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

DNA to proteins

Enzymes

Signaling

Structure

Progeny

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)

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

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.

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.

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

Imprinting

Prader-Willi: Deletion of normally active PATERNAL allele

Mental retardation

Obesity

hypogonadism

Hypotonia

At birth usually demonstrates "floppy baby" with "undescended testicles"

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

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 was

noted 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 long

head (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.

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

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!

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!

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)

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.

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

Modes of Inheritance

Mitochondrial: Transmission ONLY through the mother. All offspring of affected mothers are affected.

Variable expression due to heteroplasmy

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.

Which of the following is the most likely

explanation for the findings in this patient?

A. Chromosomal translocation

B. Lyonization

C. Nondisjunction

D. Chromosomal trisomy

E. Chromosomal Monosomy

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

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

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.

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

Autosomal Dominant Dz’s Familial Adenomatous Polyposis

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

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

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-cm

malignant lesion in his sigmoid colon.

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

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

Microsatellites

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

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

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

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

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

Marfan’s Syndrome

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

END PART I