Clinical utility gene card for: Vici Syndrome

Alternative gene names: KIAA1632; HEEW1. Most EPG5 mutations are private and only one recurrent mutation has been published to date.1 EPG5 mutations are typically inherited from unaffected carrier parents; a single (unpublished) case has been identified with an EPG5 mutation showing de novo occurrence in the proband. A small proportion of patients with diagnostic features of Vici syndrome do not have EPG5 mutations detectable on Sanger sequencing,1 suggesting either genetic heterogeneity or the presence of uncommon EPG5 mutations such as deep intronic mutations or large intragenic deletions/duplications. The birth prevalence of Vici syndrome is currently unknown but predicted to be low, with only 20 cases published to date.1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 However, a proportion of cases are probably either undiagnosed or unreported, suggesting that this figure provides an underestimate of the actual frequency. Vici syndrome has been found in equal frequencies in the different ethnic groups studied. Only one recurrent EPG5 mutation has been identified to date, in the compound heterozygous state in an Italian and in the homozygous state in an unrelated Maltese patient without known parental consanguinity,1, 11 suggesting a possible founder effect. Comment: Mutation analysis is mainly used for confirmation of a clinical diagnosis (on the basis of the presence of at least four of the five main diagnostic features, agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation and immunodeficiency) and for accurate genetic counseling. Preimplantation genetic diagnosis (PGD) may be offered to affected families with confirmed pathogenic mutations depending on the regulatory environment and facilities in their country. Sanger sequencing as the primary testing strategy will detect point mutations with close to 100% sensitivity.2 Overall sensitivity will be complete barring rare variants disrupting PCR primer binding and mutations undetectable by Sanger sequencing of coding regions, which are predicted to be in the minority. As an estimation, given the presence of a single patient with only one heterozygous EPG5 mutation identified from 24 cases screened to date in our laboratory, an analytical sensitivity of 98% (47/48 chromosomes) could be attributed. This figure does not incorporate the four patients in whom no EPG5 mutation has been identified, the rationale being that they are more likely to represent cases unlinked to the EPG5 locus, as discussed in 1.5. Sequence analysis: 100%. Clinical sensitivity in cases of Vici syndrome where all the main diagnostic features (agenesis of the corpus callosum, cataracts, cardiomyopathy, skeletal myopathy, skin hypopigmentation and immunodeficiency) are present is likely to be very high; absence of a positive result is likely to be related to the analytical sensitivity (see 2.1). Cases where not all diagnostic features are present are likely to result in a lower sensitivity. Locus heterogeneity or presence of mutations not detectable on routine Sanger sequencing has been suggested for 2/18 cases reported by Cullup et al.,1 in whom some but not all diagnostic features were present. Considering early-onset and severity of Vici syndrome, clinical specificity is likely to be 100%. Vici syndrome is a severe condition, and most signs and symptoms are present at birth. The positive clinical predictive value (for example the likelihood of a fetus to develop features of Vici syndrome if found to carry recessive familial EPG5 mutations on prenatal testing) is likely to be 100%. Some features of Vici syndrome (for example, cataracts, cardiomyopathy and the associated immunodeficiency) are not always present at birth, but are expected to evolve over the first years of life with a likelihood approaching 100%. Index case in that family had been tested: The negative clinical predictive value is likely to be 100% if the index case in the family had been tested and was found positive for EPG5 mutations. Index case in that family had not been tested: Unknown but probably high. Comment: The diagnosis of Vici syndrome is essentially a clinical diagnosis, based on the presence of at least four out of the five main diagnostic features: agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation and immunodeficiency.1 In addition to a clinical assessment, brain magnetic resonance (MR) imaging, ophthalmology assessment (including slit lamp examination), cardiology assessment (including ECG and cardiac ultrasound) and tests to assess immune function are recommended to establish the presence of the main diagnostic features. In cases where the genetic diagnosis of Vici syndrome has not been established, additional laboratory investigations (for example, transferrin isolelectric focussing), genetic testing and a muscle biopsy will often be performed to exclude multisystem disorders with similar features such as primary glycosylation defects, ciliopathies or mitochondrial disorders. Where performed, supportive features on muscle biopsy include light microscopy abnormalities comprising increased fiber size variability, increased internal nuclei and vacuolization,6 and ultrastructural changes on electron microscopy such as numerous vacuoles3 and abnormalities of mitochondrial morphology and localization. A muscle biopsy is an invasive procedure that requires local or general anesthesia and carries a small risk of bleeding, infection and scarring. Not applicable Not applicable If the test result is negative (please describe) Not applicable 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) The result of the genetic test is currently principally of use for the resolution of a clinical diagnosis in the patient and similarly affected relatives. In addition, a molecular genetic diagnosis will enable carrier parents of the index case to make informed reproductive decisions and allow future family planning. Molecular genetic confirmation of the clinical diagnosis will reduce the number of additional investigations (such as a muscle biopsy), which are invasive and expensive. The authors declare no conflict of interest. This work was supported by EuroGentest2 (Unit 2: ‘Genetic testing as part of health care’), a Coordination Action under FP7 (Grant Agreement Number 261469) and the European Society of Human Genetics. TC and HJ were supported by a grant from the Guy’s and St. Thomas’ Charitable Foundation (Grant number 070404). MG and ALK are supported by the Leducq Foundation, the MRC and the BHF.