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. 2023 Jul;191(7):1783-1791.
doi: 10.1002/ajmg.a.63202. Epub 2023 Apr 12.

The D409H variant in GBA1: Challenges in predicting the Gaucher phenotype in the newborn screening era

Adenrele M Gleason  1 , Andrea D'Souza  1 , Emory Ryan  1 , Angela R Grochowsky  2 , Camille R Carter  2 , Ozlem Goker-Alpan  3 , Grisel Lopez  1 , Nahid Tayebi  1 , Ellen Sidransky  1
Affiliations

The D409H variant in GBA1: Challenges in predicting the Gaucher phenotype in the newborn screening era

Adenrele M Gleason et al. Am J Med Genet A. 2023 Jul.

Abstract

Gaucher disease (GD) is an autosomal recessive disorder resulting from glucocerebrosidase deficiency due to pathologic variants in GBA1. While clinically heterogeneous, GD encompasses three types, non-neuronopathic (GD1), acute neuronopathic (GD2), and chronic neuronopathic (GD3). Newborn screening (NBS), which has made remarkable inroads in detecting certain diseases before detrimental health consequences and fatality ensues, is now being piloted for GD in several states and countries. Early on, clinical features of GD2 can overlap with GD3; hence, predicting outcome is challenging. As NBS for GD becomes more available, the increased detection of GD in neonates is inevitable. As a result, health care providers and families will be faced with uncertainty with respect to clinical management. Since more severe GBA1 variants are generally associated with neuronopathic GD, there has been an increased dependence on genotypic information. We present an infant detected by NBS with genotype D409H(p.Asp448His)/RecNciI (p.Leu483Pro; p.Ala495Pro;p.Val499=). To assist in genetic counseling, we performed a retrospective review of other patients in our cohort carrying D409H and reviewed the literature. The study illustrates the challenges faced in counseling for infants with neuronopathic GD, even with known GBA1 variants, and the tough management decisions that can ensue from detection in newborns.

Keywords: GBA1; Gaucher disease; genotype/phenotype correlation; glucocerebrosidase; neuronopathic Gaucher disease; newborn screening.

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References

REFERENCES

    1. Abrahamov, A., Elstein, D., Zimran, A., Farber, B., Glaser, Y., Gross-Tsur, V., Hadas-Halpern, I., Ronen, S., Horowitz, M., & Tafakjdi, M. (1995). Gaucher's disease variant characterised by progressive calcification of heart valves and unique genotype. Lancet (London, England), 346, 1000-1003. https://doi.org/10.1016/s0140-6736(95)91688-1
    1. Burlina, A. B., Polo, G., Rubert, L., Gueraldi, D., Cazzorla, C., Duro, G., Salviati, L., & Burlina, A. P. (2019). Implementation of second-tier tests in newborn screening for lysosomal disorders in north eastern Italy. International Journal of Neonatal Screening, 5, 24. https://doi.org/10.3390/ijns5020024
    1. Burton, B. K., Charrow, J., Hoganson, G. E., Waggoner, D., Tinkle, B., Braddock, S. R., Schneider, M., Grange, D. K., Nash, C., Shryock, H., Barnett, R., Shao, R., Basheeruddin, K., & Dizikes, G. (2017). Newborn screening for lysosomal storage disorders in Illinois: The initial 15-month experience. The Journal of Pediatrics, 190, 130-135. https://doi.org/10.1016/j.jpeds.2017.06.048
    1. Chabas, A., Cormand, B., Grinberg, D., Burguera, J. M., Balcells, S., Merino, J. L., Mate, I., Sobrino, J. A., Gonzalez-Duarte, R., & Vilageliu, L. (1995). Unusual expression of Gaucher's disease: Cardiovascular calcifications in three sibs homozygous for the D409H mutation. Journal of Medical Genetics, 32, 740-742. https://doi.org/10.1136/jmg.32.9.740
    1. Chan, A., Holleran, W. M., Ferguson, T., Crumrine, D., Goker-Alpan, O., Schiffmann, R., Tayebi, N., Ginns, E. I., Elias, P. M., & Sidransky, E. (2011). Skin ultrastructural findings in type 2 Gaucher disease: Diagnostic implications. Molecular Genetics and Metabolism, 104, 631-636. https://doi.org/10.1016/j.ymgme.2011.09.008

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