session 8 dallapiccola

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Bruno Dallapiccola Making the best use Making the best use of genetic testing of genetic testing

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Page 1: Session 8 dallapiccola

Bruno Dallapiccola

Making the best use Making the best use of genetic testingof genetic testing

Page 2: Session 8 dallapiccola

“Genetic tests detect the presence or absence of, or a change in, a particular gene or chromosome, or a gene product or other specific metabolite that is primarily indicative of specific genetic change”.

Human Genetic Commission, 2009, http://www.hgc.gov.uk/Client/Content.asp?ContentId=816.

Specific to a given disease: the test relates to a unique disorder (e.g. LRP5 homozygous mutations in osteoporosis-pseudoglioma syndrome).

Non-specific: the test applies to patients who share a common clinical feature (e.g. a-CGH analysis to evaluate mentally retarded subjects) .

Genetic testing

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Allelic gene mutations can result in distinct disorders i.e. diseases caused by LMNA/C gene mutations

HutchinsonHutchinson--GilfordGilford progeria progeria (HGPS (HGPS))

Mandibulo-acral dysplasia (MAD)Mandibulo-acral dysplasia (MAD)

Familial partial lipodystrophy (FPLD2)Familial partial lipodystrophy (FPLD2)

Restrictive dermopathy, lethal (RD)Restrictive dermopathy, lethal (RD)

Muscular dystrophy limb-girdle, type 1B (LGMD1B),

LipoatrophiLipoatrophicc diabetes diabetes

Cardiomyopathy, dilated 1A (CMD1A)Cardiomyopathy, dilated 1A (CMD1A)

Emery-Dreifuss muscularEmery-Dreifuss musculardystrophy, type 2 (EDMD2)dystrophy, type 2 (EDMD2)

Charcot-Marie-Tooth disease,Charcot-Marie-Tooth disease, axonal, type 2B1 (CMT2B1)axonal, type 2B1 (CMT2B1)

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Identical/similar disorders can be caused by non-allelic mutations: genetic heterogeneity

i.e. retinitis pigmentosa

Page 5: Session 8 dallapiccola

1. To make a diagnosise.g. to recognize disorders in which the clinical assessment per se is not conclusive

• BB..LL.. 10 y 10 yss• mild mental retardationmild mental retardation• long face, rounded chin, ptosis, upward slanted palpebral long face, rounded chin, ptosis, upward slanted palpebral fissures, thick alae nasi, anteverted nares, prominent philtrum fissures, thick alae nasi, anteverted nares, prominent philtrum • pectus excavatumpectus excavatum• incomplete elbows extensionincomplete elbows extension• long tapering fingerslong tapering fingers• camptodactylous fingers/toescamptodactylous fingers/toes

dup16p13.3

Page 6: Session 8 dallapiccola

2. To validate a difficult clinical diagnosise.g. Microcephalic Osteodysplastic Primordial Dwarfism, type II, MOPDII (OMIM 210720)

• L.A. 27 ys L.A. 27 ys • prenatal/postnatal growth retardationprenatal/postnatal growth retardation• adult height 123 cmadult height 123 cm• microcephaly (OFD 49 cm)microcephaly (OFD 49 cm)• dysmorphic facial featuresdysmorphic facial features• acanthosis nigricansacanthosis nigricans• tapering fingers, flat brittle nails tapering fingers, flat brittle nails • borderline mental development borderline mental development • diabetes mellitusdiabetes mellitus• arterial stenosisarterial stenosis• mesomelic limbs’ shortenimesomelic limbs’ shorteninngg

Page 7: Session 8 dallapiccola

3. To choose the most appropriate therapye.g. congenital adrenal hyperplasia

Detection ofDetection of CYP21ACYP21A gene gene homozygous mutations, prompts homozygous mutations, prompts dexamethasone therapy of affected patients to prevent dexamethasone therapy of affected patients to prevent female virilization and male precocious puberty. female virilization and male precocious puberty.

Page 8: Session 8 dallapiccola

4. To establish genotype-phenotype correlations and delineate the natural history of diseases

i.e. analysis of the RAS-MAPK pathway gene s in neuro-facio-cardio-cutaneous disorders

Noonan syndrome LEOPARD syndrome Noonan-like syndrome Noonan syndrome Noonan syndromeNoonan syndrome LEOPARD syndrome Noonan-like syndrome Noonan syndrome Noonan syndrome PTPN11 PTPN11 ex 3ex 3 PTPN11 PTPN11 ex 12ex 12 PTPN11 PTPN11 ex 13ex 13 NRASNRAS KRASKRAS classic form classic form lentigines polyarticular villonodular severe form lentigines polyarticular villonodular severe form cardiomyopathy sinovitis cardiomyopathy sinovitis NS1 (OMIM 163950) LS1 (OMIM 151100) (OMIM 163955) NS6 (OMIM 164790) NS1 (OMIM 163950) LS1 (OMIM 151100) (OMIM 163955) NS6 (OMIM 164790) NS3 (OMIM 609942) NS3 (OMIM 609942)

NoonanNoonan syndrome Noonan syndrome syndrome Noonan syndrome Noonan syndrome Noonan syndrome Noonan syndrome Neurofibromatosis- Noonan syndrome Neurofibromatosis- NoonanNoonan syndromesyndrome SHOC2 SHOC2 SOS1 SOS1 RAF1 RAF1 BRAF BRAF NF1NF1 ““loose anagen hair” mild form,normal stature loose anagen hair” mild form,normal stature cardiomyopathy CFCS-like cardiomyopathy CFCS-like mild NF1 mild NF1 (OMIM 607721) NS4 (OMIM 610733) (OMIM 607721) NS4 (OMIM 610733) NS5 (OMIM 611553) (OMIM 115150) NS5 (OMIM 611553) (OMIM 115150) (OMIM 601321) (OMIM 601321) LS2 (OMIM 611554) LS2 (OMIM 611554)

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5. To outline genetic heterogeneity of diseasesi.e. Joubert syndrome (JS)-related disorders sharing the molar tooth sign (MTS) on brain MRI

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6a. To identify newborns at risk of developing RDs by ‘genetic screening’e.g. metabolic disorders benefiting of prompt therapy

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6b. To identify at risk individuals by ‘population genetic screening’e.g. to recognize individuals heterozygous for ß-thalassemia in at risk populations

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6c. To identify unaffected at risk individuals by ‘cascade screening’ within a familye.g. to recognize SMN gene heterozygotes in families segregating spinal muscular atrophy

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7. To identify individuals at risk of developing adult-onset diseasese.g.. CTG triplet expansion within DMPK gene in myotonic dystrophy

I:1 I:2

II:1 II:2 II:3 II:4 II:5II:6

III:1 III:2 III:3

II:7

III:4 III:5

II:8

III:6

II:9

III:7 III:8

Page 14: Session 8 dallapiccola

8. To avoid non useful investigations e.g. genetic testing in families with Adenomatous Polyposis of the Colon (APC gene)

To identify individuals who are heterozygous for the pathogenic mutations and those have To identify individuals who are heterozygous for the pathogenic mutations and those have the wild genotype, in order to decide who needs to undergo a periodic check using the wild genotype, in order to decide who needs to undergo a periodic check using colonoscopy. colonoscopy.

Page 15: Session 8 dallapiccola

9. To elucidate the mechanism underlying a rare disease e.g. triallelic inheritance in Bardet-Biedl syndrome

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10. To improve genetic counselinge.g. risk assessment in Nablus-syndrome

• 21 month-old girl21 month-old girl• consanguineous parents consanguineous parents • micro-brachycephaly, upswept frontal hairline, blepharophymosis, flat micro-brachycephaly, upswept frontal hairline, blepharophymosis, flat supraorbital ridges, high-arched, misaligned eyebrows, long prominent philtrum, supraorbital ridges, high-arched, misaligned eyebrows, long prominent philtrum, flattened maxilla, receding chin, abnormal earsflattened maxilla, receding chin, abnormal ears• expressionless face expressionless face • borderline mental retardation.borderline mental retardation.

Page 17: Session 8 dallapiccola

“Molecular diagnosis is only one part of battery of tests in which clinical suspicion and your own clinical expertise are the basis of most diagnoses” Surth J Am Can Med Ass J 1994: 150, 49-52

Page 18: Session 8 dallapiccola

Appropriateness of genetic testing in Italy Dallapiccola et al., Genet Test Mol Biomarkers. 2010; 14:17-22

Genetic tests Number of testsSamples with

mutations

% confirmed clinical

diagnoses

Williams syndromedel7q11.23

2.628 74 2.82

DiGeorge/Velo-cardio-facial syndromedel22q11.2

3.683 123 3.34

Fragile-X syndromeFMR1 mutations

5.374 224 4.17

Angelman syndromedel15qmat/pat disomy/UBE3A mutations

589 52 8.83

Prader-Willi syndromedel15qpat/mat disomy/SNRPN mutations

639 112 17.53

AchondroplasiaFGFR3 mutations

140 51 36.43

Page 19: Session 8 dallapiccola

Genetic testing is a powerful tool for diagnosis and management Genetic testing is a powerful tool for diagnosis and management of rare diseases. In order to improve the best practice of genetic of rare diseases. In order to improve the best practice of genetic testing a number of points should be considered:testing a number of points should be considered:

• The request for a genetic test must be clinically driven;The request for a genetic test must be clinically driven;

• Before requesting a genetic test, first consider its usefulness Before requesting a genetic test, first consider its usefulness and the potential impact onto the patient or his/her family;and the potential impact onto the patient or his/her family;

• The quality of testing is critical for diagnosis and management;The quality of testing is critical for diagnosis and management;

• Pre- and post-test counseling must be available. Pre- and post-test counseling must be available.

Conclusion