B3.069 Congenital Disorders and Genetic Testing

Question 1

3 types of genetic disorders

Answer 1

single gene disorders
chromosomal disorders
multifactorial inheritance

Question 2

examples of single gene disorders

Answer 2

sickle cell anemia

CF

Question 3

example of multifactorial inheritance

Answer 3

spina bifida

diabetes mellitus

Question 4

congenital anomalies

Answer 4

broad term for birth abnormalities

Question 5

malformation

Answer 5

multiple defects from a single abnormal embryologic event

Question 6

example of malformation

Answer 6

DiGeorge syndrome

incomplete migration of 3rd and 4th pharyngeal arch leads to thymic hypoplasia, cleft palate

Question 7

deformation

Answer 7

abnormality from intrauterine mechanical forces

Question 8

example of deformation

Answer 8

oligohydramnios, limited fluid in womb can lead to club foot, crumpled ears

Question 9

disruption

Answer 9

abnormalities resulting from changes in the intrauterine environment

Question 10

example of disruption

Answer 10

amniotic band sequence

amniotic rupture results in tendons to amputations of extremities

Question 11

loss of function mutation

Answer 11

usually autosomal recessive of X-linked

loss of activity of protein

Question 12

gain of function mutation

Answer 12

overexpression or new function of protein

usually autosomal dominant

Question 13

examples gain of function mutation disease

Answer 13

Charcot- Marie-Tooth

achrondroplasia

Question 14

de novo mutation

Answer 14

new mutation not present in parents

accounts for significant genetic diseases

Question 15

describe features of X linked inheritance

Answer 15

male dominant disease
unaffected ort mildly affected females
carrier status for 50% female progeny

Question 16

describe the features of X-linked adrenoleukodystrophy

Answer 16

1/17,000
accumulation of very long chain fatty acids (VLCFA)
defect in ABCD1 on Xp28
adrenal dysfunction
neurologic symptoms such as seizures predict prognosis

Question 17

treatment of X-linked adrenoleukodystrophy

Answer 17

bone marrow transplantation
Lorenzo’s Oil
-binds enzymes where VLCFA typically bind and clear them

Question 18

describe features mitochondrial inheritance

Answer 18

maternal inheritance
all maternal offspring affected
impaired energy metabolism
liver, brain, muscle and heart

Question 19

examples of mitochondrial diseases

Answer 19

MERRF

Kearns-Sayre Syndrome

Question 20

describe genetic imprinting inheritance

Answer 20

some genes deactivated by methylation (epigenetics)

equal female and male offspring affected

Question 21

Prader-Willi Syndrome

Answer 21

paternal 15q13.3
maternal silence
obesity, short stature, hypogonadism, mental retardation, birth hypotonia

Question 22

Angelman Syndrome

Answer 22

maternal 15q13.3
paternal silence
ataxia, epilepsy, uncontrolled laughter, mental retardation

Question 23

what is a syndrome?

Answer 23

multiple, anatomically unrelated defects from a common cause

some defects may not be obvious so screening may be needed

Question 24

disorders associated with trisomy 21/ downs syndrome

Answer 24

AV canal defect and other heart defects
duodenal atresia
hirschsprung disease
atlantoaxial instability
obstructive sleep apnea
early alzheimers
vision difficulties
hypothyroidism
leukemia

Question 25

surveillance recommendations for downs syndrome patients

Answer 25

``` hearing every 6 mo until 5 yo optho every 2 years after 6 mo birth, yearly TSH CBC every 3 mo until 3 yo, then every 6 mo until 6 yo celiac at 1 yo echo at birth sleep study before 4 yo ```

Question 26

what is an association

Answer 26

pattern of defect without a known genetic or environmental cause some defects may not be obvious so screening may be needed

Question 27

VACTERL

Answer 27

``` association vertebral anomalies anal atresia trachea-esophageal fistula renal abnormalities limb anomalies ```

Question 28

what is a sequence

Answer 28

one anomaly leads to other defect

Question 29

example of a sequence

Answer 29

Pierre Robin Sequence- micrognathia (small jaw) changes tongue position causing airway obstruction and cleft palate

Question 30

what are some important things to keep in mind when initiating genetic testing?

Answer 30

follow index of suspicion sequential consider costs aggregate outside evaluation

Question 31

types of genetic testing

Answer 31

single gene analysis genotyping gene panel genome sequencing microarrays/ comparative genomic hybridization Fluorescence in-situ hybridization (FISH) high-resolution chromosome analysis

Question 32

single gene analysis

Answer 32

various mutations of gene coding regions -specific mutation (factor 5 leiden) -panel of common variants (CFTR, CF) usually by PCR

Question 33

what can high resolution chromosome analysis detect

Answer 33

chromosome abnormalities 1-2% live births, 50% early fetal losses identify unisomy, trisomy, and translocations identifies large deletions, translocations, nondisjunction on all or part of the chromosome deletions > 5,000

Question 34

how is high resolution chromosome analysis done

Answer 34

pre-natal: amniotic fluid, chorionic villus tissue | post-natal: peripheral lymphocytes, sometimes fibroblasts

Question 35

describe the process of comparative genomic hybridization

Answer 35

bind patient DNA (green) and reference DNA (red) to microarray grid patient DNA amplification appears green absence of patient DNA is red equal patient and reference DNA is yellow examine multiple gene and genetic regions simultaneously

Question 36

describe FISH

Answer 36

``` higher resolution than chromosome analysis use fluorescent tagged sequence/ probe -control probe -identification probe detect 50-200 kb deletion limited to one disease ```

Question 37

candidate diseases for newborn screen have:

Answer 37

1. significant morbidity and mortality 2. improved outcomes with early treatment 3. available testing

Question 38

how do newborn screenings work

Answer 38

obtained at 24 h of life available in 7-10 days sensitive but not specific, require follow up testing

Question 39

top 5 abnormalities for newborn screening

Answer 39

1. hearing loss 2. hypothyroidism 3. cystic fibrosis 4. sickle cell disease 5. medium change acyl-CoA dehydrogenase deficiency

Question 40

technologies for newborn screening

Answer 40

Guthrie test radioimmunoassay for thyroxine liquid chromatography for hemoglobinopathies tandem mass spectrometry for inborn errors of metabolism (organic acids, amino acids, fatty acids, and lysosomal storage disorders)

Question 41

commonly screened diseases in newborns

Answer 41

``` congenital hypothyroidism congenital adrenal hyperplasia hemoglobinopathies (sickle cell disease) cystic fibrosis galactosemia SCID PKU maple syrup disease cyanotic heart disease ```

Question 42

challenges/concerns with newborn screening

Answer 42

residual blood specimens role of late onset disease carrier mutation

Question 43

indications for genetic counseling

Answer 43

``` advanced parental age previous child with fam history of issues adult onset disease consanguinity teratogen repeated pregnancy loss of infertility abnormal pregnancy screen heterozygote screening by ethnic risk ```