Dr Tracy Dudding Clinical Geneticist Hunter Genetics

Transcription

1 Dr Tracy Dudding Clinical Geneticist Hunter Genetics

2 Genetic testing -Why? Confirm a clinical diagnosis and mode of inheritance Clarify management Identification of at risk family members Family planning

3 Genetic testing in familial thoracic aortic aneurysm Syndromic Marfan syndrome Loeys Dietz Marfan syndrome syndrome Filamin A aortopathy Loeys Dietz Vacular EDS Non-syndromic Exclusion of genetic syndrome Positive family history Turner Syndrome

4 Case 9 year old female? Marfan syndrome 9 years old MVP Aortic root 26mm (>95%) Pectus excavatum Wrist sign Pes planus hypermobile joints

5 In the absence of family history 1. Ao (Z 2) AND EL = MFS Marfan syndrome Revised 2010 Ghent criteria In the presence of family history 5. EL AND FH of MFS (as defined above) = MFS 2. Ao (Z 2) AND FBN1 = MFS 3. Ao (Z 2) AND Syst ( 7pts) = MFS* 4. EL AND FBN1 with known Ao = MFS 6. Syst ( 7 pts) AND FH of MFS (as defined above) = MFS* 7. Ao (Z 2 above 20 yrs old, 3 below 20 yrs) + FH of MFS (as defined above) = MFS* * Caveat: Without discriminating features of SGS, LDS or veds - AND after TGFBR1/2, collagen biochemistry, COL3A1 testing if indicated - other conditions/genes will emerge with time Loeys et al. The revised Ghent nosology for Marfan syndrome. J Med Genet 2010;47:

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7 Scoring System Systemic Features ( 7) Wrist AND thumb sign 3 (Wrist OR thumb sign only) 1 Pectus carinatum deformity 2 (Pectus excavatum or cast asymmetry) 1 Hindfoot deformity 2 (Plain pes planus) 1 Pneumothorax 2 Dural ectasia 2 Protrusio acetabuli 2 Reduced US:LS AND increased AS:Ht AND no severe scoliosis 1 Scoliosis OR thoracolumbar kyphosis 1 Reduced elbow extension 1 Facial features 3/5 (dolichocephaly, enopthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia) Skin striae 1 Myopia > 3 diopters 1 Mitral valve prolapse 1 1

8 Marfan syndrome Wrist and thumb sign Hindfoot deformity

9 Marfan syndrome Fibrillin 1 Problematic 65 exons Not all rare variants cause Marfan (isolated EL, skeletal features, or familial TAAD) Clinical diagnosis Mutation detection rate 70-90% Transforming growth factor-β receptor type 2 (TGFβR2)

10 Case 9 year old female? Marfan syndrome 9 years old MVP Aortic root 26mm (>95%) Pectus excavatum Wrist sign Pes planus No ectopia lentis Fibrillin 1 negative

11 Loeys-Dietz aortic aneurysm syndrome Characterized by the triad of 1) arterial tortuosity and aneurysms, 2) hypertelorism 3) bifid uvula or cleft palate. Heterozygous mutations in the transforming growth factor-β type 1 receptor gene (TGFBR1) and TGBR2 Why is this important?

12 Loeys-Dietz syndrome Type 1 LDS Craniofacial involvement consisting of cleft palate, craniosynostosis or hypertelorism Type 2 LDS vascular EDS (visceral rupture, easy bruising, wide and atrophic scars, joint laxity and translucent skin)- Normal type III collagen studies Both types can be due to mutations in TGFβR1 or TGFβR2

13 Characteristics of the Loeys-Dietz Syndrome Loeys BL et al. N Engl J Med 2006;355:

14 Loeys-Dietz Syndrome Type I Loeys BL et al. N Engl J Med 2006;355:

15 Characteristics Loeys-Dietz Syndrome Type II Loeys BL et al. N Engl J Med 2006;355:

16 Cardiovascular Involvement with Loeys- Dietz Syndrome Type I or II Loeys BL et al. N Engl J Med 2006;355:

17 Natural history of LDS Mean age of death 26 years 67% ruptured thoracic aneurysm 22% ruptured abdominal aortic aneurysm 7% cerebral bleed Surgical intervention is generally successful

18 Management of LDS 5.1 recommendations for genetic syndromes Class 1. (Benefit>>>risk- SHOULD) Patients with LDS should have yearly magnetic resonance imaging form the cerebrovascular circulation to the pelvis (level B evidence). It is reasonable to consider surgical repair of the aorta in adult patients with LDS or confirmed TGFBR1 or TGFBR2 mutation and an aortic diameter of 4.2 cms (Transesophageal echo) or cms ( CT or MRI). (level C evidence) 2010 Diagnosis and Management of Patients with Thoracic Aortic Disease. Circulation; e369

19 Filamin A aortopathy FLNA associated mutations X-linked Periventricular Heterotopia X-linked Periventricular Heterotopia Ehlers-Danlos Variant (increased risk of aortic dissection) X-linked Intestinal Pseudo-obstruction Otopalatodigital Spectrum Disorders X-linked Cardiac Valvular Dysplasia (Mitral and/aortic valve regurgitation) Terminal Osseous Dysplasia FG Syndrome

20 Filamin A associated PVNH X-linked brain malformation known as periventricular heterotopia Usually affected females and is lethal in males

21 deceased FLNA mutation not found FLNA mutation normal MRI Prolonged febrile seizure FLNA mutation Unilateral PHNH Absence seizures Bilateral PVNH FLNA mutation

22 Opthal: Retinal lattice degeneration Echo: Trivial MVP, TVP & aortic incompetence Opthal: Retinal lattice degeneration Hypertension Echo: Mild MVP & TVP Opthal: Retinal lattice degeneration

23 Sudden death age 46 Scoliosis Harrington rods High arched palate Tall stature High arched palate Varicose veins Tall stature Wide arm span High arched palate Joint hypermobility Skin hyperextensibility

24 X-linked Periventricular Heterotopia Ehlers-Danlos Variant OMIM # At least 14 reported cases All affected females PVNH Joint hypermobility Skin hyperextensibility/fragility Risk of aortic root dilation in early adulthood Lattice degeneration not previously described

25 X-linked Chronic Intestinal Pseudo-obstruction

26 Familial aortic aneurysms Syndromic Non-syndromic Marfan syndrome Fibrillin 1 Loeys-Dietz syndrome Type 1 Loeys-Dietz sydrome Type 2 TGF βr 1 & TGF βr 2 Filamin A Aortopathy (Filamin A) Vascular EDS (COL3A1) Turner syndrome (XO)

27 Familial thoracic aortic aneurysms Syndromic Marfan syndrome Fibrillin 1 Loeys-Dietz syndrome Type 1 Loeys-Dietz sydrome Type 2 TGF βr 1 & TGF βr 2 Filamin A Aortopathy (Filamin A) Vascular EDS (COL3A1) Turner syndrome (XO) Non-syndromic FTAAD 19% of patients with TAAD without a genetic syndrome have a first degree relative with TAAD Younger age Autosomal dominant inheritance Incomplete penetrance Clinically and genetically heterogeneous

28 Familial TAAD (non-syndromic) Clinical heterogeneity Variability of the cardiovascular diseases segregating in the families with the TAAD BAV* patent ductus arterosis The region of the initial ascending aortic enlargement can vary Sinus of valsalva (similar to MFS and LDS) or sparing the sinus of valsalva. Aneursyms in other arteries 12% of families have AAAs 9%-14% of families cerebral aneurysms 5% of families iliac or popliteal aneurysms

29 Familial TAA Genetic heterogeneity Four causative genes (20%) TGFBR1 and TGFBR2 cause familial disease in the absence of features of LDS Smooth muscle contractile proteins Smooth muscle cell-specific isoform of βmyosin heavy chain (MYH11) smooth muscle specific α actin (ACTA2)

30 TGFBR1 and TGFBR2 in Familial TAAD TGFBR2 < 5% of familial TAAD. Do not have features of LDS Have dissections before reaching an aortic diameter of 5cm.

31 Spectrum of TGRBR1 and TGRBR2 mutations LDS ( with early onset aortic disease) Arterial tortuosity of the aorta or cerebrovascular arteries, thin skin and bluish sclera. Multigenerational families with no features of LDS

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33 Mutations in β-myosin (MYH11) MYH11 mutations rare families with TAAD associated with PDA Not a common cause of familial TAAD Limited data

34 Mutations in genes of the smooth muscle cell-specific isoform of α-actin (ACTA2) ACTA2 14% of familial TAAD Skin rash livedo reticularis. iris flocculi, PDA and BAV penetrance is low Dissection can occur lower 50mm ( Disabella et al Heart 2011)

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36 Mutations in genes of the smooth musclespecific isoforms of α-actin (ACTA2) Early onset ischemic stroke and coronary artery disease. Consider ACTA2 sequencing in all familial TAAD patients CAD and CVD screening Guo et al AJHG 2009

37 SMAD3 early onset aneursyms with early onset osteoarthritis Van de Laar et al Nature Genetics 2011 All had radiological proven OA of one or more joints at a mean age of 42 years Hand and wrist Only scaphotrapeziotrapezoid, first carpometacarpal and occasionlly MCP joints DIP and PIJ not affected Intervertebral abnormality of the cervical and lumbar discs as early as 12 years

38 5.1.6 Recommendations for Familial TAAD Class I (benefit >>>risk- SHOULD) 1. Aortic imaging is recommended for first degree relatives of patients with thoracic aortic aneurysm and/or dissection to identify those with asymptomatic disease. (level of evidence: B) 2. If the mutant gene(fbn1, TGFβ1, TGFβ2, COL3A1, ACTA2,MYH11) is identified in the patient, first degree relatives should undergo counselling and testing Diagnosis and Management of Patients with Thoracic Aortic Disease. Circulation; e Diagnosis and Management of Patients with Thoracic Aortic Disease. Circulation; e369

39 5.1.6 Recommendations for Familial TAAD Class IIa (Benefit >> Risk- REASONABLE) 1. If one or more first degree relatives of a patient with known thoracic aneurysm and/or dissection are found to have a thoracic aneurysm and/or dissection, then imaging of second degree relatives is reasonable (level of evidence B) 2. Sequencing of the ACTA2 gene is reasonable in patients with a family history of thoracic aortic aneurysms /dissection (level B evidence) 2010 Diagnosis and Management of Patients with Thoracic Aortic Disease. Circulation; e369

40 5.1.6 Recommendations for Familial TAAD Class IIb (benefit risk : may be considered) 1. Sequencing of other genes known to cause familial TAAD (TGFβ1, TGFβ2,,MYH11) may be considered in patients with a family history and clinical features associated with mutations in these genes Diagnosis and Management of Patients with Thoracic Aortic Disease. Circulation; e369

41 Fibrillin deficiency increases activation of TGFβ pathway TGF-βs: family of cytokines Binding of the ligand with TGF-β receptor 2 followed by activated phosphorylation of the TGF-β 1. Activated TGFβR1/TGFβR2 Complex mediates through its downstream signaling pathway involving the Smad proteins, the transcription of multiple genes TGFβ signalling is enhanced by TGFβR1/TGFβR2 mutations

42 We are moving closer to a time when routine genetic testing is available and useful for FTAAD