Bruno Dallapiccola Making the best use  of genetic testing
“ Genetic tests detect the presence or absence of, or a change in, a particular gene or chromosome, or a gene product or o...
Allelic gene mutations can result in distinct disorders  i.e. diseases caused by LMNA/C gene mutations Hutchinson - Gilfor...
Identical/similar disorders can be caused by non-allelic mutations:  genetic heterogeneity  i.e. retinitis pigmentosa
<ul><li>To make a diagnosis </li></ul><ul><li>e.g. to recognize disorders in which the clinical assessment per se is not c...
2. To  validate  a difficult clinical diagnosis e.g.  Microcephalic Os t eodysplastic Primordial Dwarfism ,  type II ,  MO...
3 . To choose the most appropriate therapy e.g. congenital adrenal hyperplasia Detection of   CYP21A   gene  homozygous mu...
4. To establish genotype-phenotype correlations  and delineate the natural history   of diseases i.e. analysis of  the  RA...
5. To outline genetic heterogeneity of diseases i.e. Joubert syndrome (JS)-related disorders sharing the molar tooth sign ...
6a. To identify newborns at risk of developing RDs by ‘genetic screening’ e.g. metabolic disorders benefiting of prompt th...
6b. To identify at risk individuals by ‘population genetic screening’ e.g. to recognize individuals heterozygous for ß-tha...
6c. To identify unaffected at risk individuals by ‘cascade screening’ within a family e.g. to recognize SMN gene heterozyg...
7. To identify individuals at risk of developing adult-onset diseases e.g.. CTG triplet expansion within DMPK gene in myot...
8. To avoid non useful investigations   e.g. genetic testing in families with  A denomatous  P olyposis of the  C olon  ( ...
9. To elucidate the mechanism underlying a rare disease  e.g. triallelic inheritance in Bardet-Biedl syndrome
10. To improve genetic counseling e.g. risk assessment in Nablus-syndrome <ul><li>21 month-old girl </li></ul><ul><li>cons...
“ Molecular diagnosis is only one part of  battery of tests in which clinical suspicion and your own clinical expertise ar...
Appropriateness of genetic testing in Italy  Dallapiccola  et al., Genet Test Mol Biomarkers. 2010 ;  14:17-22  Genetic te...
<ul><li>Genetic testing is a powerful tool for diagnosis and management of rare diseases. In order to improve the best pra...
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Session 8 dallapiccola

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Session 8 dallapiccola

  1. 1. Bruno Dallapiccola Making the best use of genetic testing
  2. 2. “ 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
  3. 3. Allelic gene mutations can result in distinct disorders i.e. diseases caused by LMNA/C gene mutations Hutchinson - Gilford progeria (HGPS ) Mandibulo-acral dysplasia (MAD) Familial partial lipodystrophy (FPLD2) Restrictive dermopathy, lethal (RD) Muscular dystrophy limb-girdle, type 1B (LGMD1B), Lipoatrophi c diabetes Cardiomyopathy, dilated 1A (CMD1A) Emery-Dreifuss muscular dystrophy, type 2 (EDMD2) Charcot-Marie-Tooth disease, axonal, type 2B1 (CMT2B1)
  4. 4. Identical/similar disorders can be caused by non-allelic mutations: genetic heterogeneity i.e. retinitis pigmentosa
  5. 5. <ul><li>To make a diagnosis </li></ul><ul><li>e.g. to recognize disorders in which the clinical assessment per se is not conclusive </li></ul><ul><li>B . L . 10 y s </li></ul><ul><li>mild mental retardation </li></ul><ul><li>long face, rounded chin, ptosis, upward slanted palpebral fissures, thick alae nasi, anteverted nares, prominent philtrum </li></ul><ul><li>pectus excavatum </li></ul><ul><li>incomplete elbows extension </li></ul><ul><li>long tapering fingers </li></ul><ul><li>camptodactylous fingers/toes </li></ul>dup16p13.3
  6. 6. 2. To validate a difficult clinical diagnosis e.g. Microcephalic Os t eodysplastic Primordial Dwarfism , type II , MOPDII ( OMIM 210720 ) <ul><li>L.A. 27 ys </li></ul><ul><li>prenatal/postnatal growth retardation </li></ul><ul><li>adult height 123 cm </li></ul><ul><li>microcephaly (OFD 49 cm) </li></ul><ul><li>dysmorphic facial features </li></ul><ul><li>acanthosis nigricans </li></ul><ul><li>tapering fingers, flat brittle nails </li></ul><ul><li>borderline mental development </li></ul><ul><li>diabetes mellitus </li></ul><ul><li>arterial stenosis </li></ul><ul><li>mesomelic limbs’ shorteni n g </li></ul>
  7. 7. 3 . To choose the most appropriate therapy e.g. congenital adrenal hyperplasia Detection of CYP21A gene homozygous mutations, prompts dexamethasone therapy of affected patients to prevent female virilization and male precocious puberty.
  8. 8. 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 syndrome PTPN11 ex 3 PTPN11 ex 12 PTPN11 ex 13 NRAS KRAS classic form lentigines polyarticular villonodular severe form cardiomyopathy sinovitis NS1 (OMIM 163950) LS1 (OMIM 151100) (OMIM 163955) NS6 (OMIM 164790) NS3 (OMIM 609942) Noonan syndrome Noonan syndrome Noonan syndrome Noonan syndrome Neurofibromatosis- Noonan syndrome SHOC2 SOS1 RAF1 BRAF NF1 “ loose anagen hair” mild form,normal stature cardiomyopathy CFCS-like mild NF1 (OMIM 607721) NS4 (OMIM 610733) NS5 (OMIM 611553) (OMIM 115150) (OMIM 601321) LS2 (OMIM 611554)
  9. 9. 5. To outline genetic heterogeneity of diseases i.e. Joubert syndrome (JS)-related disorders sharing the molar tooth sign (MTS) on brain MRI
  10. 10. 6a. To identify newborns at risk of developing RDs by ‘genetic screening’ e.g. metabolic disorders benefiting of prompt therapy
  11. 11. 6b. To identify at risk individuals by ‘population genetic screening’ e.g. to recognize individuals heterozygous for ß-thalassemia in at risk populations
  12. 12. 6c. To identify unaffected at risk individuals by ‘cascade screening’ within a family e.g. to recognize SMN gene heterozygotes in families segregating spinal muscular atrophy
  13. 13. 7. To identify individuals at risk of developing adult-onset diseases e.g.. CTG triplet expansion within DMPK gene in myotonic dystrophy
  14. 14. 8. To avoid non useful investigations e.g. genetic testing in families with A denomatous P olyposis of the C olon ( APC gene) 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 colonoscopy.
  15. 15. 9. To elucidate the mechanism underlying a rare disease e.g. triallelic inheritance in Bardet-Biedl syndrome
  16. 16. 10. To improve genetic counseling e.g. risk assessment in Nablus-syndrome <ul><li>21 month-old girl </li></ul><ul><li>consanguineous parents </li></ul><ul><li>micro-brachycephaly, upswept frontal hairline, blepharophymosis, flat supraorbital ridges, high-arched, misaligned eyebrows, long prominent philtrum, flattened maxilla, receding chin, abnormal ears </li></ul><ul><li>expressionless face </li></ul><ul><li>borderline mental retardation. </li></ul>
  17. 17. “ Molecular diagnosis is only one part of battery of tests in which clinical suspicion and your own clinical expertise are th e basis of most diagnoses” S urth J Am Can Med Ass J 1994: 150, 49-52
  18. 18. Appropriateness of genetic testing in Italy Dallapiccola et al., Genet Test Mol Biomarkers. 2010 ; 14:17-22 Genetic tests Number of tests Samples with mutations % confirmed clinical diagnoses Williams syndrome del7q11.23 2.628 74 2.82 DiGeorge/Velo-cardio-facial syndrome del22q11.2 3.683 123 3.34 Fragile-X syndrome FMR1 mutations 5.374 224 4.17 Angelman syndrome del15qmat/pat disomy/UBE3A mutations 589 52 8.83 Prader-Willi syndrome del15qpat/mat disomy/SNRPN mutations 639 112 17.53 Achondroplasia FGFR3 mutations 140 51 36.43
  19. 19. <ul><li>Genetic testing is a powerful tool for diagnosis and management of rare diseases. In order to improve the best practice of genetic testing a number of points should be considered: </li></ul><ul><li>The request for a genetic test must be clinically driven; </li></ul><ul><li>Before requesting a genetic test, first consider its usefulness </li></ul><ul><li>and the potential impact onto the patient or his/her family; </li></ul><ul><li>The quality of testing is critical for diagnosis and management; </li></ul><ul><li>Pre- and post-test counseling must be available. </li></ul>Conclusion

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