1 Genomic Technologies & Syndrome Recognition By Samantha Leib, MD, FAAP Pediatrician Department of Genetics and Genomic Medicine Saint Peter’s University Hospital Objectives • Understand the benefits and limitations of commercially-available genetic testing • Recognize presenting features of common genetic syndromes • Improve comfort level managing and monitoring patients with genetic conditions in the primary care setting Understanding the Basics
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1
Genomic Technologies
&
Syndrome Recognition
By Samantha Leib, MD, FAAP
Pediatrician
Department of Genetics and Genomic Medicine
Saint Peter’s University Hospital
Objectives
• Understand the benefits and limitations of
commercially-available genetic testing
• Recognize presenting features of common
genetic syndromes
• Improve comfort level managing and
monitoring patients with genetic conditions
in the primary care setting
Understanding the Basics
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Genomic Technologies
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Reasons to Diagnose
• Comprehensive information regarding the diagnosis or probable diagnosis
• Medical management
• Anticipatory guidance and surveillance
• Risk and recurrence assessments for the patient and other family members
Prenatal Screening
Non-invasive Prenatal Testing (NIPT)
• The use of NIPT to screen for the presence of fetal
aneuploidy became feasible with the development of
massive parallel sequencing (MPS) and counting of
cfDNA fragments.
• Most current tests for this purpose use whole
genome MPS in order to quantitatively compare the
amount of, for example, chromosome 21 DNA
molecules in a maternal sample with that of an
euploid reference sample.
• Other tests use targeted sequencing, mapping only
the chromosome regions of interest, or use a
qualitative SNP-based approach.
What is NIPT?
• Non-invasive prenatal testing
• Cell-free fetal DNA (cffDNA)
• Fetal DNA that circulates
freely in the mother’s
bloodstream (2-6% of total)
• Originates from apoptosis
of trophoblasts that make
up the placenta due to
maternal immune system
interaction
• cffDNA is significantly smaller
than maternal DNA and can
be distinguished by size
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How does it actually work?
• Maternal blood sample
obtained
• PCR to replicate DNA to
analyze
• Massively parallel
sequencing (next-
generation sequencing)
• Amount of fetal DNA
compared with
reference DNA with
expected amount
Common Screens
MaterniT21 Plus:
Trisomy 21
Trisomy 18
Trisomy 13
Sex chromosome aneuploidy
22q deletion syndrome (DiGeorge)
5p (Cri-du-chat syndrome)
15q (Prader-Willi/Angelman
syndromes)
1p36 deletion syndrome
4p (Wolf-Hirschhorn syndrome)
8q (Langer-Giedion syndrome)
11q (Jacobsen syndrome)
Trisomy 16
Trisomy 22
Harmony Screens for:
Trisomy 21
Trisomy 18
Trisomy 13
Sex chromosome aneuploidy
Screening Limitations
• These screening tools do not provide a definitive
genetics risk in all individuals.
• Cell-free fetal DNA does not replace the accuracy
and precision of prenatal diagnosis with CVS or
amniocentesis.
• A patient with a positive test result should be
referred for genetic counseling and offered invasive
prenatal testing for confirmatory diagnosis.
• A negative test result does not ensure an
unaffected pregnancy.
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Average Cost
1. Karyotype: $600
2. Microarray: $750 - $2,500
3. NIPT: $100 - $400
4. Gene panels: $1,000 - $3,000
5. Whole exome: $2,500 - $5,000
Syndrome Recognition
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Williams SyndromeFacts:
• Affects an estimated 1 in 7,500 to 10,000 people
• Occurs equally in both males and females
• Autosomal dominant condition
• Majority are de novo deletions
• Caused by a deletion from a specific region on chromosome 7
Distinctive Facies:
Clinical Features
• Broad forehead, bitemporal
narrowing, periorbital fullness
• A stellate/lacy iris pattern, strabismus,
short nose with a broad nasal tip,
malar flattening
• Long philtrum, wide mouth with full
lips, malocclusion, micrognathia, and
large ear lobes (seen at all ages)
• Young children have epicanthal folds,
full cheeks, and widely spaced teeth
• Adults have long face and neck, resulting in a gaunt appearance
Clinical Features
Unique Personality:
• Overfriendliness
• Empathy
• Generalized anxiety
• Specific phobias
• ADHD
Intellect/Cognitive Profile:
• Developmental delays
• Strengths in verbal short-term memory and
language (affinity towards music)
• Weakness in visuospatial construction
• Most have some degree of intellectual disability
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Clinical Features
Cardiovascular disease:
• Any artery may be narrowed (elastin arteriopathy)
• Most commonly supravalvar aortic stenosis (75%)
• Peripheral pulmonic stenosis common in infancy
(PPS)
Connective Tissue Abnormalities:
• Joint limitation or laxity
• Hernias
• Soft/lax skin
• Rectal prolapse
Clinical Features
Growth Abnormalities:
• FTT in infancy
• Short stature
Endocrine Abnormalities:
• Hypercalcemia
• Hypothyroidism
• Early puberty
• DM
Yearly SurveillanceInterval/Age Test/Measurement
InfancySerum calcium determination every
4-6 months until age 2 years
Annual
•Medical evaluation
•Vision screening to monitor for
refractive errors and strabismus
•Hearing evaluation
•Monitoring of blood pressure in both arms
•Measurement of calcium/creatinine
ratio in a random spot urine and
urinalysis
•Cardiology evaluation at least yearly for the first 5 years, every 2-3