Clinical utility gene card for: Loeys-Dietz syndrome (TGFBR1|[sol]|2) and related phenotypes

So far no deletions/duplications have been reported after screening by MLPA, so the usefulness of MLPA for testing of the TGFBR1/2 need to be determined (personal communication). Comment: TGFBR1/2 testing is indicated as the first test to perform in the following indications: TGFBR1/2 testing is also indicated as a secondary test in patients in whom FBN1 testing remains negative despite MFS-like phenotype. TGFBR1/2 mutations have been described in Shprintzen-Goldberg, but most of these patients have many characteristics in common with LDS. Many patients with true Shprintzen-Goldberg syndrome do not have TGFBR1/2 mutations.1, 6 Although initially two clinical presentations were distinguished (LDS type I with more typical craniofacial findings and LDS type II with more prominent cutaneous findings), it is now recognized that LDS is a continuum that includes a wide range of clinical presentations. The respective clinical spectrum of TGFBR1 and TGFBR2 mutation is not fully recognized. The possibility of preferential amplification of one allele, if primers are localized on a SNP (hampering primer binding) or because of deletion (making amplification impossible) exists, although these events are exceptional. Classical criteria for determining the pathogenicity of a mutation are the following: Unknown, dependent on the depth of clinical evaluation and cardiovascular imaging. By definition 100%. Mutations within the TGFBR1 and TGFBR2 genes have been reported in patients with LDS.1, 2 TGFBR1/2 mutations have also been found in MFS or suspected MFS.3 Sakai et al7 found one patient with a TGFBR1 mutation (2%) and two TGFBR2 mutations (4%) out of a series of 49 MFS-like patients; Màtyàs et al8 reported 10 TGFBR1 or TGFBR2 mutations in 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in FBN1; Singh et al9 found two TGFBR1 and five TGFBR2 mutations in 41 unrelated patients who did or did not fulfill the diagnostic criteria for MFS, in whom mutations in the FBN1-coding region were not identified; Stheneur et al10 found six mutations in the TGFBR2 gene and one in the TGFBR1 gene in 105 MFS patients, and nine mutations in the TGFBR2 gene and two mutations in the TGFBR1 gene in 247 patients with incomplete or probable MFS that were negative for a FBN1 gene mutation. Chung et al11 found six TGFBR2 mutations in 41 MFS-like probands (previously negative for FBN1). None of these six patients with TGFBR2 mutations fulfilled the clinical MFS criteria from the Ghent nosology. TGFBR1/2 mutations have been described in familial thoracic aortic aneurysm families,4, 5 but many of these families have not been evaluated in detail for clinical features that are common in LDS. Finally, as stated above, some mutations have been described in Shprintzen-Goldberg syndrome, but these patients have features that are believed to be more common in LDS.6 No TGFBR1/2 mutations have been found in families with presentation of isolated bicuspid aortic valve with or without aortic dilatation.12 Incomplete penetrance,1 as well as somatic mosaicism13 have been reported. Index case in that family had been tested: Nearly 100%. Index case in that family had not been tested: Predictive testing for family members should only be proposed, if a pathogenic mutation has been identified in an index case. Yes. All individuals with LDS require echocardiography at frequent intervals to monitor the status of the ascending aorta (usually yearly, but depending on the severity of the phenotype); the frequency of magnetic resonance angiography (MRA) or computerized tomography angiography (CTA) evaluations depend on clinical findings. Individuals with cervical spine instability and severe or progressive scoliosis should be followed by an orthopedic surgeon. Contact sports, competitive sports, isometric exercise, agents that stimulate the cardiovascular system including routine use of decongestants should be avoided, as well as activities that cause joint injury or pain. If the test result is negative (please describe): Follow-up is dispensable and restriction of sports is unnecessary, if a familial mutation can be excluded. A negative result should be interpreted with care, if the mutation is unknown in the index patient. Testing for mutation in other genes should be considered, depending on the phenotype (FBN1, ACTA2 and MYH11). Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe) Yes, other diagnostic testing becomes unnecessary. Patients and parents of affected children are usually relieved that the disease has been identified (‘received a name’). They can seek contact with other persons affected by this disease through patient organization, which is usually seen as an enormous help in coping with the condition. Genetic testing also allows early recognition of affected members who may benefit from preventive medical/surgical care due to wide intrafamilial variability. Lastly, a negative test is very useful for the patient and their children as it removes the aortic threat, and abolishes needs for medical care and follow-up. The authors declare no conflict of interest. This work was supported by EuroGentest, an EU-FP6 supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical genetics, community genetics and public health’, Workpackage 3.2).