European Journal of Human Genetics (2015) 23, doi:10.1038/ejhg.2015.9 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg CLINICAL UTILITY GENE CARD Clinical utility gene card for: ALG1 defective congenital disorder of glycosylation Jaak Jaeken*,1, Dirk Lefeber2 and Gert Matthijs3 European Journal of Human Genetics (2015) 23, doi:10.1038/ejhg.2015.9; published online 4 February 2015 1. DISEASE CHARACTERISTICS are known to the authors. The frequency and the prevalence of the 1.1 Name of the disease (synonyms) disease are not known. Deficiency of GDP-Man:GlcNAc2-PP-Dol mannosyltransferase, manno- syltransferase 1 deficiency, ALG1-CDG, CDG-Ik. 1.9 Diagnostic setting 1.2 OMIM# of the disease 608540 Yes No A. (Differential) diagnostics ⊠ ⊠ 1.3 Name of the analysed genes or DNA/chromosome segments: B. Predictive testing C. Risk assessment in relatives ⊠ □ ALG1. D. Prenatal ⊠ □ 1.4 OMIM# of the gene 605907. Comment: ALG1-CDG belongs to the five most common N-glycosylation 1.5 Mutational spectrum disorders together with PMM2-CDG, ALG6-CDG, MPI-CDG and Thirteen variants have been reported: ten missense variants, two SRD5A3-CDG. It is an autosomal recessive disease with a broad splicing variants and one deletion variant. The most frequent variant clinical spectrum, and with early death at the second day of life to – is c.773C4T(p.Ser258Leu)1–6 (www.lovd.nl/ALG1). The standard survival beyond the age of 20 years.1 10 Its phenotype is characterized reference sequence indicating reported variants (ENSG00000033011) by a predominant neurological involvement. Constant features are an and a reference for exon numbering (ENST00000262474) can be intellectual developmental disorder (mostly severe) and hypotonia found at http://www.ensembl.org. (sometimes only infantile). A majority of patients show dysmorphism (facial dysmorphism, inverted nipples, fat pads, contractures, arachno- 1.6 Analytical methods dactyly a.o.), microcephaly (mostly neonatal), intractable seizures Sanger sequencing of the thirteen coding exons and flanking intronic (with neonatal or later onset), visual disturbances (strabismus, nystagmus, retinopathy and/or (in some patients) severe visual loss), sequences of the ALG1 gene using primers designed to discriminate tremor, ataxia, severe infections/episodes of unexplained fever and between this gene and its documented pseudogenes (NCBI reference cerebral abnormalities (cerebral infarct, general atrophy and/or sequence: NM_019109.4). periventricular white matter abnormalities). Symptoms reported in only one or a few patients are feeding problems, gastrointestinal 1.7 Analytical validation problems (diarrhoea and ascites), growth retardation, hearing loss, fi 4 Sanger sequencing identi es the variants in 99% of patients. areflexia, spastic tetraparesis, stereotypic movements, peripheral neu- Deep intronic variants, large deletions and duplications would not ropathy, repiratory problems (including pleural effusion), pericardial be detected using this approach. Novel variants with uncertain effusion, oedema, hepatomegaly, cholestatic jaundice, portal hyperten- pathogenic nature are of course possible. sion, Budd–Chiari syndrome, nephrotic syndrome, spontaneous haemorrhage and venous thrombosis. Biochemical abnormalities are 1.8 Estimated frequency of the disease decreased levels of serum LDL cholesterol, blood coagulation factor XI (Incidence at birth (‘birth prevalence’) or population prevalence. and anticoagulation factors antithrombin, protein C and protein S, If known to be variable between ethnic groups, please report): as well as variable hypoalbuminemia, increased serum transaminases, Nineteen patients (belonging to fourteen families) have been decreased serum cholinesterase and immunoglobulins, and endocri- reported1–10 and thirteen unpublished patients (from nine families) nological abnormalities (such as decreased serum IGF1 and IGFBP3). 1Centre for Metabolic Disease, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium; 2Department of Neurology, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboudumc, Nijmegen, The Netherlands; 3Centre for Human Genetics, KU Leuven, Leuven, Belgium *Correspondence: Professor J Jaeken, Centre for Metabolic Disease, University Hospital Gasthuisberg, Herestraat 49, BE 3000 Leuven, Belgium. Tel: +32 16 343827; Fax: +32 16 343842; E-mail: [email protected] Received 8 September 2014; revised 11 December 2014; accepted 19 December 2014; published online 4 February 2015 Clinical Utility Gene Card e2 Serum transferrin isoelectrofocusing, capillary zone electrophoresis or 2.6 Negative clinical predictive value HPLC show a type 1 pattern, and analysis of short dolichol-linked (probability not to develop the disease if the test is negative) oligosaccharides (DLO) in fibroblasts shows an increase of Assume an increased risk based on the family history for a GlcNAc2-PP-dolichol. The diagnosis has to be confirmed by mutation nonaffected person. Allelic and locus heterogeneity may need to be analysis of ALG1. As the DLO analysis, especially of short DLO’s, is considered. cumbersome, produces sometimes equivocal results, and is only Index case in that family had been tested: available in very few centres in a research setting, an upcoming 100% strategy is to subject the DNA to Next-Generation Sequencing Index case in that family had not been tested: methods such as a CDG panel of genes known to be involved in 100% CDG or whole-exome sequencing. The identification of the variant that affects function will permit heterozygote detection in the family 3. CLINICAL UTILITY and prenatal diagnosis. 3.1 (Differential) diagnostics: the tested person is clinically affected Since the patients with ALG1-CDG may have dysmorphic features (To be answered if in 1.9 ‘A’ was marked) resembling those observed in PMM2-CDG (that is, inverted nipples, subcutaneous fat pads), ALG1-CDG should be considered when 3.1.1 Can a diagnosis be made other than through a genetic test? PMM2-CDG was searched and ruled out by PMM2 molecular analysis. No □ (continue with 3.1.4) Yes ⊠ 2. TEST CHARACTERISTICS Clinically ⊠ Imaging □ Endoscopy □ A: True positives C: False negative Genotype or disease Biochemistry ⊠ B: False positives D: True negative Electrophysiology □ Present Absent Other (please describe): Test Positive A B Sensitivity: A/(A+C) 3.1.2 Describe the burden of alternative diagnostic methods to the fi Speci city: D/(D+B) patient Negative C D Positive predictive value: A/(A+B) The blood sampling for the serum transferrin isoelectrofocusing Negative predictive value: D/(C+D) screening test and that for the mutation analysis is a minor burden to the patient. 2.1 Analytical sensitivity 3.1.3 How is the cost effectiveness of alternative diagnostic methods to (proportion of positive tests if the genotype is present) be judged? Close to 100% when using the serum transferrin isoelectro- It differs among countries. In Belgium and The Netherlands the cost focusing test. of these tests is largely carried by the national assurance organism. 2.2 Analytical specificity fl (proportion of negative tests if the genotype is not present) 3.1.4 Will disease management be in uenced by the result of a Close to 100% when using the serum transferrin isoelectrofocusing genetic test? test. This test can be positive in secondary glycosylation disturbances No □ such as galactosemia and hereditary fructose intolerance, and due to Yes ⊠ bacterial sialidase.11–13 Therapy (please Treatment of ALG1-CDG is purely symptomatic. describe) 2.3 Clinical sensitivity Prognosis (please Molecular testing is essential for confirmation of the (proportion of positive tests if the disease is present) describe) diagnosis and the genetic counselling of the families The clinical sensitivity can be dependent on variable factors such as concerned. age or family history. In such cases a general statement should Management (please ALG1-CDG is a multi-system disease with major neuro- be given, even if a quantification can only be made case by case. describe) logical involvement. Follow-up by a multidisciplinary Close to 100%. team is important. 2.4 Clinical specificity (proportion of negative tests if the disease is not present) 3.2 Predictive setting: the tested person is clinically unaffected but fi The clinical speci city can be dependent on variable factors such as carries an increased risk based on family history age or family history. In such cases a general statement should be (To be answered if in 1.9 ‘B’ was marked) given, even if a quantification can only be made case by case. Close to 100%. 3.2.1 Will the result of a genetic test influence lifestyle and prevention? 2.5 Positive clinical predictive value If the test result is positive (please describe): (lifetime risk to develop the disease if the test is positive) Not applicable 100%, based on positive serum transferrin isoelectrofocusing If the test result is negative (please describe): screening and ALG1 mutation analysis. Not applicable European Journal of Human Genetics Clinical Utility Gene Card e3 3.2.2 Which options in view of lifestyle and prevention does a person ACKNOWLEDGEMENTS at risk have if no genetic test has been done (please describe)? This work was supported by EuroGentest2 (Unit 2: ‘Genetic testing as part of Not applicable. health care’), a Coordination Action under FP7 (Grant Agreement Number 261469) and the European Society of Human Genetics. 3.3 Genetic risk assessment in family members of a diseased person (To be answered if in 1.9 ‘C’ was marked)