An unusual diagnosis of alpha-mannosidosis with ocular anomalies: Behind the scenes of a hidden copy number variation.
CNV
MAN2B1
alpha-mannosidosis
exome sequencing
retinopathy
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
08 Jan 2024
08 Jan 2024
Historique:
revised:
09
12
2023
received:
10
10
2023
accepted:
22
12
2023
medline:
9
1
2024
pubmed:
9
1
2024
entrez:
9
1
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38192009
doi: 10.1002/ajmg.a.63532
doi:
Types de publication
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
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