Genetics

1. Medical Genetics

2. Genetics Terms • Basic Terms (Review) • Gene: A hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and determines a particular characteristic in an organism. • Trait: A distinguishing feature, a genetically determined characteristic or condition. • Allele: Versions of a gene • Genotype: Genetic makeup, distinguished from the physical appearance. (G for genetic and genotype) • Phenotype: The observable physical or biochemical characteristics as determined by both genetic makeup and environment

3. DNA to proteins Enzymes Signaling Structure Progeny

4. Genetics Terms (cont.) • High Yield Terms: • Classical Dominance: Dominant allele is expressed if present • Incomplete Penetrance: Not all individuals with a mutant genotype display the phenotype (many genetics dz’s but good example is NF1) • Variable Expression: Nature and severity of phenotype changes between individuals • Co-dominance: Neither of two alleles is dominant (e.g. blood types) • Anticipation: Severity of disease worsens or age of onset is earlier in succeeding generations (e.g. Huntington’s Dz)

5. Genetics Terms (cont.) • High Yield Terms (cont.) • Loss of heterozygosity: When a tumor suppressor gene is mutated or deleted, the complimentary allele must be lost before a cancer develops. Not true with oncogenes! • Dominant negative mutation: a non-functioning protein also prevents a normal protein from functioning appropriately (e.g Marfan’s syndrome) • Heteroplasmy: Both NL and mut mtDNA results in variable expression in mitochondrial inherited dz’s • Uniparental disomy: offspring receives 2 copies of a chromosome from 1 parent and none from the other

7. Imprinting • Normally at a given locus we have two alles one from mother and the other from father • Definition: At a single locus, only one allele is active, the other is inactive.

10. Why DNA methylation causes epigentic silencing • DNA methylation acts as an epigenetic modification in vertebrate DNA. Recently it has become clear that the DNA and histone lysine methylation systems are highly interrelated and rely mechanistically on each other for normal chromatin function in vivo.

11. Imprinting • Definition: At a single locus, only one allele is active, the other is inactive; • Phenotype depends on origin of mutation  paternal v. maternal • Both syndromes due to inactivation or deletion of genes on chromosome 15 q (11-13) • Can also occur as a result of uniparental disomy Deletion of normal chromosome 15q(11-13) from Paternal side: Pader Willi Deletion of normal chromosome 15q(11-13) from Maternal side: Angel Man Syndrome

12. Imprinting • Prader-Willi: Deletion of normally active PATERNAL allele • Mental retardation • Obesity • hypogonadism • Hypotonia • At birth usually demonstrates "floppy baby" with "undescended testicles"

13. Imprinting • Angelman’s syndrome “Happy Puppet Syndrome” : Deletion of normally active MATERNAL allele • Mental retardation • seizures • ataxia • innapropriate laughter • AS is named after a British pediatrician, Harry Angelman, who first described the syndrome in 1965

14. QUESTION • A 3-year-old boy is evaluated by a pediatric endocrinologist because of excessive weight gain. The boy has had problems since birth. He wasnoted to have neonatal central hypotonia, which has improved somewhat since 1 year of age. He was also noted as a baby to have an unusually longhead (dolichocephaly) with almond-shaped eyes and a small mouth. His testes were undescended .Initially, he had feeding problems with poor weight gain in infancy, but since 1 year of age he has shown excessive weight gain. As a baby, he was lethargic and had a weak cry. His motor milestones and speech development have been delayed.

15. Which of the following is the most likely diagnosis? A. Angelman syndrome B. Down syndrome C. Prader-Willi syndrome D. Triple X syndrome E. Turner syndrome

16. Modes of Inheritance • Autosomal Dominant: Affects both males and females in all generations. Presents clinically after puberty and FH is essential for diagnosis. • Examples: Achondroplasia, Huntington’s dz, Neurofibromatosis types 1 & 2, and many many more!

17. Autosomal Recessive • only offspring of 2 carrier parents can be affected. Usually only seen in one generation, usually due to enzyme deficiencies. • Commonly more severe than dominant disorders, presents in childhood • Examples: Albinism, Cystic Fibrosis, PKU, Wilson’s dz, and many more!

18. X-Linked Recessive • only sons of heterozygous mothers can be affected, no father to son transmission. • Examples: Fragile X, Lesch-Nyhan, Hemophilia A and B • Females may rarely be affected due to random inactivation of X chrom (e.g. Lyonization)

19. Lyonization X-inactivation (also called lyonization) is a process by which one of the copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by its being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin.

20. Modes of Inheritance • X-linked dominant: Transmitted through both parents, males and females can be affected, but all females of affected fathers are affected. • Example- • Hypophosphatemic rickets: increased phosphate wasting at proximal tubule

21. Modes of Inheritance • Mitochondrial: Transmission ONLY through the mother. All offspring of affected mothers are affected. • Variable expression due to heteroplasmy

22. Question • A 40 year old woman whose son has Hemophilia comes to the physician because of ecchymosis and increased menstrual bleed for the past 2 years. Genetic analysis of the specimen obtained from the woman shows findings typical of hemizygous for Hemophilia.

23. Which of the following is the most likely explanation for the findings in this patient? A. Chromosomal translocationB. LyonizationC. NondisjunctionD. Chromosomal trisomy E. Chromosomal Monosomy

24. Autosomal Dominant Dz’s • Achondroplasia • Genetics and Cell Level: • Defect in Fibroblast Growth Factor receptor 3 • Causes abnormal cartilage development • Phenotypic Traits: • Dwarfism: short limbs, head and neck normall size • Misc info: • Associated with advance paternal age • AD so if one parent affected then 50% of children affected • Homozygotes die either before or shortly after birth

25. Autosomal Dominant Dz’s • APKD (adult polycystic kidney dz) • Genetics and Cell Level: • 90% due to mut in APKD1 on chromosome 16 • Phenotypic Traits: • Bilateral enlargement of kidney due to multiple cysts • Clinical Presentation: • b/l flank pain, hematuria, HTN, • progressive renal failure • Usually presents in adulthood (hence the name!) • Misc info: cysts in the liver ( 30% ) berry aneurysms of the circle of Willis ( 10-15%)   • mitral valve prolapse (MVP) Colonic diverticulosis

26. Question • A 42-year-old man presents to his physician with dark urine and intermittent flank pain. He has no significant past medical history. Vital signs are as follows: Temp 37C, HR 78, BP 180/105, RR 13, and O2 saturation 99% on room air. Physical examination is significant for bilateral palpable flank masses. Urinary analysis is positive for hemoglobin.

27. Which of the following diagnostic modalities should be used to screen members of this patient's family to assess if they are affected by the same condition? • A. Abdominal CT B. Renal ultrasound C. Renal biopsy D. Voiding cystourethrogram E. Genetic sequencing

28. Autosomal Dominant Dz’s • Familial AdenomatousPolyposis • Genetics and Cell Level: • Deletion on chromosome 5q21-22 (APC gene) • Phenotypic Traits: • Colon covered with polyps after puberty that progress to 100 % cancer if not resected around 30 years • Clinical Presentation: anemia, melena, changes in bowel habits • Misc info: (Screening, Definite ? Will need yearly colonoscopies beginning age of 12 • Once you see polyps do colectomy • Also do upper GI endoscopy to rule out polyps congenital hypertrophy of retinal pigment epithelium

29. Autosomal Dominant Dz’s • Lynch Syndrome (HNPCC or hereditary nonpolyposis colorectal cancer) • Other Cancer like endometrial (2nd most common), ovarian and gastric cancers common • Genetics and Cell Level: • Due to defects in Mismatch Repair Genes • Misc info: • Three or more family members with colon cancers, one of whom is a first degree relative of the other two • Two successive affected generations • Colon cancer in one family member under age 50 years • Will need yearly colonoscopies beginning age of 20 to 25 • Endometrial sampling beginning at age of 30 • Gastric and ovarian cancer screening at age of 30

30. USE CEA levels to monitor for colon cancer recurrence • A 72-year-old male visits his gastroenterologist for a check-up one year following resection of a 2-cmmalignant lesion in his sigmoid colon.

31. Serum levels of which of the following can be used in this patient to test for cancer recurrence? A. Alpha-fetoprotein B. Carcinoembryonic antigen C. Cancer antigen 125 (CA-125) D. Gamma glutamyl transferase E. CA-19-9 tumor marker

32. Microsatellites • A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from 2–5 base pairs) are repeated, typically 5–50 times • High Mutation Rate

33. Microsatellites

34. Autosomal Dominant Dz’s • Familial hypercholesterolemia (HLP type 2A) • Phenotypic Traits: • Xanthelasma palpebrarum • tendon xanthomas (classically on the Achilles tendon) • severe atherosclerotic dz • MI may develop early

35. Autosomal Dominant Dz’s • Huntington’s Disease • Gene located on Chromosome 4, trinucleotide repeat disorder (CAG)n • Normally 9 to 35 repeats but people with Huntingtons have 36 to 121 repeats • Affects the folding of Huntingtons protein which accumulates and clumps. • Clumps kill the neuron producing GABA & ACH • Decreased levels of GABA and Ach in the brain

36. Autosomal Dominant Dz’s • Huntington’s Disease • Clinical Presentation: depression, progressive dementia, choreiform movements, caudate atrophy • Usually presents between the ages of 20 to 50 • Misc info: • Age of onset is variable but typically the more repeats you have the earlier the onset of the disease

37. Autosomal Dominant Dz’s • Marfan’s Syndrome • Genetics and Cell Level: • Mutation in the fibrillin gene (Chrom 15) • The mutated fibrillin protein has irregular shape and assembles into irregular shaped microfibril in connective tissue • Phenotypic Traits: • Connective tissue disorder affecting skeleton, heart, and eyes • Clinical Presentation: tall with long extremities, pectus excavatum, hyperextensive joints, and long tapering fingers and toes • Misc info: • Cystic medial necrosis of the aorta leads to aortic incompetence and dissecting aortic aneurysms • Floppy mitral valve • Subluxation of lenses

38. Autosomal Dominant Dz’s • Marfan’s Syndrome • Phenotypic Traits: • Connective tissue disorder affecting skeleton, heart, and eyes • Clinical Presentation: tall with long extremities • pectus excavatum • hyperextensive joints • long tapering fingers and toes • Misc info: • Cystic medial necrosis of the aorta leads to aortic incompetence and dissecting aortic aneurysms • Floppy mitral valve • Subluxation of lenses

39. Marfan’s Syndrome

40. Marfanoid Habitus • Marfanoid (or Marfanoid habitus) is a constellation of symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that exceeds the height of the individual, and a crowded oral maxilla, sometimes with a high arch in the palate, arachnodactyly, and hyperlaxity

41. END PART I