A child with Fructose-1, 6-bisphosphatase deficiency due to variant of FBP1 gene: Genetic and clinical analysis and literature review
10.3760/cma.j.cn511374-20241011-00529
- VernacularTitle:FBP1基因变异致果糖-1，6-二磷酸酶缺乏症患儿1例的临床及遗传学分析并文献复习
- Author:
Yingwen LIU
1
;
Lulu YAN
;
Yuxin ZHANG
;
Haibo LI
Author Information
1. 宁波大学附属妇女儿童医院出生缺陷综合防治中心，宁波 315000
- Publication Type:Journal Article
- Keywords:
Fructose-1, 6-bisphosphatase deficiency;
Fructose-bisphosphatase;
FBP1 gene;
Whole exome sequencing;
Genetic variation;
Child
- From:
Chinese Journal of Medical Genetics
2025;42(6):719-728
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the clinical characteristics and variant of FBP1 gene in a child with Fructose-1, 6-bisphosphatase deficiency (FBP1D), and review the literature on the clinical characteristics and gene mutations of FBP1D in the Chinese population. Methods:A FBP1D proband due to variant of FBP1 gene who was admitted to Women and Children′s Hospital of Ningbo University on August 10, 2021 due to "vomiting for 1 day" was selected as the study subject. The clinical data of the child were retrospectively collected. Whole exome sequencing (WES) was performed on the child, and candidate variants identified in the child were validated by Sanger sequencing in both the child and parents. The difference between wild type and variant FBP1 protein were performed using AlphaFold v3.0.1 and PyMOL v2.5.6. The pathogenicity of variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by American College of Medical Genetics and Genomics(ACMG)(hereinafter referred to as ACMG guidelines). Using keywords such as " FBP1 gene" and "fructose-1, 6-bisphosphatase deficiency" both in Chinese and English, relevant literature on FBP1D patients caused by FBP1 gene variants in Chinese population were retrieved from the PubMed databases, CNKI, and Wanfang Data Knowledge Service Platform, and the genetic variant and clinical phenotypes of FBP1D patients reported in the retrieved literature were analyzed. The literature retrieval time was set from the establishment of each database to October 31st, 2024. This study was approved by Women and Children′s Hospital of Ningbo University (Ethics No.: 2020-048). Results:The proband was presented with repeated infection, nausea, vomiting, mental illness. The auxiliary examination finding revealed hypoglycemia, acidosis, liver and kidney dysfunction, hyperlipidemia and hepatomegaly. WES and Sanger sequencing revealed that the child has harbored compound heterozygous variants of FBP1 gene, including a nonsense variant c. 778G>T (p.G260*) in exon 6 was de novo and a missense variant c. 923C>G (p.P308R) in exon 7 derived from his mother. The c. 923C>G was a known likely pathogenic variant, while c. 778G>T has not been included in databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Protein structure prediction shows that c. 778G>T (p.G260*) causes the termination codon of its encoded protein to appear prematurely, resulting in the loss of a β-fold in a core region, which may significantly reduce the stability of the protein and affect its normal function. Based on the ACMG guidelines, the c. 778G>T (p.G260*) was rated as likely pathogenic (PVS1_Strong+ PM2_Supporting+ PP4+ PM6). The literature review identified 32 patients from 23 Chinese families with FBP1D caused by FBP1 gene variants. Including the case in this study, a total of 33 patients were analyzed. Among them, 22 cases were male (66.7%), with hypoglycemia, metabolic acidosis, vomiting, seizures, hyperlactatemia, and ketosis as the primary clinical phenotypes. After treatment, only 1 case (3.0%) died due to cerebral hernia, while the remaining 32 (97.0%) had favorable outcomes. Four cases (12.1%) exhibited developmental delay. A total of 66 FBP1 gene variant sites were identified, involving 22 variant types, predominantly missense mutations (31 gene variant sites). These variants were mainly concentrated in exon 7 of the gene (25 gene variant sites), with c. 490G>A (16.7%, 11/66), c. 960_961insG (19.7%, 13/66), c. 355G>A (12.1%, 8/66), and c. 704delC (9.1%, 6/66) had the highest frequency of variants. Conclusion:The compound heterozygous variant of FBP1 gene probably underlay the FBP1D in this child. Above finding has enriched the phenotypic and mutational spectrum of the FBP1 gene and provides a basis for genetic counseling and clinical decision-making.
