human genetics sagi josefsberg, md clinical genetics institue kaplan medical center
TRANSCRIPT
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Human Genetics
Sagi Josefsberg, MD
Clinical Genetics Institue
Kaplan Medical Center
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Techniques
• Cytogenetics• Molecular
biology• Biochemical
analysis
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Old and new cytogenetics
CytogenticsMolecular cytogenetics FISH
M-FISH/SKYCGHArray CGH
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Preparation of a karyotype.
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G-banded metaphase spread
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normal male karyotype
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FISH
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From chromosomes to DNA
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Fluorescence in situ hybridization
A DNA probe finding its target “in place”
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Unique Sequence Probes
Metaphase & interphaseRefined region specific detectionChromosome enumeration
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DiGeorge/VCFS
Clinical: cardiac, facial and immune anomalies
Cytogenetics: 46, XX del(22q11.2)
Frequency: 1/4,000
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Whole chromosome paints
Metaphase studiesChromosome identificationMarker analysis
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Chromosome painting showing two normal number 17 chromosomes and a small ring 17 chromosome (arrowed)
CMA comparative microarray analysis
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DNA Arrays
CMA Comparative Microarray Analysis
CGH Comparative Genomic Hybridization
Genetic ChipaCGH Array CGH
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CGH ratio profiles for the CGH analysis shown. The vertical lines adjacent to each chromosome show fluorescence ratios of 0.5 to 1.5 between test and control DNA .
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Conventional CGH
Label patient DNA with Cy3
Label control DNA with Cy5
Mix
Label patient DNA with Cy5
Label control DNA with Cy3
Mix
Hybridize DNA to genomic clone microarray
Analyze Cy3/ Cy5 fluorescence ratio of patient to control
Cy3/ Cy5 ratio >1 Duplication
Cy3/ Cy5 ratio <1 Deletion
Cy3/ Cy5 ratio >1 Deletion
Cy3/ Cy5 ratio <1 Duplication
Label patient DNA with Cy3
Label control DNA with Cy5
Mix
Cy3/ Cy5 ratio >1 Duplication
Cy3/ Cy5 ratio <1 Deletion
Array CGH ( aCGH )
CMA Methodology
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Array CGH
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CMA Technology
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aCGH examples
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Trisomy 21 (Down syndrome)
Karyotype X
20
2221
GainLoss
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DIGEORGE SYNDROME/VCFS
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GainLoss
FISH
Deletion chromosome 1p (short arm)
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Normal chromosome 6
Partial duplication of chromosome 6
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About resolutionChromosome G banding 5
– 10MbArray CGH 1kb – 1Mb*
*The resolution of the array is limited only by the size of the cloned DNA target and the distance between these sequences located on the chromosome
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הכרומוזומים
זוגות+זוג כ.המין )46XY ) 22לזכר • ( " " " " )46XXלנקבה •
החומר הגנטי DNA –RNA—PROTEIN ( חלבון )•
.החלבון = התוצר הסופי המתפקד•
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DNA
RNA
PROTEIN
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מהילודים סובלים ממחלה 2%-3%•בה יש משמעות חשובה שלמרכיב הגנטי
)Genetic Factor Play an Important role.(
מתמותת 50%מחלות גנטיות אחראיות ל- •)).Childhood Deathsילדים
30%מחלות גנטיות אחראיות לעד •מהאשפוזים בילדות.
מהאוכלוסייה סובלת 5% 25עד גיל •ממחלה שלמרכיב הגנטי בה משמעות
.חשובה
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20,000-25,000בגנום ההומני קיימים בין •.גנים
כרומוזומים ועל כל אחד 46לאדם הבריא •מהכרומוזומים הללו יושבים אלפי גנים.
במידה ויש בעיה במספר הכרומוזומים •או במבנה הכרומוזומים או במבנה הגן
. למחלההתקין, הדבר גורם
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Chromosomal abnormalities
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Down Syndrome
47,XY,+21
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Down - Trisomy 21
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תסמונת דאון
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Common findings in Down syndrome
• Newborn period Hypotonia, sleepy, excess nuchal skin• Craniofacial Brachycephaly, epicanthic folds, protruding tongue,
small ears, upward sloping palpebral fissures• Limbs Single palmar crease, small middle phalanx of fifth finger,
wide gap between first and second toes• Cardiac Atrial and ventricular septal defect, common
atrioventricular canal, patent ductus arteriosus• Other Anal atresia, duodenal atresia, Hirschsprung disease, short
stature, strabismus
• IQ 25-75• Happy and affectionate• Short stature• Alzheimer disease
• 1/600-700
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13,18טריזומיה
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18טריזומיה
מבנה כף היד
Clenched
כף יד =.קפוצה
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• גפיים תחתונות בתינוק עם
13טריזומיה
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Sex Chromosomal abnormalities
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Turner Syndrome
45,X0
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נערה עם טרנר ואחותה
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Turner 45X0
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Turner Syndrome
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Clinical Findings in Turner Syndrome and Their Incidence
Finding Approximate Incidence(%)Short stature 100Short neck 40Scoliosis 35Characteristic facial features 35Webbed neck 25Low posterior hairline 42Edema of hands/feet 22Ovarian failure 95Infertility 99Moles 25Heart abnormalities 55Kidney abnormalities 39Thyroid disease 35
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Turner growth chart
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Klinefelter Syndrome
• 47,XXY• 1 in 1000 male live births• Slightly taller• Gynecomastia • Infertile• Clumsiness• Delayed speech• Mild learning difficulties
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Klinefelter Syndrome
• Treatment with testosterone
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המשך – שינויים במבנה הכרומוזומים
Cri du Chat של כרומוזום – דוג' חסר חלקי•Sy 5 ( 5 חסר חלקי של כרומוזוםp.( -
•Wolf-Hirschhorn Sy חסר חלקי של כרומוזום 4 ) 4p .( -
Cat Eye מהכרומוזום – דוג' הכפלה של חלק•Sy 22 ( 22 הכפלה של מקטע מכרומוזוםq11
Duplication(
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חסרים או הכפלות של חלקי כרומוזום קטנים ( תת
מיקרוסקופי ) הדבר מחייב טכניקה מיוחדת שלא נעשית •באופן רוטיני בבדיקת סיסי שליה או מי
שפיר.. FISHבדיקת •
הנובעת מחסר VCF SY לדוג' תסמונת .22q11.2 Delחלקי תת-מיקרוסקופי של
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חסר חלקי תת
מיקרוסקופי של כרומוזום
22,q;11.2
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VCF-Velo-Cardio-Facial-Syndrome – DiGeorge Syndrome, 22q11.2 del
מומים בחייך, אף בולט בולבוסי•)Conu-Truncalמומי לב (בעיקר •מבנה פנים אופיני•מבנה אצבעות מאורך וצר•הפרעות בשמיעה• hypoparathyrodismהיפוקלצמיה מולדת - ••Hypothyroidism•Thymus Hypoplasiaחסר חיסוני - ADHDהיפוטוניה, אחור התפתחותי, הפרעות בדיבור, •
).15%הפרעות התנהגותיות עד סכיזופרניה (
1:6000-2000שכיחות •
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תינוק עם חסר
חלקי של
כרומוזום 22
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חסר חלקי של
22כרומוזום בילד
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כפות ידיים
בנערה
עם חסר חלקי של
22כרומוזום
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FISH
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Inheritance patterns
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Mendelian Inheritance
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Autosomal recessive
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Family tree of an autosomal recessive trait.
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Autosomal recessive
• many inherited errors of metabolism• enzyme deficiencies manifest only in
homozygotes• heterozygotes have sufficient enzyme
levels • Consanguinity• Recurrence risk for the parents 25%
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Autosomal recessive disorders
• Tay Sachs
• cystic fibrosis
• Gaucher
• Canavan
• Bloom
• Fanconi
• Thalassemia a & b
• Familial
dysautonomia
• FMF
• Niemann-Pick
• phenylketonuria
(PKU)
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בדיקות סקר גנטיותבדיקות סקר גנטי הן בדיקות דם שמטרתן לאתר
נשאות סמויה של מחלה גנטית באנשים בריאים
שאין במשפחתם חולים במחלה גנטית זו.
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המשךבדיקות סקר גנטיות - איגוד הגנטיקאים הגדיר את הסיבות להכללת
בדיקה גנטית כבדיקת סקר באוכלוסיה:
המחלה מוכרת היטב והבסיס הגנטי שלה ידוע באוכלוסיה הנבדקת
שיעור הנשאים של המחלה באוכלוסייה הוא 1:60לפחות
קיימת נגישות גבוהה של האוכלוסייה לביצוע הבדיקה ולייעוץ גנטי
מנשאי 90%הבדיקה מאפשרת גילוי של לפחות המחלה.
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המשךבדיקות סקר גנטיות - בדיקות הסקר חולקו על ידי איגוד הגנטיקאים
לארבע קטגוריות:
בדיקות מומלצות - לכלל האוכלוסייה או לאוכלוסיות בסיכון.
בדיקות שניתן לבצע - מדובר בבדיקות סקר למחלות גנטיות חמורות, ששכיחותן נמוכה מ-
. בקטגוריה זו יש בדיקות סקר גנטיות, 1:60שאין חובה להציע אותן למי שנמנים עם
האוכלוסיות המתאימות, אך יש חובה לידע על קיומן.
בדיקות לא מומלצות.
בדיקות שהכללתן בסקר שנויה עדיין במחלוקת.
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המשךבדיקות סקר גנטיות - בדיקה מוצעות לבני הזוג לפי מוצאם
בדיקות המוצעות לבני רוב העדות: השביר, Xקבוצה זו כוללת את המחלות: תסמונת ה-
SMAציסטיק פיברוזיס ו-
בדיקות המוצעות לבני הזוג ממוצא אשכנזי:טיי-זקס, דיסאוטונומיה משפחתית, מחלת קנוואן.
, מחלת 4 , מוקוליפידוזיס A, מחלת בלום, מחלת נימן פיקCאנמיה ע"ש פנקוני מסוג Usher מחלת1 , מחלת אגירת גליקוגן מסוג ,MSUD , nemaline myopathy
,.MGA 3ליהודים ממוצא עירקי: מחלת קוסטףליהודים ממוצא צפון אפריקאי (במיוחד מרוקו וטוניס): אטקסיה טלנגיאקטזיה, מחלת אגירת
A, מחלת פנקוני 3גליקוגן מסוג ליהודים יוצא בלקן: דיסאוטונומיה משפחתית
.Iומחלת אגירת גליקוגן מסוג ליהודים ממוצא תימני: מחלת פניל קטונוריה
)PKU ומטכרומטיק לאוקודיסטרופי (MLDליהודים ממוצא לובי: מחלת ניוון שרירים מסוג
2B מחלת ,MLC1.
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Autosomal Dominant
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Family tree of an autosomal dominant trait
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Autosomal DominantHeterozygotes are affectedA heterozygote has:
50% affected heterozygote offspring50% unaffected offspring
Some disease manifest:Variable penetranceVariable expression
New mutation vs. affected parent
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Autosomal Dominant disorders
Neurofibromatosis
Marfan
Achondroplasia
Osteogenesis imperfecta
Ehlers-Danlos
Crouzon
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Neurofibromatosis 1 (NF1) is characterized by:
multiple cafeי au lait spots (6),axillary and inguinal freckling,multiple discrete dermal neurofibromas,iris Lisch nodules.Learning disabilities are present in at least 50% of individuals
with NF1. Scoliosis, vertebral dysplasia, pseudarthrosis, and overgrowth
are the most serious bony complications of NF1.Optic gliomaMalignancy
1 of 2500-3300 live births
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Marfan Syndrome• connective-tissue disorder • Caused by mutations in FBN1 gene located on
chromosome 15q21.1 • Skeletal findings:
– Pectus excavatum that requires surgery or pectus carinatum– Positive wrist and thumb signs – Reduced upper-to-lower body segment ratio or arm span–to-
height ratio greater than 1.05 • Aortic root dilatation caused by mutations in FBN1 gene
located on chromosome 15q21.1 • Ectopia lentis•
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X-linked Disorders
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X-linked disordersNo male to male transmission
Male phenotype different / more pronounce then in female
Carrier female - 50% of her boys affected
50% of her girls are carriers
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X-linked disorders• Duchenne muscular dystrophy• X-Linked Mental Retardation• X-linked hydrocephaly• Hemophilia• Color blindness• G6PD deficiency• OTC – Ornithine transcarbamylase
deficiency
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X-linked “recessive” disorders
• X-linked hydrocephaly• Mutation L1CAM• Aqueduct stenosis• Agenesis corpus callosum• Mental retardation• Adducted thumbs
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Boy with Duchenne muscular dystrophy; note the enlarged calves and wasting of the thigh muscles.
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Family tree of Duchenne muscular dystrophy with the disorder being transmitted by carrier females and affecting males who do not survive to transmit the disorder.
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non-Mendelian Inheritance
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Multifactorial
• Polygenic – additive effect of several genes is cumulative
• Common diseases• Interaction genes and environment
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Multifactorial Inheritance
GeneticThreshold
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Multifactorial Inheritance
Factors Increasing Risks to Relatives• close relationship to proband
• high heritability of the disorder
• proband of more rarely affected sex
• severe or early onset disease in proband
• multiple family members affected
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Multifactorial Inheritance
• Asthma• Autism• Diabetes mellitus• Epilepsy• Manic depression• Hypertension• Ischemic heart disease
Cleft lip and palatePyloric stenosis
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(A) Severe and (B) mild forms of cleft lip/palate.
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Mitochondrial Inheritance
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Mitochondrial Genome
• Circular DNA molecule • Contains 16,569 bp• Encodes 13 polypeptides of OXPHOS• Uses a slightly different genetic code• Inherited exclusively from the mother
through oocyte which contains ~ 105 mtDNA molecules
• Mutations affect muscle and nerve more commonly
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Mitochondrial Disease
• Leber's Hereditary Optic Neuropathy (LHON)• Kearns-Sayre chronic progressive external
ophthalmoplegia (CPEO) • Myoclonic epilepsy with ragged red fibers
(MERRF), • Mitochondrial myopathy, encephalopathy, lactic
acidosis with stroke-like episodes (MELAS)
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Family tree consistent with mitochondrial inheritance.
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The progressive effects of heteroplasmy on the clinical severity of disease due to mutations in the mitochondrial genome. Low proportions of mutant mitochondria are tolerated well, but as the proportion increases different thresholds for cellular, and hence tissue, dysfunction are breached (gray circle represents the cell nucleus).
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Trinucleotide Expansion
n=80
n=120n=120
n=160 n=250 n=300
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Trinucleotide Expansion
CGG CGG..... CGG CGG
UTR
NORMAL < 50
CGG CGG CGG CGG CGG ..... CGG CGG
UTR
50 < PREMUTATION < 230
CGG CGG CGG CGG CGG CGG CGG CGG CGG CGG....... CGG CGG
UTR
FULL MUTATION > 230
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Example
Fragile X
• X-linked Mental Retardation
• FMR1 gene on Xq28
• 1:1250 males, 1:2500 females
• Most common inherited MR
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Genomic Imprinting
• Most genes are expressed equally from both maternal and paternal copy
• Some regions have differential expression of genes depending on whether inherited from mother or father
• The inexpression results from Parent-of- Origin dependent inactivation
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Genomic Imprinting
• Inactivation = imprinting = methylation• X inactivation in females is a form of
inactivation by methylation, by XIST gene• Some diseases manifest Parent-of-Origin
inheritance
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Genomic Imprinting - Maternal
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Genomic Imprinting - Paternal
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Genomic Imprinting
Prader-Willi syndrome• Infantile hypotonia• Initial FTT • Hypogonadism • Obesity• Mental Retardation• Short stature• SNRPN gene
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Prader Willi Sy.
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• Prader-Willi Sy• בחלק מהמקרים
נובע מחסר חלקי תת- מיקרוסקופי של כרומוזום 15q11 . חסר זה
ניתן לבדיקה FISH-ב
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Genomic Imprinting
Prader Willi Syndrome• ~ 70% of PWS 15q11 microdeletion on
paternally-derived chromosome • Maternal copy is imprinted• Deletion in manifested only when
inherited from the father• A deleted copy inherited from the
mother is not expressed anyway
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Female child with Prader-Willi syndrome.
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Genomic Imprinting
Angelman syndrome• Eepilepsy• Severe learning difficulties• Ataxic gait • Happy affect
• UBE3A gene• Microdeletion on maternally-derived
chromosome • Paternal copy is imprinted
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Germline Mosaicism
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Germline Mosaicism• Adults have 1012 cells• Mutations occur ~1: 106 cell divisions• At some loci 1: 5x 104
• Thus we are all mosaic !!• Somatic mutations in the embryo may
lead to 2 different cell-line in the gonads
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Germline Mosaicism
normal gamete
mutant gamete
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examples
Germline Mosaicism
• Duchenne muscular dystrophy (15%)
• Osteogenesis imperfecta (7%)
• Achondroplasia
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Uniparental Disomy (UPD)• Both copies of a chromosome are
inherited from the same parent• Usually results from “corrected trisomy”
Maternal nondisjunction
Trisomy 15 UPD 15
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example
Uniparental Disomy (UPD)
Prader Willi Syndrome• ~ 30% of PWS have Maternal UPD• “Confined placental mosaicism” for #15
required molecular studies to r/o UPD15
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Prader Willi - Deletion Type
Maternal #15deletion
Paternal #15deletion
M
M
M
M
Prader WilliNormal carrier