Long-read single molecule real-time (SMRT) sequencing of GBA1 locus in Gaucher disease national cohort from Argentina reveals high frequency of complex allele underlying severe skeletal phenotypes: Collaborative study from the Argentine Group for Diagnosis and Treatment of Gaucher Disease

Drelichman, Guillermo; Escobar, Nicolás Fernandez; Soberon, Barbara C.; Basack, Nora; Frabasil, J.; Schenone, Andrea; Aguilar, Gabriela; Larroudé, M.S.; Knight, James; Zhao, Dongmei; Ruan, Jiapeng; Mistry, Pramod K.

doi:10.1016/j.ymgmr.2021.100820

Cited by 5 publications

(4 citation statements)

References 31 publications

(39 reference statements)

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“…Rec Nci I is the most frequent recombinant allele, and includes the variants L444P, A456P and V460V (p.[Leu483Pro;Ala495Pro;Val499=]). Similarly, in a cohort of 126 Argentinean GD patients [ 21 ], the most frequent allele was N370S followed by Rec Nci l (but with a higher allele frequency: 86.3% and 52.7%, respectively), and the most frequent genotype was N370S/Rec Nci l (46.6%, approximately twice the frequency found in Brazil). The differences between the Brazilian and Argentinean cohorts reflects the higher genetic homogeneity of the Argentinean population.…”

Section: Discussionmentioning

confidence: 92%

GBA1 variants in Brazilian Gaucher disease patients

Basgalupp,

Altmann,

Vairo

et al. 2023

Molecular Genetics and Metabolism Reports

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Section: Discussionmentioning

confidence: 92%

GBA1 variants in Brazilian Gaucher disease patients

Basgalupp,

Altmann,

Vairo

et al. 2023

Molecular Genetics and Metabolism Reports

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“…Diagnosis of GD was based on diminished levels (<10% compared to controls) of acid β-glucosidase activity in peripheral blood leukocytes and full GBA1 sequencing using a combination of pacBio sequencing, WES, and Sanger sequencing, as described previously ( Drelichman et al, 2021 ). Patients were followed every 1–2 years with standard of care evaluations, including MRI to assess organomegaly and marrow infiltration, and laboratory testing ( Charrow et al, 1998 ).…”

Section: Methodsmentioning

confidence: 99%

Osteonecrosis in Gaucher disease in the era of multiple therapies: Biomarker set for risk stratification from a tertiary referral center

Basiri

Ghaffari

Ruan

et al. 2023

eLife

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Background: A salutary effect of treatments for Gaucher disease (GD) has been reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT), and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity or anti-drug antibodies.Objective: Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center.Methods: Longitudinal follow-ups of 155 GD patients between 2001 and 2021, were analyzed for episodes of AVN on therapy, type of therapy, GBA1 genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment.Results: The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI,1.5 - 67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI,1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001).Conclusions: There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found increased risk of AVN was related to GBA genotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization.Funding: LSD Training Fellowship from Sanofi to MB.

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“…Diagnosis of GD was based on diminished levels (<10% compared to controls) of acid β-glucosidase activity in peripheral blood leukocytes and full GBA1 sequencing using a combination of pacBio sequencing, WES and Sanger sequencing, as described previously 27 . Patients were followed every 1 to 2 years with standard of care evaluations, including MRI to assess organomegaly and marrow infiltration, and laboratory testing 28 .…”

Section: Patientsmentioning

confidence: 99%

Osteonecrosis in Gaucher Disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center

Basiri¹,

Ghaffari²,

Ruan³

et al. 2023

Preprint

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BACKGROUND:A salutary effect of treatments for Gaucher disease (GD) has been reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT) , and it is not known whether it is related to individual treatments,GBAgenotypes, phenotypes, biomarkers of residual disease activity or anti-drug antibodies.OBJECTIVE:Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center.METHODS:Longitudinal follow-ups of 155 GD patients between 2001 and 2021, were analyzed for episodes of AVN on therapy, type of therapy,GBA1genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment.RESULTS:The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI,1.5 - 67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI,1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001).CONCLUSIONS:There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found increased risk of AVN was related toGBAgenotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT, developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization.Funding:LSD Training Fellowship from Sanofi to MB.

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Long-read single molecule real-time (SMRT) sequencing of GBA1 locus in Gaucher disease national cohort from Argentina reveals high frequency of complex allele underlying severe skeletal phenotypes: Collaborative study from the Argentine Group for Diagnosis and Treatment of Gaucher Disease

Cited by 5 publications

References 31 publications

GBA1 variants in Brazilian Gaucher disease patients

GBA1 variants in Brazilian Gaucher disease patients

Osteonecrosis in Gaucher disease in the era of multiple therapies: Biomarker set for risk stratification from a tertiary referral center

Osteonecrosis in Gaucher Disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center

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