B3.069 Congenital Disorders and Genetic Testing Flashcards
3 types of genetic disorders
single gene disorders
chromosomal disorders
multifactorial inheritance
examples of single gene disorders
sickle cell anemia
CF
example of multifactorial inheritance
spina bifida
diabetes mellitus
congenital anomalies
broad term for birth abnormalities
malformation
multiple defects from a single abnormal embryologic event
example of malformation
DiGeorge syndrome
incomplete migration of 3rd and 4th pharyngeal arch leads to thymic hypoplasia, cleft palate
deformation
abnormality from intrauterine mechanical forces
example of deformation
oligohydramnios, limited fluid in womb can lead to club foot, crumpled ears
disruption
abnormalities resulting from changes in the intrauterine environment
example of disruption
amniotic band sequence
amniotic rupture results in tendons to amputations of extremities
loss of function mutation
usually autosomal recessive of X-linked
loss of activity of protein
gain of function mutation
overexpression or new function of protein
usually autosomal dominant
examples gain of function mutation disease
Charcot- Marie-Tooth
achrondroplasia
de novo mutation
new mutation not present in parents
accounts for significant genetic diseases
describe features of X linked inheritance
male dominant disease
unaffected ort mildly affected females
carrier status for 50% female progeny
describe the features of X-linked adrenoleukodystrophy
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
treatment of X-linked adrenoleukodystrophy
bone marrow transplantation
Lorenzo’s Oil
-binds enzymes where VLCFA typically bind and clear them
describe features mitochondrial inheritance
maternal inheritance
all maternal offspring affected
impaired energy metabolism
liver, brain, muscle and heart
examples of mitochondrial diseases
MERRF
Kearns-Sayre Syndrome
describe genetic imprinting inheritance
some genes deactivated by methylation (epigenetics)
equal female and male offspring affected
Prader-Willi Syndrome
paternal 15q13.3
maternal silence
obesity, short stature, hypogonadism, mental retardation, birth hypotonia
Angelman Syndrome
maternal 15q13.3
paternal silence
ataxia, epilepsy, uncontrolled laughter, mental retardation
what is a syndrome?
multiple, anatomically unrelated defects from a common cause
some defects may not be obvious so screening may be needed
disorders associated with trisomy 21/ downs syndrome
AV canal defect and other heart defects duodenal atresia hirschsprung disease atlantoaxial instability obstructive sleep apnea early alzheimers vision difficulties hypothyroidism leukemia
surveillance recommendations for downs syndrome patients
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
what is an association
pattern of defect without a known genetic or environmental cause
some defects may not be obvious so screening may be needed
VACTERL
association vertebral anomalies anal atresia trachea-esophageal fistula renal abnormalities limb anomalies
what is a sequence
one anomaly leads to other defect
example of a sequence
Pierre Robin Sequence- micrognathia (small jaw) changes tongue position causing airway obstruction and cleft palate
what are some important things to keep in mind when initiating genetic testing?
follow index of suspicion
sequential
consider costs
aggregate outside evaluation
types of genetic testing
single gene analysis
genotyping
gene panel
genome sequencing
microarrays/ comparative genomic hybridization
Fluorescence in-situ hybridization (FISH)
high-resolution chromosome analysis
single gene analysis
various mutations of gene coding regions
-specific mutation (factor 5 leiden)
-panel of common variants (CFTR, CF)
usually by PCR
what can high resolution chromosome analysis detect
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
how is high resolution chromosome analysis done
pre-natal: amniotic fluid, chorionic villus tissue
post-natal: peripheral lymphocytes, sometimes fibroblasts
describe the process of comparative genomic hybridization
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
describe FISH
higher resolution than chromosome analysis use fluorescent tagged sequence/ probe -control probe -identification probe detect 50-200 kb deletion limited to one disease
candidate diseases for newborn screen have:
- significant morbidity and mortality
- improved outcomes with early treatment
- available testing
how do newborn screenings work
obtained at 24 h of life
available in 7-10 days
sensitive but not specific, require follow up testing
top 5 abnormalities for newborn screening
- hearing loss
- hypothyroidism
- cystic fibrosis
- sickle cell disease
- medium change acyl-CoA dehydrogenase deficiency
technologies for newborn screening
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)
commonly screened diseases in newborns
congenital hypothyroidism congenital adrenal hyperplasia hemoglobinopathies (sickle cell disease) cystic fibrosis galactosemia SCID PKU maple syrup disease cyanotic heart disease
challenges/concerns with newborn screening
residual blood specimens
role of late onset disease
carrier mutation
indications for genetic counseling
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
