Making the best use
            of genetic testing




Bruno Dallapiccola
“Genetic tests detect the presence or absence of, or a change in, a
particular gene or chromosome, or a gene product or ot...
Lipoatrophic diabetes
 Hutchinson-Gilford progeria (HGPS)




                                                            ...
Identical/similar disorders can be caused by non-allelic mutations:
                        genetic heterogeneity
        ...
• B.L. 10 ys
                                              • mild mental retardation
                                     ...
• L.A. 27 ys
                                                • prenatal/postnatal growth retardation
                     ...
Detection of CYP21A gene homozygous mutations, prompts
                          dexamethasone therapy of affected patient...
Noonan syndrome       LEOPARD syndrome     Noonan-like syndrome Noonan syndrome           Noonan syndrome
                ...
JS + congenital heaptic fibrosis
                           ± ocular colobomas (COACH)
                                   ...
6a. To identify newborns at risk of developing a RD by ‘genetic screening’
                e.g. metabolic disorders benefi...
6b. To identify at risk individuals by ‘population genetic screening’
  e.g. to recognize individuals heterozygous for ß-t...
6c. To identify unaffected at risk individuals by ‘cascade screening’ within a family
       e.g. to recognize SMN gene he...
I:1          I:2




        II:1           II:6           II:2    II:7          II:3                 II:8   II:4   II:9  ...
To identify individuals who are heterozygous for the pathogenic mutation and those have
     the wild genotype, in order t...
9. To elucidate the mechanism underlying a rare disease
         e.g. triallelic inheritance in Bardet-Biedl syndrome
• 21 month-old girl
• parents originating from a small village in Sicily, likely related
• micro-brachycephaly, upswept fr...
“Molecular diagnosis is only one part of battery of tests in which clinical suspicion
and your own clinical expertise are ...
Samples with   % confirmed
             Genetic tests                              Number of tests                        ...
Genetic testing is a powerful tool for diagnosis and management
of rare diseases. In order to improve the best practice of...
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Session 8 bruno_dallapiccola

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Session 8 bruno_dallapiccola

  1. 1. Making the best use of genetic testing Bruno Dallapiccola
  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 in mentally retarded subjects) Genetic testing
  3. 3. Lipoatrophic diabetes Hutchinson-Gilford progeria (HGPS) Cardiomyopathy, dilated 1A (CMD1A) Mandibulo-acral dysplasia (MAD) Emery-Dreifuss muscular dystrophy, type 2 (EDMD2) Familial partial lipodystrophy (FPLD2) Charcot-Marie-Tooth disease, axonal, type 2B1 (CMT2B1) Restrictive dermopathy, lethal (RD) Muscular dystrophy limb-girdle, type 1B (LGMD1B), Allelic gene mutations can result in distinct disorders i.e. diseases caused by LMNA/C gene mutations
  4. 4. Identical/similar disorders can be caused by non-allelic mutations: genetic heterogeneity i.e. retinitis pigmentosa
  5. 5. • B.L. 10 ys • mild mental retardation • long face, rounded chin, ptosis, upward slanted palpebral fissures, thick alae nasi, anteverted nares, prominent philtrum • pectus excavatum • incomplete elbows extension • long tapering fingers • camptodactylous fingers/toes dup16p13.3 1. To make a diagnosis e.g. to recognize disorders in which the clinical assessment per se is not conclusive
  6. 6. • L.A. 27 ys • prenatal/postnatal growth retardation • adult height 123 cm • microcephaly (OFD 49 cm) • dysmorphic facial features • acanthosis nigricans • tapering fingers, flat brittle nails • borderline mental development • diabetes mellitus • arterial stenosis • mesomelic limbs’ shortenig 2. To validate a clinical diagnosis e.g. Microcephalic Osteodysplastic Primordial Dwarfism, type II, MOPDII (OMIM 210720)
  7. 7. Detection of CYP21A gene homozygous mutations, prompts dexamethasone therapy of affected patients to prevent female virilization and male precocious puberty. 3. To choose the most appropriate therapy e.g. congenital adrenal hyperplasia
  8. 8. 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) 4. To establish genotype-phenotype correlations and to delineate the natural history of diseases i.e. to predict the outcome of Noonan syndrome based on analysis of genes in the RAS-MAPK pathway
  9. 9. JS + congenital heaptic fibrosis ± ocular colobomas (COACH) TMEM67 5. To outline the heterogeneity of genetic 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 a RD 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. I:1 I:2 II:1 II:6 II:2 II:7 II:3 II:8 II:4 II:9 II:5 III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:8 7. To identify individuals at risk of developing adult onset diseases e.g.. CTG triplet expansion within DMPK gene in myotonic dystrophy
  14. 14. To identify individuals who are heterozygous for the pathogenic mutation and those have the wild genotype, in order to decide who needs to undergo a periodic check using colonoscopy 8. To avoid non useful investigations e.g. genetic testing in families with Adenomatous Polyposis of the Colon (APC gene)
  15. 15. 9. To elucidate the mechanism underlying a rare disease e.g. triallelic inheritance in Bardet-Biedl syndrome
  16. 16. • 21 month-old girl • parents originating from a small village in Sicily, likely related • micro-brachycephaly, upswept frontal hairline, blepharophymosis, flat supraorbital ridges, high-arched, misaligned eyebrows, long prominent philtrum, flattened maxilla, receding chin, abnormal ears • expressionless face • borderline mental retardation 10. To improve genetic counseling e.g. risk assessment in Nablus-syndrome
  17. 17. “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
  18. 18. Samples with % confirmed Genetic tests Number of tests clinical mutations diagnoses Williams syndrome 2.628 74 2.82 del7q11.23 DiGeorge/Velo-Cardio-Facial syndrome 3.683 123 3.34 del22q11.2 Fragile X syndrome 5.374 224 4.17 FMR1 mutations Angelman syndrome 589 52 8.83 del15qmat/pat disomy/UBE3A mutations Prader-Willi syndrome 639 112 17.53 del15qpat/mat disomy/SNRPN mutations Achondroplasia 140 51 36.43 FGFR3 mutations Appropriateness of genetic testing in Italy Dallapiccola et al., Genet Test Mol Biomarkers. 2010; 14:17-22
  19. 19. 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: • The request for a genetic test must be clinically driven; • Before requesting a genetic test, first consider its usefulness and the potential impact onto the patient or his/her family; • The quality of testing is critical for diagnosis and management; • Pre- and post-test counseling must be available. Conclusion

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