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

Abstract

AbstractAlpha‐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.