The Global ALPL gene variant classification project: Dedicated to deciphering variants

Farman, Mariam R.; Rehder, Catherine; Malli, Theodora; Rockman-Greenberg, Cheryl; Dahir, Kathryn; Martos-Moreno, Gabriel Ángel; Linglart, Agnès; Ozono, Keiichi; Seefried, Lothar; del Angel, Guillermo; Webersinke, Gerald; Barbazza, Francesca; John, Lisa K.; Delana Mudiyanselage, Sewmi M.A.; Högler, Florian; Nading, Erica Burner; Huggins, Erin; Rush, Eric T.; El-Gazzar, Ahmed; Kishnani, Priya S.; Högler, Wolfgang

doi:10.1016/j.bone.2023.116947

Cited by 9 publications

(1 citation statement)

References 30 publications

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“…To further classify VUS, the ClinGen expert group adopted a Bayesian framework to facilitate the automatic quantitative evaluation of pathogenicity ( Tavtigian et al, 2018 ). In addition, multidisciplinary cooperation such as clinical phenotypic assessment, in-depth literature research including artificial intelligence, and protein structure analysis have become important tools for VUS classification ( Caswell et al, 2022 ; Casaletto et al, 2023 ; Farman et al, 2024 ). However, the pathogenicity of rare diseases still lacks sufficient samples, and artificial intelligence is easily affected by parameter changes.…”

Section: Discussionmentioning

confidence: 99%

Using metabolic abnormalities of carriers in the neonatal period to evaluate the pathogenicity of variants of uncertain significance in methylmalonic acidemia

Xiao,

Shi,

Zhang

et al. 2024

Front. Genet.

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ObjectiveTo accurately verify the pathogenicity of variants of uncertain significance (VUS) in MUT and MMACHC genes through mass spectrometry and silico analysis.MethodsThis multicenter retrospective study included 35 participating units (ClinicalTrials.gov ID: NCT06183138). A total of 3,071 newborns (within 7 days of birth) were sorted into carrying pathogenic/likely pathogenic (P/LP) variants and carrying VUS, non-variant groups. Differences in metabolites among the groups were calculated using statistical analyses. Changes in conservatism, free energy, and interaction force of MMUT and MMACHC variants were analyzed using silico analysis.ResultsThe percentage of those carrying VUS cases was 68.15% (659/967). In the MMUT gene variant, we found that C3, C3/C2, and C3/C0 levels in those carrying the P/LP variant group were higher than those in the non-variant group (p < 0.000). The conservative scores of those carrying the P/LP variant group were >7. C3, C3/C0, and C3/C2 values of newborns carrying VUS (c.1159A>C and c.1286A>G) were significantly higher than those of the non-variant group and the remaining VUS newborns (p < 0.005). The conservative scores of c.1159A>C and c.1286A>G calculated by ConSurf analysis were 9 and 7, respectively. Unfortunately, three MMA patients with c.1159A>C died during the neonatal period; their C3, C3/C0, C3/C2, and MMA levels were significantly higher than those of the controls.ConclusionCommon variants of methylmalonic acidemia in the study population were categorized as VUS. In the neonatal period, the metabolic biomarkers of those carrying the P/LP variant group of the MUT gene were significantly higher than those in the non-variant group. If the metabolic biomarkers of those carrying VUS are also significantly increased, combined with silico analysis the VUS may be elevated to a likely pathogenic variant. The results also suggest that mass spectrometry and silico analysis may be feasible screening methods for verifying the pathogenicity of VUS in other inherited metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

Using metabolic abnormalities of carriers in the neonatal period to evaluate the pathogenicity of variants of uncertain significance in methylmalonic acidemia

Xiao,

Shi,

Zhang

et al. 2024

Front. Genet.

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New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry

Kishnani,

Seefried,

Dahir

et al. 2024

American J of Med Genetics Pt A

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Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue‐nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease‐causing variants; 4.4% had variants of uncertain significance. Disease‐causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%–23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty‐three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population.

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Pyridoxine challenge reflects pediatric hypophosphatasia severity and thereby examines tissue-nonspecific alkaline phosphatase's role in vitamin B6 metabolism

Whyte,

Zhang,

Mack

et al. 2024

Bone

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The Global ALPL gene variant classification project: Dedicated to deciphering variants

Cited by 9 publications

References 30 publications

Using metabolic abnormalities of carriers in the neonatal period to evaluate the pathogenicity of variants of uncertain significance in methylmalonic acidemia

Using metabolic abnormalities of carriers in the neonatal period to evaluate the pathogenicity of variants of uncertain significance in methylmalonic acidemia

New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry

Pyridoxine challenge reflects pediatric hypophosphatasia severity and thereby examines tissue-nonspecific alkaline phosphatase's role in vitamin B6 metabolism

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