An unusual diagnosis of alpha-mannosidosis with ocular anomalies: Behind the scenes of a hidden copy number variation.

Autor: Uguen K; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.; Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Redon S; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.; Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Rouault K; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.; Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Pensec M; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France., Benech C; Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Schutz S; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.; Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Zanlonghi X; Centre de compétence maladie rare, Service d'Ophtalmologie, CHU Rennes, Rennes, France., Nadjar Y; Département de Neurologie, Centre de Référence des Maladies Lysosomales, Hôpital Pitié-Salpêtrière, AP-HP.Sorbonne Université, Paris, France., Le Maréchal C; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.; Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Férec C; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.; Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Audebert-Bellanger S; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 May; Vol. 194 (5), pp. e63532. Date of Electronic Publication: 2024 Jan 08.
DOI: 10.1002/ajmg.a.63532
Abstrakt: Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in the MAN2B1 gene and characterized by a wide clinical heterogeneity. Diagnosis for this multisystemic disorder is confirmed by the presence of either a deficiency in the lysosomal enzyme acid alpha-mannosidase or biallelic mutations in the MAN2B1 gene. This diagnosis confirmation is crucial for both clinical management and genetic counseling purposes. Here we describe a late diagnosis of alpha-mannosidosis in a patient presenting with syndromic intellectual disability, and a rare retinopathy, where reverse phenotyping played a pivotal role in interpreting the exome sequencing result. While a first missense variant was classified as a variant of uncertain significance, the phenotype-guided analysis helped us detect and interpret an in-trans apparent alu-element insertion, which appeared to be a copy number variant (CNV) not identified by the CNV caller. A biochemical analysis showing abnormal excretion of urinary mannosyloligosaccharide and an enzyme assay permitted the re-classification of the missense variant to likely pathogenic, establishing the diagnosis of alpha-mannosidosis. This work emphasizes the importance of reverse phenotyping in the context of exome sequencing.
(© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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