Medical genetics

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Medical genetics
Dr. Lina Basel Schneider Childrens Medical
Center of Israel
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Benefits of genetic evaluation
1. What is the problem 2. Why did it happen 3.
What will it mean for our baby 4. Will it happen
again
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Benefits of genetic evaluation
Reproductive counseling carrier testing,
prenatal diagnosis Presymptomatic screening for
associated complications Referral to support
groups
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How do you make a syndrome diagnosis?
History Examination Investigations
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• Family history
• Any relative with mental retardation or known
  malformations
• Neonatal deaths, stillbirths or childhood deaths
  
• Familial disorders or physical features
• Consanguinity in parents
• Ethnic background
• Prior genetic testing or screening

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History
Family history pedigree what is the mode of
inheritance? - AR, AD, XL, Y-linked,
mitochondrial, trinucleotide repeat expansion
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History
Maternal health, vitamin supplements and drug
use hydantoin
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History
Maternal health, vitamin supplements and drug
use valproic acid
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History
Maternal health, vitamin supplements and drug
use alcohol
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History
Pregnancy investigations NT US Biochemical
screening Amniocentesis Fetal MRI
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Physical examination
Height plot on appropriate growth chart
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Physical examination
Proportions U/L segment Arm span Hand length
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Physical examination
Posture and tone trisomy 18 PWS
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Physical examination
Facial expression Angelman syndrome
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Physical examination
Movements and behavior Rett syndrome
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Physical examination
Characteristic personality Williams syndrome
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Molecular tests (sequencing, specific mutation
testing)
CHG arrays, SNP arrays, MLPA
Karyotype, FISH, low-resolution CGH
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Chromosomal tests
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Chromosomal structure
Subtelomeric regions
Subtelomeric regions
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Cytogenetic tests - karyotype
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Cytogenetic tests - karyotype

• Indications
• Mental retardation
• Dysmorphic features
• Major anomaly
• Recurrent spontaneous abortions
• Family history of multiple affected individuals
  with MR/malformations

5-10 Mb resolution (300-600 cytogenetic bands)
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ECARUCA
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Cytogenetic tests high resolution karyotype
Indications High suspicion of chromosomal anomaly
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Microdeletions and microduplications
DiGeorge/VCFS
Williams
Smith-Magenis
Miller-Dieker lissencephaly
Rubinstein-Taybi
Wolf-Hirshhorn
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Cytogenetic tests FISH (Fluorescent in situ
hybridization)
Fluorescence in situ hybridization (FISH) Need
to suspect a specific diagnosis!
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Cytogenetic tests FISH
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Cytogenetic tests FISH

• Indications
• Detects specific microdeletions/microduplications
  
• Quick test for detection of abnormal chromosome
  number (pregnancy)

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Di George/VCFS
Aortic arch abnormalities Hypocalcemia Cleft
palate Immunodeficiency Developmental
delay Psychiatric disorders
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Williams syndrome
Characteristic facies Supravalvular AS
Hypercalcemia Microcephaly Kidney
abnormalities Musculoskeletal problems Developmen
tal delay
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Prader Willi/Angelman syndrome
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Cytogenetic tests subtelomeric FISH
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Cytogenetic tests subtelomeric FISH
Indications Mental retardation/dysmorphic
features/congenital anomalies Familial cases
(especially if variable clinical
features Detects deletions/duplications of the
subtelomeric regions
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Cytogenetic tests subtelomeric FISH
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SKY spectral karyotyping
Indications Unidentified chromosomal
marker Multiple chromosomal translocations
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Molecular cytogenetic techniques
Array CGH SNP array
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Molecular cytogenetic techniques
Array CGH
Genomic rearrangements detectable by array
CGH 10-15 in patients with syndromic
MR Depends on the stringency of the clinical
criteria
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Array CGH resolution
Various levels of resolution the higher the
resolution, the higher the detection rate

• Targeted array
• 1 Mb resolution (aCGH with 3,000-3,500 BAC
  clones)
• 10-100 kb resolution (aCGH with 32,447
  BACs/oligos)
• Exon aCGH (all 250,000 exons in human genome)

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Array CGH
Indications Mental retardation/dysmorphic
features/congenital anomalies Detection of
microdeletions, microduplications No need for
specific diagnosis
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Copy number variants (CNVs)
How much copy number variations (CNVs) exist?
What is the contribution of copy number
variation to genetic disease?
What role has copy number variation played in
recent human evolution?
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SNP array
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SNP array
Density 10K, 50/100K, 500K
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DNA tests
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DNA tests

• Direct mutation analysis
• DNA sequencing
• Specific mutation analysis
• Deletion analysis
• Linkage analysis
• utilization of traceable gene markers next
  to the gene of interest

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Testing for the specific mutation
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Sequencing
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Deletion testing MLPA (Multiplex
Ligation-dependent Probe Amplification )
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Southern blotting
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Linkage analysis

• Looks for pattern of DNA markers near gene of
  interest that segregate with disease
• Requires DNA analysis of multiple family members

1, 2
3, 4
1, 3
1, 4
2, 3
2, 4
1 2 3 4
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X inactivation
0/100
50/50
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Genetic testing in the fetus
The parent is at 50 risk and is not showing
symptoms. In this case, to find that the fetus
carries the gene for Huntington's disease
automatically reveals that the parent is a
gene-carrier as well
Non-disclosing prenatal testing
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Non-disclosing prenatal testing
Ill grandparent
parent
fetus
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How do we diagnose children with heterogeneic
conditions?
Sequencing of all the genes laborious
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MR etiology
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Resequencing microarray
Recently, a resequencing microarray has been
developed for XLMR genes On this chip 17 XLMR
genes are represented, including frequently
mutated genes such as ARX, JARID1C and
PQBP1 Together they account for approximately
40 of all mutations in MR genes on the X
chromosome
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Genetic testing
Identification of molecular defect in the
affected individual
Research lab - no costs - might take a long
time - need to confirm the test in the clinical
lab
Clinical lab - usually quick/reliable - expensive
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Attitude of different populations towards
prenatal testing
Non religious Jews prenatal testing by CVS or
amniocentesis (pregnancy interruption possible up
to birth, even at 40 weeks of pregnancy)
preimplantation genetic diagnosis Orthodox
Jews preimplantation genetic diagnosis
(pregnancy interruption possible up to 40 days
only no prenatal testing possible) Muslim
Arabs prenatal testing by CVS or amniocentesis
(pregnancy interruption possible up to 120 days
of pregnancy) preimplantation genetic diagnosis
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Prenatal testing
If mutation in the affected individual found
molecular testing of the fetus by CVS or
amniocenthesis Or Preimplantation genetic
diagnosis (PGD) If gene unknown for X-linked
diseases fetal sexing