Clinical utility gene card for: Cantú syndrome

KCNJ8 – *600935. Unknown. There is no known variation in incidence or prevalence among ethnic groups. Comment: Testing is useful for confirming or making the diagnosis of Cantú syndrome in an affected individual. Testing of relatives allows assessment of reproductive risks – for example, in the parents of an affected child. Prenatal diagnosis is an option where one parent is affected and a pathogenic variant has been identified. Targeted non-invasive prenatal diagnosis (NIPD) is an emerging option for families in which the father is affected. NIPD may be possible where a previous affected child has a de novo variant, but the suitability of this will depend on the healthcare setting. Nearly 100%. Nearly 100%. The sensitivity of a clinical diagnosis can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case. Of 30 patients with a clinical diagnosis of Cantú syndrome included in two papers,1, 2 28 had variants identified in ABCC9. One of the two with no identified variant was subsequently found to have a different disorder, with a duplication of the 17q24.2-q24.3 region. This suggests that the clinical sensitivity of testing for variants in ABCC9 is >95%; addition of KCNJ8 sequencing would be expected to improve this to close to 100%. However, this assumes accurate clinical phenotyping. Depending on the specific features in an affected individual, there are a number of disorders which can present with similar features. In addition to 17q24.2-q24.3 copy number variants, these include lysosomal storage disorders, Beckwith-Wiedemann syndrome, endocrine disorders such as congenital hypothyroidism and acromegaly, Wiedemann-Steiner syndrome, Zimmerman-Laband and Temple-Baraitser syndromes and Berardinelli-Seip congenital lipodystrophy. Treatment with minoxidil can also produce very similar clinical features.6 The clinical sensitivity of testing will depend at least in part on the extent to which alternative diagnoses have been excluded, on clinical grounds or by specific testing, prior to testing for variants in ABCC9 and KCNJ8. The specificity of a clinical diagnosis can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case. If the disease is not present, no pathogenic variants should be found in either ABCC9 or KCNJ8, and thus clinical specificity should be 100%. Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered. Index case in that family had been tested: 100% if there is a proven pathogenic variant in the index case. Index case in that family had not been tested: This depends on whether the clinical diagnosis in the proband is correct. If a confident clinical diagnosis has been made in the proband, negative clinical predictive value would be expected to be high (but difficult to quantify) in this scenario as well. If the test result is negative (please describe)Depends on clinical manifestations in the individual who has been tested. 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 main application of testing (other than the medical issues discussed in 3.1.4) is for reproductive purposes. In addition to the option of prenatal diagnosis (see 3.4.1) identification of a pathogenic variant in an adult makes it possible to consider preimplantation genetic diagnosis. 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, 6th Joint call for European Research Projects on Rare Diseases (JTC 2014, project CantuTreat), and by a grant from the Children’s Discovery Institute at Washington University (CH-MI-II-2015-488).