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Genotype-phenotype correlations
Original research
Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement
  1. Sonal Mahajan1,
  2. Bobby George Ng1,
  3. Lama AlAbdi2,3,
  4. Paul Daniel James Earnest4,
  5. Paulina Sosicka1,
  6. Nisha Patel2,
  7. Rana Helaby2,
  8. Firdous Abdulwahab2,
  9. Miao He4,
  10. Fowzan S Alkuraya2,
  11. Hudson H Freeze1
  1. 1Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
  2. 2Department of Translational Genomics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  3. 3Department of Zoology, College of Science, King Saud University, Riyadh, Riyadh Province, Saudi Arabia
  4. 4Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Hudson H Freeze, Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; hudson{at}sbpdiscovery.org

Abstract

Background Enzymes of the Golgi implicated in N-glycan processing are critical for brain development, and defects in many are defined as congenital disorders of glycosylation (CDG). Involvement of the Golgi mannosidase, MAN2A2 has not been identified previously as causing glycosylation defects.

Methods Exome sequencing of affected individuals was performed with Sanger sequencing of the MAN2A2 transcript to confirm the variant. N-glycans were analysed in patient-derived lymphoblasts to determine the functional effects of the variant. A cell-based complementation assay was designed to assess the pathogenicity of identified variants using MAN2A1/MAN2A2 double knock out HEK293 cell lines.

Results We identified a multiplex consanguineous family with a homozygous truncating variant p.Val1101Ter in MAN2A2. Lymphoblasts from two affected brothers carrying the same truncating variant showed decreases in complex N-glycans and accumulation of hybrid N-glycans. On testing of this variant in the developed complementation assay, we see the complete lack of complex N-glycans.

Conclusion Our findings show that pathogenic variants in MAN2A2 cause a novel autosomal recessive CDG with neurological involvement and facial dysmorphism. Here, we also present the development of a cell-based complementation assay to assess the pathogenicity of MAN2A2 variants, which can also be extended to MAN2A1 variants for future diagnosis.

  • Human Genetics
  • Genetic Variation

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmg-2022-108821

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Twitter @Sonallmahajan

    • Contributors Conceptualisation: BGN, SM and HHF. Clinical data collection and analysis: BGN, LA, NP, RH, FA and FSA. Methodology: BGN, SM, PS and PDJE. Formal analysis and investigation: SM. Writing and original draft preparation: SM. Writing, review and editing: SM, BGN and HHF. Resources: HHF, FSA and MH. All authors reviewed the final manuscript. HF act as guarantor of the study and hereby accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

    • Funding This work was supported by The Rocket Fund, R01DK 099551, U54 NS115198 NIH-FCDGC (Frontiers for Congenital Disorders of Glycosylation Consortium, Rare Disease Consortium), King Salman Centre for Disability Research through Research Group no RG-2022–011 (FSA) and King Saud University through Researchers Supporting Project number RSP-2021/181 (LA). SM is FCDGC fellow.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.