Clinical utility gene card for: CHARGE syndrome

European Journal of Human Genetics (2011) 19; doi:10.1038/ejhg.2011.45 & 2011 Macmillan Publishers Limited All rights reserved 1018-4813/11 www.nature.com/ejhg CLINICAL UTILITY GENE CARD Clinical utility gene card for: CHARGE syndrome Kim Blake*,1, Conny MA van Ravenswaaij-Arts2, Lies Hoefsloot3 and Alain Verloes4 European Journal of Human Genetics (2011) 19, doi:10.1038/ejhg.2011.45; published online 16 March 2011 1. DISEASE CHARACTERISTICS 1.1 Name of the disease (synonyms) CHARGE syndrome (CHARGE association, Hall–Hittner syndrome). 1.2 OMIM# of the disease #214800. 1.3 Name of the analysed genes or DNA/chromosome segments CHD7. 1.4 OMIM# of the gene(s) #608892. 1.5 Mutational spectrum Predominantly heterozygous point mutations (72% nonsense or frame shift, 13% splice site and 10% missense). Less than 5% of the whole-exon deletions or microdeletions of 8q12.1, including CHD7.1–3 1.6 Analytical methods Sequencing of all coding exons, including their boundaries of CDH7, MLPA covering most coding exons, including the 5¢UTR and the first non-coding exon of CHD7. Array CGH in selected cases.4,5 Conventional cytogenetics is usually normal. Translocations with breakpoint through CHD7 have been reported incidentally (Jongmans1). 1.7 Analytical validation Sequence analysis detects 499% of the (point) mutations present in the area that has been investigated, MLPA has an estimated sensitivity of 490% for individual exons, and 495% for deletions covering more probes. 1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence’) or population prevalence) Prevalence at birth: 1:10 000 (ranges from 1:8500 to 1:15 000 in the literature).6 1.9 If applicable, prevalence in the ethnic group of investigated person There is no evidence at present for a different prevalence in various ethnic groups. 1.10 Diagnostic setting Yes No A. (Differential) diagnostics B. Predictive testing 2 2 & & C. Risk assessment in relatives D. Prenatal 2 2 & & Comment: 2. TEST CHARACTERISTICS Genotype or disease A: True positives C: False negatives B: False positives D: True negatives A/(A+C) D/(D+B) Present Absent A B Sensitivity: Specificity: Negative C D Positive predictive value: A/(A+B) Negative predictive value: D/(C+D) Test Positive 2.1 Analytical sensitivity (proportion of positive tests if the genotype is present) Depends on the method used. If only CHD7 sequencing is performed, deletions are missed less than 5% due to whole-exon or whole-gene deletions.5,7 If sequencing is combined with MLPA, 100%. 2.2 Analytical specificity (proportion of negative tests if the genotype is not present) Almost 100% (some variants may erroneously be interpreted as pathogenic). 2.3 Clinical sensitivity (proportion of positive tests if the disease is present) The clinical sensitivity 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. Depends on the clinical criteria used. In over 95% of the patients who fulfil the criteria of Blake or Verloes8,9 a mutation is found.1 In those who are suspected for CHARGE syndrome in 60–70% a mutation is found 1Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada; 2Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands; 3Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 4AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UF de Génétique Clinique, Paris, France *Correspondence: Professor K Blake, Department of Pediatrics, Dalhousie University, 5850/5980 University Avenue, Halifax, Nova Scotia, Canada. Tel: +1 902 470 6499; Fax: +1 902 470 6913; E-mail: Gene Card (CHARGE syndrome sometimes can be excluded if a patient does not fulfil the clinical criteria and does not carry a mutation or deletion of CHD7). Some conditions can mimic CHARGE syndrome: 22q11 deletion syndrome, VACTERL association, chromosomal disorders (eg, deletions 3p12p21.210), disorders caused by teratogens (eg, maternal diabetes, Accutane), and Kallmann syndrome. 2.4 Clinical specificity (proportion of negative tests if the disease is not present) The clinical specificity 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. The clinical variability of the syndrome is considerable. If the diagnosis is based on the Blake or Verloes criteria, some people with CHARGE will be missed. The clinical specificity is over 95%, since less than 5% of the patients with a CHD7 mutation do not completely fulfil these criteria. However, it should be taken into account that the mild end of the phenotypic spectrum is not completely known yet. For example, CHD7 mutations are also found in patients diagnosed with Kallmann syndrome or hypogonadotropic hypogonadism with minimal additional features of CHARGE syndrome.11,12 3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged? Gene testing is still expensive, and for that reason many parents, particularly those with older children, have not had their child tested.14 Either gene testing or clinical criteria can miss some individuals with CHARGE syndrome. However, gene testing may be important in patients who do not have the classical CHARGE characteristics and may be at risk for the long-term complications of CHARGE syndrome. 3.1.4 Will disease management be influenced by the result of a genetic test? No & Yes 2 Therapy Depends on clinical manifestations: severe gastroesophageal (please describe) reflux resulting in tube feeding, problems with swallowing and aspiration, and secretions are a cluster of the hidden problems in CHARGE Syndrome. Earlier identification of hearing and visual loss with multidisciplinary educational team, physiotherapy, occupational therapy, speech therapy, psychology. Some patients require growth hormone and many require hormones to enter puberty. Problems with bone mineral density 2.5 Positive clinical predictive value (life-time risk to develop the disease if the test is positive) 100%, but high clinical variability (see also 2.4). means nutritional therapy and physiotherapy, early in life and into adolescence (increased levels of vitamin D and calcium 2.6 Negative clinical predictive value (probability of not developing the disease if the test is negative) 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%. Index case in that family had not been tested: This depends on the a priori chance of the index to find a mutation, which varies between 60–90%. There is always a residual risk, but complete analysis (sequencing and MLPA) will reduce this by 90–95%. 3. CLINICAL UTILITY 3.1 ( (...truncated)