Clinical Genetics

Question 1

Genomics definition

Answer 1

study of fxn and interaction of all genes in genome

-Broader than genetics

Question 2

Clinical Genetics definition

Answer 2

direct clinical care of those with genetic disorder

Question 3

Medical Genetics definition

Answer 3

study of genetics of human diseases

Question 4

Dysmorphology

Answer 4

study of abnormal physical development

Question 5

Single Gene disorders

Mendelian conditions

Answer 5

1. Exhibit characteristic patterns of inheritance
   1/500
   Ex: sickle cell, fragile X, achondroplasia, hereditary forms of breast and colon cancer

Question 6

Chromosome disorders

Answer 6

1. excess of deficiency of a chromosome segment or entire chromosome
2. Generally not inherited
3. Mental and physical retardation, unique physical features, congenital anomalies
4. Sex chromosomes: mild developmental and behavioral problems, tall/short stature, infertility
   Ex: trisomy 21- down syndrome

Question 7

Multifactorial disorders

Answer 7

1. Combination of genetic predisposition and environmental factors
2. Do not show a specific inheritance pattern
3. Account for many chronic conditions
   Ex: mental illnesses, asthma, some heart diseases, certain cancers, diabetes
   *may also be in birth defects: cleft lip/palate, clubfoot, congenital heart defects

Question 8

Mitochondrial disorders

Answer 8

1. Rare

2. Transmitted via mothers only

Question 9

Inherited mutations

Answer 9

Germline mutations: present in every cell throughout life

Question 10

De novo mutation

Answer 10

Occurs in fertilized egg; not inherited

Question 11

Acquired mutation

Answer 11

Somatic mutations: occur sometime in person’s life

• Caused by environmental factors (UV radiation), viruses, DNA replication errors
• Can not be passed on to offspring

Question 12

Polymorphism

Answer 12

an allele sequence that occurs in 1% or more of population

Question 13

Rare variant

Answer 13

allele sequence that occurs in <1% of population

Question 14

Types of mutation (3)

Answer 14

1. Point mutation: missense or nonsense
2. Insertion
3. Deletion

Question 15

Mutation effect on protein: loss of fxn

Answer 15

Ex: retinoblastoma (RB1 gene- tumor suppressor, regulates cell cycle)
40%: born with one mutation; acquire second
bilateral, early onset
60% acquire new mutation somatically in both alleles; unilateral, later onset in childhood

Question 16

Mutation effect on protein: gain of fxn

Answer 16

increase in normal fxn of protein
Ex: achondroplasia (FGFR3 gene)
turned on in absence of FGF (positive regulator) –> cartilage cells always inhibited

Question 17

Mutation effect on protein: dominant negative

Answer 17

A mutation in one allele disrupts or antagonizes the fxn or product of another allele (usually related to structural proteins)
Ex: osteogeneis imperfecta (fragile bones)
-results from defective product of type 1 collagen fiber chains –> impartial heterotrimers or decrease in collagen amt
Ex: Ehlers Danlos syndrome

Question 18

Clinical Heterogeneity

Answer 18

mutations in the same gene cause different phenotypes/ disease
Ex: mutations in RET gene can cause MEN2B or Hirschsprung

Question 19

Genetic Heterogeneity

Answer 19

1. Allelic: different mutations/ alleles cause similar phenotype
   - Ex: Cystic fibrosis
2. Locus: different loci (diff genes) cause similar phenotype
   - Ex: retinitis pigmentosa

Question 20

Phenocopy

Answer 20

Environmentally induced phenotype that mimics a phenotype produced by a specific genotype
Ex: 22q11 deletion/ DiGeorge syndrome
Retinoic acid embryopathy

Question 21

Teratogens

Answer 21

agent that crosses the placental barrier and induces structural malformations, growth deficiency, and/or fxnal alterations during prenatal development
1. Prescription drugs (thalidomide, dilantin)
2. Illicit substances
3. Chemical and physical agents (fetal alcohol syndrome)
4. Maternal metabolic/genetic factors –> maternal diabetes
5. Infectious agents
EX: retinoic acid embryopathy

Question 22

Pleiotropy

Answer 22

multiple phenotypic effects of a single gene
Ex: Stickler syndrome (collagen 2A1 mut)
-eye: myopia (nearsight), retinal detachment
-ear: deafness
-mouth: cleft palate
-midface hypoplasia
-skeletal dysplasia

Question 23

Malformation

Answer 23

A primary morphologic defect of an organ or body part due to abnormal development (intrinsic to embryo)

• Major: requires medical attention, interferes with normal fxn
• Minor: no serious health problem

Question 24

Dysplasia

Answer 24

Primary defect involving abnormal organization of cells onto tissue (intrinsic)
Ex: Hemangioma (abnormal build up of blood vesels on skin or internal organs)
Ex: ectodermal: improper tooth and fingernail development, thin hair

Question 25

Deformation

Answer 25

Alteration in form, shape or position of a body part by mechanical forces (usually occurs during fetal period) extrinsic
Ex: Changes in case of oligohydramnios, joint constrictures, akinesia, pterygium (connective tissue preventing movement)

Question 26

Disruption

Answer 26

morphological defect of an organ due to an extrinsic breakdown of a normally developmental process (extrinsic)
Ex: Amniotic banding: vascular event causing a limb defect –> amputation (secondary)

Question 27

Syndrome

Answer 27

pattern of multiple primary malformations caused by a single etiology
Ex: Down syndrome

Question 28

Association

Answer 28

Grouping of congenital abnormalities found together more often than expected by chance with NO COMMON etiology
Ex: VACTERL- vertebral defects, anal atresia, CV abnormalities, tracheo-esophageal fistula, esophageal atresia, renal/radial abnormalities, limb defects

Question 29

Sequence

Answer 29

A primary defect with its secondary structural changes
Ex: Pierre Robin sequence: poor mandibular development –> small jaw –> glossoptosis (posterior tongue displacement –> inhibit palate closure –> cleft palate

Question 30

Genetic counseling

Answer 30

Address human problems associated with occurrence or risk of occurrence of a genetic disorder

• ACCURATE DIAGNOSIS*
• Medical facts (diagnosis, probable course, management)
• Inheritance pattern (risk of recurrence in other family members)
• Emotional support (family goals, ethical, religious standards)