β-Mannosidosis caused by a novel homozygous intragenic inverted duplication in MANBA
- Maria Blomqvist1,2,
- Marie Falkenberg Smeland3,
- Julia Lindgren1,
- Per Sikora4,5,
- Hilde Monica Frostad Riise Stensland3 and
- Jorge Asin-Cayuela1,2
- 1Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg 413 45, Sweden;
- 2Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg 413 45, Sweden;
- 3Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø 9038, Norway;
- 4Laboratory Medicine, Sahlgrenska University Hospital, Gothenburg 413 45, Sweden;
- 5Clinical Genomics Gothenburg, Science for Life Laboratories, Gothenburg 405 30, Sweden
- Corresponding author: maria.k.blomqvist{at}vgregion.se
Abstract
β-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme β-mannosidase. The disease is caused by mutations in MANBA and is extremely rare in humans. Although the clinical presentation is heterogeneous, common symptoms include various degrees of developmental delay, behavioral disturbances, hearing loss, and frequent infections. We report a 15-yr-old girl presenting with mild intellectual disability, sensorineural hearing loss, severe behavioral disturbances, dysmorphic traits, and evolving angiokeratomas. Copy-number variation analysis of next-generation sequencing (NGS) data indicated increased coverage in exons 8–11 of MANBA. Low β-mannosidase activity (1 µkatal/kg protein, refv 25–40) established the diagnosis of β-mannosidosis. Whole-genome sequencing (WGS) and cDNA analysis revealed a novel homozygous intragenic inverted duplication in MANBA, where a 13.1-kb region between introns 7 and 11 was duplicated and inserted in an inverted orientation, creating a 67-base nonduplicated gap at the insertion point. Both junctions showed microhomology regions. The inverted duplication resulted in exon skipping of exons 8–9 or 8–10. Our report highlights the importance of copy-number variation analysis of data from NGS and in particular the power of WGS in the identification and characterization of copy-number variants.
- abnormality of the vasculature of the conjunctiva
- aggressive behavior
- alacrima
- angiokeratoma corporis diffusum
- attention-deficit hyperactivity disorder
- bilateral sensorineural hearing impairment
- broad nasal tip
- chronic constipation
- hypohidrosis/hyperhidrosis
- impulsivity
- increased urinary disaccharide excretion
- intellectual disability, mild
- sleep disturbance
- thin upper lip vermilion
- upslanted palpebral fissure
- wide nasal ridge
Footnotes
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[Supplemental material is available for this article.]
- Received January 11, 2019.
- Accepted March 4, 2019.
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