Severe congenital neutropenia type 4: a rare disease harboring a &lt;i&gt;G6pc3&lt;/i&gt; gene pathogenic variant particular to the mexican population

López-Rodríguez, Larissa; Svyryd, Yevgeniya; Benitez-Alonso, Edmar; Rivero-García, Pamela; Luna‐Muñoz, Leonora; Mutchinick, Osvaldo M.

doi:10.24875/ric.22000234

Cited by 3 publications

(3 citation statements)

References 23 publications

(39 reference statements)

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“…Among all the mutations causing G6PC3 deficiency, a few are only found in specific ethnic groups, implying founder effects 6 . For instance, the c.210delC variant has been reported in 13 G6PC3 deficient patients, who are either homozygous or compound heterozygous for this variant 4,15–17 . Among them, 12 patients are of Mexican descent, while another patient is included from the North American Severe Chronic Neutropenia International Registry 15 .…”

Section: Resultsmentioning

confidence: 99%

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

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Background: G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Objective: The G6PC3 c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it. Methods: Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date. Results: Based on the length of haplotypes shared amongst ten carriers of the G6PC3 c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency. Conclusion: The G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

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Section: Resultsmentioning

confidence: 99%

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

Self Cite

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“…The G6PC3 c.210delC variant found in Mexico originated from a founder effect Among all the mutations causing G6PC3 de ciency, a few are only found in speci c ethnic groups, implying founder effects 6 . For instance, the c.210delC variant has been reported in 13 G6PC3 de cient patients, who are either homozygous or compound heterozygous for this variant 4,[32][33][34] . Among them, 12 patients are of Mexican descent, while another patient is included from the North American Severe Chronic Neutropenia International Registry 32 .…”

Section: Resultsmentioning

confidence: 99%

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

View full text Add to dashboard Cite

G6PC3 deficiency is a monogenic immunometabolic disorder that causes syndromic congenital neutropenia. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican origin. Based on the shared haplotypes amongst carriers of the c.210delC mutation, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it originated in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived cells. G6PC3 pathology is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the variant c.210delC impacts glycolysis by performing extracellular flux assays on patient-derived cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3 deficient patients reported in the literature to date, and we found that c.210delC carriers display all prominent clinical features observed in prior G6PC3 deficient patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

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“…Published information on cohorts of patients with IBMFS from LMICs, including Mexico, remains scarce. Comprehensive available data of Mexican patients with IBMFS are predominantly case reports or small case series, such as those for patients with FA ( García-de Teresa et al, 2019 ; Reyes et al, 2022 ), or case reports from a limited number of patients with DC or SCN ( López-Rodríguez et al, 2022 ; Picos-Cárdenas et al, 2022 ; Velez-Tirado et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico

Leal-Anaya,

Kimball,

Yanez-Felix

et al. 2024

Front. Genet.

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Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS.Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), Shwachman–Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI).Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (<1 year), followed by DBA (2 years) and DC (5 years).Conclusions: Thorough examination of reported clinical data allowed us to highly suspect a specific IBMFS in approximately 70% of patients; however, an important number of patients remained with suspicion of an undefined IBMFS. Implementation of NGS and telomere length measurement are forthcoming measures to improve IBMFS diagnosis in Mexico.

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Severe congenital neutropenia type 4: a rare disease harboring a <i>G6pc3</i> gene pathogenic variant particular to the mexican population

Cited by 3 publications

References 23 publications

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico

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