Critical appraisal of genotype assessment in molybdenum cofactor deficiency.

Autor: Hinderhofer K; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Mechler K; Pediatric Psychopharmacology, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J 5, 68159, Mannheim, Germany. konstantin.mechler@zi-mannheim.de., Hoffmann GF; Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, and Center for Rare Disorders, Heidelberg University Hospital, Heidelberg, Germany., Lampert A; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.; Cooperation Unit Clinical Pharmacy, Heidelberg University Hospital, Heidelberg, Germany., Mountford WK; University of North Carolina Wilmington, Wilmington, NC, USA.; Quintiles Inc., Smyrna, GA, USA., Ries M; Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, and Center for Rare Disorders, Heidelberg University Hospital, Heidelberg, Germany.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2017 Nov; Vol. 40 (6), pp. 801-811. Date of Electronic Publication: 2017 Sep 12.
DOI: 10.1007/s10545-017-0077-8
Abstrakt: Introduction: Molybdenum cofactor deficiency (MoCD) is an ultra-orphan, life-threatening disease. Substrate substitution therapy has successfully been performed in single cases of MoCD type A and clinical trials are underway for drug registration. We present an innovative approach for classification of genotype severity to test the hypothesis that milder sequence variants in MoCD result in a less severe disease phenotype quantitated by patient survival.
Methods: All available worldwide published cases with clinical and genetic data were included (n = 40). We stratified the already published disease causing sequence variants as mild or severe with the use of in silico prediction programs, where possible and assessed the possible impact of the variants on the expression of the gene or function of the expressed protein. In a compound heterozygous situation the mildest sequence variant determined the genotype. Subsequently, clinical manifestations and outcomes of both groups were compared.
Results: Patients with a severe genotype showed a median survival of 15 months and had a lower probability of survival compared to patients with mild genotypes who were all alive at last reported follow-up (p = 0.0203, Log-rank test).
Discussion: The severity of the genotype assessed by in silico prediction and further classification explained survival in molybdenum cofactor deficiency and may therefore be considered a confounder for the outcome of therapeutic clinical trials requiring adjustment in the clinical trial design or analysis. These results should further be investigated by future in vitro or in vivo functional studies. Caution should be taken with this approach for the classification of variants in molecular genetic diagnostics or genetic counseling.
Databáze: MEDLINE
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