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.

Objective:To apply optical genome mapping (OGM) technique for the analysis of genetic etiology in two rare families with complex chromosomal rearrangements (CCRs) and to provide precise reproductive guidance to them.Methods:Two Chinese families diagnosed with chromosomal rearrangements by chromosomal microarray analysis (CMA) or whole-exome sequencing (WES) between June and December 2023 at the Affiliated Women and Children′s Hospital of Ningbo University were selected as the study subjects. In both cases, unbalanced chromosomal translocations were suspected. Clinical data were collected, and peripheral blood from the couple, amniotic fluid sample and aborted fetal tissue was subjected to combined G-banding karyotyping and OGM for comprehensive genetic analysis. This study has been approved by the Medical Ethics Committee of the Hospital (Ethic No.: EC2023-094).Results:In family 1, the fetus was signaled to have abnormal chromosome 7 by non-invasive prenatal testing (NIPT), prompting amniocentesis and CMA detection. In family 2, a pregnancy loss had occurred at 10 weeks′ gestation, and trio-WES was carried out. Both fetuses were found to harbor copy number variations (CNVs) suggestive of unbalanced CCRs. Further analysis with OGM has revealed that, in family 1, an unbalanced rearrangement involving chromosomes 7, 8, and 10 was carried by the fetus and the pregnant woman, which has formed der(8) and der(10) derivative chromosomes. In family 2, a maternal CCR was found, which involved chromosomes 2 and 13 with seven breakpoints, resulting in unbalanced fetal CNVs. After genetic counseling, family 1 opted to continue with the pregnancy, considering the woman′s normal appearance and inheritance of the rearrangement. For both families remained to have a risk for unbalanced rearrangements in subsequent pregnancies, preimplantation genetic testing (PGT) was recommended.Conclusion:In both families, the OGM has precisely delineated the genetic basis of fetal CNVs and mapped the maternal CCR breakpoints, providing critical insights for genetic counseling and reproductive decision-making.

Objective:To explore the clinical characteristics and gene variant of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant. Methods:A fetus with Farber lipogranulomatosis caused by ASAH1 gene variant diagnosed at Women and Children′s Hospital of Ningbo University in August 2024 was selected as the subject. Clinical data and abortion tissue samples of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Sanger sequencing validation and bioinformatics analysis were performed on candidate variants. This study was approved by Women and Children′s Hospital of Ningbo University (Ethics No. EC2020-048). Results:Generalized skin oedema, pericardial effusion, right pleural effusion and increased bowel echogenicity of the fetus were founded by prenatal ultrasound. WES revealed that the fetus has harbored a homozygous c. 101C>A(p.Ser34Ter) variation in exon 2 of the ASAH1 gene. Sanger sequencing confirmed that both parents carry the heterozygous nonsense variation c. 101C>A (p.Ser34Ter) in ASAH1 gene, which has not been included in databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Based on the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PM2_Supporting+ PVS1+ PM3_Supporting). The AlphaFold3 model protein structure prediction reveals that the c. 101C>A variant caused the premature appearance of a termination codon, resulting in only a small partial α-helix structure in the N-terminal of the encoded ASAH1 protein, with the complete loss of the α-helix structure in the core domain, which might lead to the loss of function of this protein. Conclusion:The c. 101C>A(p.Ser34Ter) variant of the ASAH1 gene probably underlay the Farber lipogranulomatosis with hydrops fetalis in this fetus. The newly discovered c. 101C>A(p.Ser34Ter) variant has enriched the mutational spectrum of Farber lipogranulomatosis.

Objective:To explore the genetic characteristics of a fetus affected with Structural heart defects and renal anomalies syndrome (SHDRA).Methods:A pedigree with SHDRA (fetus and the parents) who had visited the Affiliated Women and Children′s Hospital of Ningbo University in April 2023 was selected as the study subject. Clinical data of the family were collected. A total of 10 mL of amniotic fluid cells from the fetus and 5 mL of peripheral blood samples from the parents were collected for genomic DNA extraction. Trio whole-exome sequencing (Trio-WES) was performed, and Sanger sequencing was used to validate candidate variants in the family. The identified variants were classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the " ACMG Guidelines). Relevant research literature on SHDRA in domestic and international databases were searched for literature review. This study was approved by the Affiliated Women and Children′s Hospital of Ningbo University (Ethics No. EC2023-094).Results:①In this family, prenatal ultrasound at 18 weeks of gestation revealed left renal multicystic dysplasia in the fetus. After birth, the infant exhibited an ostium secundum atrial septal defect, patent ductus arteriosus, and left renal multicystic dysplasia. Trio-WES revealed that the fetus had carried c. 344dup(p.L116Afs*32) and c. 90_104dup(p.Ala31_Ala35dup) compound heterozygous variants in the TMEM260 gene, which were respectively inherited from its father and mother. According to the ACMG guidelines, the c. 344dup(p.L116Afs*32) and c. 90_104dup (p.Ala31_Ala35dup) variants were classified as pathogenic (PM2_Supporting+ PVS1+ PP4) and likely pathogenic (PM2_Supporting+ PM4+ PM3+ PP4), respectively. ②According to the literature search strategy set for this study, a total of 6 literature was retrieved, involving 25 SHDRA patients from 20 families. Together with the patients in this study, there were 14 TMEM260 gene variants, most of which were frameshift variants (7 types) and had located in exons 3, 11 and 13. The main clinical features of SHDRA were congenital heart malformation, renal abnormality and neurodevelopmental abnormality, and there was a lack of genotype-phenotype correlation. Conclusion:The c. 344dup(p.L116Afs*32) and c. 90_104dup(p.Ala31_Ala35dup) variants of the TMEM260 gene probably underlay the SHDRA in this family. Above finding has provided a basis for clinical diagnosis and genetic counseling for the family.

OBJECTIVE: To explore the clinical characteristics and gene variant of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant. METHODS: A fetus with Farber lipogranulomatosis caused by ASAH1 gene variant diagnosed at Women and Children's Hospital of Ningbo University in August 2024 was selected as the subject. Clinical data and abortion tissue samples of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Sanger sequencing validation and bioinformatics analysis were performed on candidate variants. This study was approved by Women and Children's Hospital of Ningbo University (Ethics No. EC2020-048). RESULTS: Generalized skin oedema, pericardial effusion, right pleural effusion and increased bowel echogenicity of the fetus were founded by prenatal ultrasound. WES revealed that the fetus has harbored a homozygous c.101C>A (p.Ser34Ter) variation in exon 2 of the ASAH1 gene. Sanger sequencing confirmed that both parents carry the heterozygous nonsense variation c.101C>A (p.Ser34Ter) in ASAH1 gene, which has not been included in databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Based on the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PM2_Supporting+PVS1+PM3_Supporting). The AlphaFold3 model protein structure prediction reveals that the c.101C>A variant caused the premature appearance of a termination codon, resulting in only a small partial α-helix structure in the N-terminal of the encoded ASAH1 protein, with the complete loss of the α-helix structure in the core domain, which might lead to the loss of function of this protein. CONCLUSION The c.101C>A (p.Ser34Ter) variant of the ASAH1 gene probably underlay the Farber lipogranulomatosis with hydrops fetalis in this fetus. The newly discovered c.101C>A (p.Ser34Ter) variant has enriched the mutational spectrum of Farber lipogranulomatosis.
Humans ; Female ; Pregnancy ; Acid Ceramidase/chemistry* ; Farber Lipogranulomatosis/diagnostic imaging* ; Fetus ; Exome Sequencing ; Adult

OBJECTIVE: To explore the genetic characteristics of a fetus affected with Structural heart defects and renal anomalies syndrome (SHDRA). METHODS: A pedigree with SHDRA (fetus and the parents) who had visited the Affiliated Women and Children's Hospital of Ningbo University in April 2023 was selected as the study subject. Clinical data of the family were collected. A total of 10 mL of amniotic fluid cells from the fetus and 5 mL of peripheral blood samples from the parents were collected for genomic DNA extraction. Trio whole-exome sequencing (Trio-WES) was performed, and Sanger sequencing was used to validate candidate variants in the family. The identified variants were classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the "ACMG Guidelines). Relevant research literature on SHDRA in domestic and international databases were searched for literature review. This study was approved by the Affiliated Women and Children's Hospital of Ningbo University (Ethics No. EC2023-094). RESULTS: In this family, prenatal ultrasound at 18 weeks of gestation revealed left renal multicystic dysplasia in the fetus. After birth, the infant exhibited an ostium secundum atrial septal defect, patent ductus arteriosus, and left renal multicystic dysplasia. Trio-WES revealed that the fetus had carried c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) compound heterozygous variants in the TMEM260 gene, which were respectively inherited from its father and mother. According to the ACMG guidelines, the c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants were classified as pathogenic (PM2_Supporting+PVS1+PP4) and likely pathogenic (PM2_Supporting+PM4+PM3+PP4), respectively. According to the literature search strategy set for this study, a total of 6 literature was retrieved, involving 25 SHDRA patients from 20 families. Together with the patients in this study, there were 14 TMEM260 gene variants, most of which were frameshift variants (7 types) and had located in exons 3, 11 and 13. The main clinical features of SHDRA were congenital heart malformation, renal abnormality and neurodevelopmental abnormality, and there was a lack of genotype-phenotype correlation. CONCLUSION The c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants of the TMEM260 gene probably underlay the SHDRA in this family. Above finding has provided a basis for clinical diagnosis and genetic counseling for the family.
Humans ; Female ; Pedigree ; Membrane Proteins/genetics* ; Male ; Heart Defects, Congenital/genetics* ; Kidney/abnormalities* ; Pregnancy ; Adult ; Kidney Diseases/congenital* ; Exome Sequencing ; Mutation ; Genetic Testing

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. 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 his parents. The difference between wild type and variant FBP1 protein were compared using AlphaFold v3.0.1 and PyMOL v2.5.6. The pathogenicity of candidate 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 the Chinese population were retrieved from the PubMed database, CNKI, and Wanfang Data Knowledge Service Platform, and the genetic variant and clinical phenotypes of FBP1D patients reported in the literature were analyzed. The literature retrieval time was set from the establishment of each database to October 31st, 2024. This study was approved by the Women and Children's Hospital of Ningbo University (Ethics No.: 2020-048). RESULTS: The proband was presented with repeated infections, nausea, vomiting, and mental illness. The auxiliary examination revealed hypoglycemia, acidosis, liver and kidney dysfunction, hyperlipidemia and hepatomegaly. WES and Sanger sequencing revealed that the child has harbored compound heterozygous variants of the FBP1 gene, including a de novo nonsense variant c.778G>T (p.G260*) in exon 6 and a maternally derived missense variant c.923C>G (p.P308R) in exon 7. The c.923C>G was known as a likely pathogenic variant, while c.778G>T has not been included in the databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Protein structure prediction shows that the c.778G>T (p.G260*) variant may result in a premature termination codon, resulting in loss of a β-fold in a core region, which may significantly reduce the stability of its protein product and affect its function. Based on the ACMG guidelines, the c.778G>T (p.G260*) variant was rated as likely pathogenic (PVS1_Strong+PM2_Supporting+PP4+PM6). Literature review has identified 32 patients from 23 Chinese families with FBP1D due to FBP1 gene variants. Together with the case reported in this study, in total 33 patients were analyzed. Among them, 22 cases were males (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, which involved 22 variant types, predominantly missense mutations (31 gene variant sites). These variants were mainly located in exon 7 of the gene (25 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) being the most common variants. CONCLUSION The heterozygous variant of the FBP1 gene probably underlay the FBP1D in this child. Above finding has enriched the phenotypic and mutational spectrum of the FBP1 gene and provided a basis for genetic counseling and clinical decision-making.
Humans ; Fructose-1,6-Diphosphatase Deficiency/genetics* ; Fructose-Bisphosphatase/genetics* ; Male ; Exome Sequencing ; Mutation ; Female ; Child

OBJECTIVE: To apply optical genome mapping (OGM) technique for the analysis of genetic etiology in two rare families with complex chromosomal rearrangements (CCRs) and to provide precise reproductive guidance to them. METHODS: Two Chinese families diagnosed with chromosomal rearrangements by chromosomal microarray analysis (CMA) or whole-exome sequencing (WES) between June and December 2023 at the Affiliated Women and Children's Hospital of Ningbo University were selected as the study subjects. In both cases, unbalanced chromosomal translocations were suspected. Clinical data were collected, and peripheral blood from the couple, amniotic fluid sample and aborted fetal tissue was subjected to combined G-banding karyotyping and OGM for comprehensive genetic analysis. This study has been approved by the Medical Ethics Committee of the Hospital (Ethics No.: EC2023-094). RESULTS: In family 1, the fetus was signaled to have abnormal chromosome 7 by non-invasive prenatal testing (NIPT), prompting amniocentesis and CMA detection. In family 2, a pregnancy loss had occurred at 10 weeks' gestation, and trio-WES was carried out. Both fetuses were found to harbor copy number variations (CNVs) suggestive of unbalanced CCRs. Further analysis with OGM has revealed that, in family 1, an unbalanced rearrangement involving chromosomes 7, 8, and 10 was carried by the fetus and the pregnant woman, which has formed der(8) and der(10) derivative chromosomes. In family 2, a maternal CCR was found, which involved chromosomes 2 and 13 with seven breakpoints, resulting in unbalanced fetal CNVs. After genetic counseling, family 1 opted to continue with the pregnancy, considering the woman's normal appearance and inheritance of the rearrangement. For both families remained to have a risk for unbalanced rearrangements in subsequent pregnancies, preimplantation genetic testing (PGT) was recommended. CONCLUSION In both families, the OGM has precisely delineated the genetic basis of fetal CNVs and mapped the maternal CCR breakpoints, providing critical insights for genetic counseling and reproductive decision-making.
Adult ; Female ; Humans ; Male ; Pregnancy ; Chromosome Aberrations ; Chromosome Disorders/genetics* ; Chromosome Mapping/methods* ; Genetic Testing/methods* ; Pedigree ; Prenatal Diagnosis/methods* ; Translocation, Genetic

Objective:To explore the clinical characteristics and gene variant of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant. Methods:A fetus with Farber lipogranulomatosis caused by ASAH1 gene variant diagnosed at Women and Children′s Hospital of Ningbo University in August 2024 was selected as the subject. Clinical data and abortion tissue samples of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Sanger sequencing validation and bioinformatics analysis were performed on candidate variants. This study was approved by Women and Children′s Hospital of Ningbo University (Ethics No. EC2020-048). Results:Generalized skin oedema, pericardial effusion, right pleural effusion and increased bowel echogenicity of the fetus were founded by prenatal ultrasound. WES revealed that the fetus has harbored a homozygous c. 101C>A(p.Ser34Ter) variation in exon 2 of the ASAH1 gene. Sanger sequencing confirmed that both parents carry the heterozygous nonsense variation c. 101C>A (p.Ser34Ter) in ASAH1 gene, which has not been included in databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Based on the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PM2_Supporting+ PVS1+ PM3_Supporting). The AlphaFold3 model protein structure prediction reveals that the c. 101C>A variant caused the premature appearance of a termination codon, resulting in only a small partial α-helix structure in the N-terminal of the encoded ASAH1 protein, with the complete loss of the α-helix structure in the core domain, which might lead to the loss of function of this protein. Conclusion:The c. 101C>A(p.Ser34Ter) variant of the ASAH1 gene probably underlay the Farber lipogranulomatosis with hydrops fetalis in this fetus. The newly discovered c. 101C>A(p.Ser34Ter) variant has enriched the mutational spectrum of Farber lipogranulomatosis.

Objective:To explore the genetic characteristics of a fetus affected with Structural heart defects and renal anomalies syndrome (SHDRA).Methods:A pedigree with SHDRA (fetus and the parents) who had visited the Affiliated Women and Children′s Hospital of Ningbo University in April 2023 was selected as the study subject. Clinical data of the family were collected. A total of 10 mL of amniotic fluid cells from the fetus and 5 mL of peripheral blood samples from the parents were collected for genomic DNA extraction. Trio whole-exome sequencing (Trio-WES) was performed, and Sanger sequencing was used to validate candidate variants in the family. The identified variants were classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the " ACMG Guidelines). Relevant research literature on SHDRA in domestic and international databases were searched for literature review. This study was approved by the Affiliated Women and Children′s Hospital of Ningbo University (Ethics No. EC2023-094).Results:①In this family, prenatal ultrasound at 18 weeks of gestation revealed left renal multicystic dysplasia in the fetus. After birth, the infant exhibited an ostium secundum atrial septal defect, patent ductus arteriosus, and left renal multicystic dysplasia. Trio-WES revealed that the fetus had carried c. 344dup(p.L116Afs*32) and c. 90_104dup(p.Ala31_Ala35dup) compound heterozygous variants in the TMEM260 gene, which were respectively inherited from its father and mother. According to the ACMG guidelines, the c. 344dup(p.L116Afs*32) and c. 90_104dup (p.Ala31_Ala35dup) variants were classified as pathogenic (PM2_Supporting+ PVS1+ PP4) and likely pathogenic (PM2_Supporting+ PM4+ PM3+ PP4), respectively. ②According to the literature search strategy set for this study, a total of 6 literature was retrieved, involving 25 SHDRA patients from 20 families. Together with the patients in this study, there were 14 TMEM260 gene variants, most of which were frameshift variants (7 types) and had located in exons 3, 11 and 13. The main clinical features of SHDRA were congenital heart malformation, renal abnormality and neurodevelopmental abnormality, and there was a lack of genotype-phenotype correlation. Conclusion:The c. 344dup(p.L116Afs*32) and c. 90_104dup(p.Ala31_Ala35dup) variants of the TMEM260 gene probably underlay the SHDRA in this family. Above finding has provided a basis for clinical diagnosis and genetic counseling for the family.