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

Abstract

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.

• Authors: Kevin Uguen, Sylvia Redon, Karen Rouault, Marine Pensec, Caroline Benech, Sacha Schutz, Xavier Zanlonghi, Yann Nadjar, Cédric Le Maréchal, Claude Férec, Séverine Audebert-Bellanger
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 194 Issue 5 Pg. e63532 (May 2024) ISSN: 1552-4833 [Electronic] United States
• PMID: 38192009 (Publication Type: Case Reports)
• Copyright: © 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.

Chemical References

• alpha-Mannosidase

Topics

• Humans
• alpha-Mannosidosis (diagnosis, genetics)
• DNA Copy Number Variations (genetics)
• alpha-Mannosidase (genetics)
• Mutation, Missense (genetics)
• Phenotype