2: Introduction To Clinical Genetics

Question 1

Chromosomal Disorders (definition)

Answer 1

Problems with number or structure of chromosomes:

Alterations-too many genes, too few genes, altered genes

Polyploidy and Aneuploidy

Insertions, Deletions, Translocations

Question 2

Single Gene Disorders (definition)

Answer 2

Loss (typical), gain or alteration of the protein

Mendelian inheritance: autosomal (#’d chromosomes) disorders and sex-linked disorders.

Question 3

Mitochondrial Disorders (definition)

Answer 3

Non-Mendelian Disorders

• Maternal inheritance for mutations in mitochondrial DNA
• Mendelian inheritance for mitochondrial genes on nuclear DNA

Question 4

Multifactorial Disorders (definition)

Answer 4

Combination of both genes and environment:

• Polygenic: many genes working together
• Teratogenic: mostly environment induced
• Multifactorial: both genetic and environmental

Question 5

Inheritance Patterns (tools for genetic diagnosis)

Answer 5

Construct Pedigree

Autosomal dominant/recessive, X-linked recessive, X-linked dominant (uncommon)

Question 6

Autosomal Dominant Pedigree

Answer 6

Father to son is helpful

Equal number of males:females

Does not skip generations

Question 7

Chromosome Analysis (tools for genetic diagnosis)

Answer 7

Karyotype

FISH

CGH

Exome and Whole Genome Sequencing

Question 8

Karyotype

Answer 8

Alterations in number, large duplications/deletions, translocations

Question 9

Down Syndrome

Answer 9

47 (chromosome), XX, +21 (extra chromosome)

Aneuploidy= abnormal number of chromosomes

Dosage is 3

*CAN USE KARYOTYPE

Question 10

FISH

Answer 10

Detects small deletions (fluorescent in-situ hybridization)

Use probe for area of interest and a control probe

Will see small deletion

Question 11

Williams Syndrome

Answer 11

Elastin gene on Chromosome 7

Triangular face, small jaw, etc.

*CAN USE FISH OR CGH

Question 12

Comparative Genomic Hybridization (CGH)

Answer 12

Deletions/Duplications

Can use over whole genome

Take patient (green color) and control (red color) DNA and mix them

Red: deletion
Green: duplication
Yellow: normal

Question 13

Exome (coding) and Whole Genome Sequencing Problems (tools for genetic diagnosis)

Answer 13

We are all carriers for many diseases

Detect diseases with future consequences

Sequence variation with unknown clinical significance

Question 14

Biochemical Tests (tools for genetic diagnosis)

Answer 14

Look for abnormal products of metabolism or proteins

• Gas liquid chromatography
• Enzyme assays
• Newborn screening

Question 15

Phenylketonuria (PKU)

Answer 15

Loss of phenylalanine hydroxylase (PAH) activity

Too much phenylalanine (TOXIC)

Diet: avoid high amounts of protein

Question 16

DNA Diagnostics (tools for genetic diagnosis)

Answer 16

Direct mutation analysis (DNA sequencing + small DNA probes that hybridize to mutated DNA)

Linkage analysis (not used much anymore)

DNA fingerprinting (variation of sequence analysis to identify individuals: CSI + Paternity)

Question 17

Non-Mendelian Inheritance (types)

Answer 17

Mosaicism 
Mitochondrial Inheritance
Genetic Imprinting
Uniparental disomy (both chromosomes of a pair come from one parent) 
Unstable triplet repeat mutations

Question 18

Mosaicism

Answer 18

More than one genotype in a person

Question 19

Genetic Imprinting

Answer 19

Parent-of-origin difference in gene expression

One of the parental genes is epigenetically silenced

Question 20

Presymptomatic Testing

Answer 20

Test for genetic mutation that will certainly cause disease later in life

“Family member has one and you want to know”

Looking for fully penetrant genes (have gene and will develop disorder)= definite answer

Ex. muscular dystrophy, CF, Huntington disease, familial adenomatous colon cancer

Offered: to children if medical benefit, to adults but informed consent (affect insurance)

Question 21

Predisposition Testing

Answer 21

Test for genetic mutation which will possibly cause a disease later in life

“For ladies worried about breast cancer”

Problematic predictions, incompletely penetrant genes

Question 22

Genetic Counseling Risk

Answer 22

Detection of false paternity

Stigma, including survivor guilt

Loss of employment or insurance

Psychological harm