key: cord-0013936-gdr4l0uo authors: Jaeken, Jaak; Lefeber, Dirk J.; Matthijs, Gert title: SRD5A3 defective congenital disorder of glycosylation: clinical utility gene card date: 2020-05-18 journal: Eur J Hum Genet DOI: 10.1038/s41431-020-0647-3 sha: b281f3a5cedb03883551113443842431d9e30431 doc_id: 13936 cord_uid: gdr4l0uo nan 1.1 Name of the disease (synonyms) CDG-Iq; ocular coloboma with ichthyosis, brain malformations, and endocrine abnormalities; Kahrizi syndrome; mental retardation, cataract, coloboma, and kyphosis, autosomal recessive; polyprenol reductase deficiency; SRD5A3-CDG; SRD5A3 deficiency; SRD5A2L1 deficiency; steroid 5αreductase 3 deficiency; steroid 5-α-reductase 2-like deficiency. At least 15 variants have been reported: 11 nonsense variants, 3 missense variants, and a large deletion (www.lovd. nl/SRD5A3). The standard reference sequence indicating reported variants (ENSG00000128039) and a reference for exon numbering (ENST00000264228.9) can be found at http://www.ensembl.org. Sanger sequencing of the five coding exons and flanking intronic sequences of the SRD5A3 gene (NCBI reference sequence: NM_024592.4). Sanger sequencing identifies variants in >99% of patients. Deep intronic variants, large deletions and duplications would not be detected using this approach. 1.8 Estimated frequency of the disease (Incidence at birth ("birth prevalence") or population prevalence. If known to be variable between ethnic groups, please report): At least 38 genetically confirmed patients (from 26 families) have been reported [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . The frequency and the prevalence of the disease are not known. The clinical presentation of steroid 5α-reductase 3 (SRD5A3) deficiency has first been reported in 2001 [1] and the molecular defect in 2010 [6, 7] . SRD5A3 is located in the endoplasmic reticulum (ER) membrane and catalyzes the conversion of polyprenol to dolichol. Dolichol-specific kinase transfers a phosphate from cytidine triphosphate to dolichol, and synthesis of dolicholphosphate is the step just before the start of N-glycosylation and O-and C-mannosylation. SRD5A3-CDG is one of the some 130 known congenital disorders of glycosylation (CDG), genetic defects in protein and lipid glycosylation. Most CDG are multisystem disorders with predominant neurological involvement. All SRD5A3-CDG patients showed psychomotor disability, and in the majority there were various combinations of other neurological abnormalities (hypotonia, ataxia, midline brain malformation, global/cerebellar vermis hypoplasia), as well as facial dysmorphism, ophthalmological abnormalities (nystagmus, visual loss, coloboma, optic disk/nerve hypoplasia) and cutaneous symptoms (hyperpigmentation, dry skin, hypertrichosis, ichthyosis, loose skin, palmoplantar keratoderma). Symptoms reported in a minority of patients were a.o. feeding problems, cardiac malformations/hypertrophy, joint hypermobility, and hepatosplenomegaly. Symptoms that may develop over time are kyphosis, cataracts and retinitis pigmentosa. Biochemical abnormalities include increased serum transaminases, hypothyroidism, and decreased blood clotting factors antithrombin and protein C. Most patients have been reported from Afghanistan, the Czech Republic, Iran, Pakistan, Poland, Puerto Rico and Turkey. Screening for the disease is performed by serum transferrin isoelectrofocusing, showing a type 1 pattern. The diagnosis is confirmed by mutation analysis of the gene. Identification of the pathogenic variant(s) will permit heterozygote detection in the family, and prenatal diagnosis. (proportion of positive tests if the genotype is present) Close to 100% when using the serum transferrin isoelectrofocusing test. (proportion of negative tests if the genotype is not present) Close to 100% when using the serum transferrin isoelectrofocusing test. This test can be positive in secondary glycosylation disturbances e.g. due to chronic alcoholism or bacterial sialidase. 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. Close to 100%. 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. Close to 100%. (life time risk to develop the disease if the test is positive) 100%, based on positive serum transferrin isoelectrofocusing screening and SRD5A3 mutation analysis. 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: 100% (To be answered if in 1.9 "A" was marked) The prognosis regarding quality of life is mainly determined by the nature and the degree of the brain and eye involvement. Since SRD5A3-CDG is a multisystem disease, follow-up by a multidisciplinary team is mandatory. The tested person is clinically unaffected but carries an increased risk based on family history (To be answered if in 1.9 "B" was marked). (To be answered if in 1.9 "C" was marked). Usually yes, by testing the potential heterozygous persons (carriers) in the family. No. Not applicable. (To be answered if in 1.9 "D" was marked). Yes. Prenatal diagnosis should be performed by molecular analysis. SRD5A3 defective congenital disorder of glycosylation: clinical utility gene card 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). Knowledge of the diagnosis will stop unnecessary further investigations. It will also help patients and parents of affected children in the process of accepting the disease although no curative treatment is yet available. A new subtype of a congenital disorder of glycosylation (CDG) with mild clinical manifestations A new case of CDG-x with stereotyped dystonic hand movements and optic atrophy A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family An autosomal recessive syndrome Ophthalmological abnormalities in children with congenital disorders of glycosylation type I SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder A novel cerebelloocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3 Life with too much polyprenol: polyprenol reductase deficiency SRD5A3-CDG: a patient with a novel mutation A novel missense mutation in SRD5A3 causes congenital disorder of glycosylation type I (Cerebello-Ocular-Syndrome) Adult phenotype and further phenotypic variability in SRD5A3-CDG Phenotypic expansion of congenital disorder of glycosylation due to SRD5A3 null mutation SRD5A3-CDG: expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features Association of steroid 5α-reductase type 3 congenital disorder of glycosylation with early-onset retinal dystrophy Identification of a case of SRD5A3-congenital disorder of glycosylation (CDG1Q) by exome sequencing Early-onset retinal dystrophy and chronic dermatitis in a girl with an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG) Review of SRD5A3 disease-causing sequence variants and ocular findings in steroid 5α-reductase type 3 congenital disorder of glycosylation, and a detailed new case Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain Acknowledgements This work was supported by EuroGentest2 (Unit