Molecular Genetics & Genomic Medicine最新文献

Background: SRP72-associated hereditary bone marrow failure syndrome type 1 (BMFS1) has recently been described and only six families have been reported so far. BMFS1 is an autosomal dominant condition characterized by early-onset aplastic anemia or pancytopenia in some patients and adult-onset myelodysplasia in others. This paper presents the clinical and genetic characteristics of a rare case of hereditary bone marrow failure syndrome 1 (BMFS1) and explores its pathogenesis.

Methods: Blood samples and clinical data were collected from the proband and his biological parents. Next-generation sequencing (NGS) was employed to sequence the genes associated with the proband, and the identified variants were subsequently confirmed via Sanger sequencing. Additionally, minigene splicing assays were conducted to assess the functional alterations of SRP72.

Results: A new splicing variant, c.1502+1G>A, was identified in the SRP72 gene through gene sequencing, and this finding was confirmed by Sanger sequencing. Neither parent carried this mutation. Minigene splicing assays revealed an insertion of two bases (AG) at the mRNA level (r.1503-2_1503-1insAG), potentially resulting in a premature stop codon (p.Leu502ValfsTer14). According to ACMG guidelines, the variant is classified as "Likely pathogenic". The c.1502+1G>A mutation in SRP72 is implicated as the potential cause of BMFS1 in this child.

Conclusions: Our study identified a novel classical splicing mutation, marking the first report of BMFS1 in China. This case broadens the spectrum of pathogenic variants associated with the SRP72 gene and expands our understanding of its phenotypic manifestations. It also serves as a typical example for early diagnosis and appropriate treatment of BMFS1.

Background: Congenital factor XIII (FXIII) deficiency is an extremely rare autosomal recessive blood clotting disorder with an incidence of approximately one in two million, which is caused mainly by mutations in the F13A1 gene. Recently, we identified a Chinese family with FXIII deficiency carrying a likely pathogenic variant and explored its pathogenic mechanism.

Aim: The aim of this study was to investigate the pathogenic mechanism associated with the Ser414 mutation in the F13A1 gene.

Methods: We performed clinical diagnosis, phenotypic assessment, and genetic analysis of the proband and her family members.

Results: The FXIII antigen level of the proband was 1.3%, which was significantly lower than the normal reference range. A mutation was identified through targeted next-generation sequencing (NGS). The effects of these variations on protein function were assessed using bioinformatics tools. Homology analysis revealed that Ser414 was also highly conserved in homologous species. Protein model analysis revealed that the Ser414Leu variation could induce alterations in the spatial structure of F13A1, potentially increasing its instability. This is the first time that F13A1 gene variants have been analyzed in a patient with FXIII deficiency, contributing to the expansion of the pathogenic variant database for congenital FXIII deficiency.

Conclusion: These findings provide valuable data accumulation that can contribute to the prevention of congenital FXIII deficiency, the exploration of potential pathogenic mechanisms, and the enrichment of genetic mutation databases.

Background: Pseudohypoaldosteronism type I (PHA1) is a rare genetic disorder characterized by renal or systemic resistance to aldosterone, resulting in hyponatremia, hyperkalemia, and metabolic acidosis. The autosomal recessive systemic form (PHA1B), caused by mutations in SCNN1A, SCNN1B, or SCNN1G, is particularly severe and typically manifests in the neonatal period. Among these, SCNN1B-related cases occur less frequently than SCNN1A-related cases.

Case presentation: We report a pair of dizygotic preterm twins (male and female) born at 35 + 5 weeks of gestation who presented at 8 days of age with poor feeding, weight loss, and severe jaundice. Both developed life-threatening hyperkalemia, hyponatremia, and metabolic acidosis, and these conditions were unresponsive to initial management including hydrocortisone. Laboratory findings showed markedly elevated plasma renin and aldosterone levels, with no evidence of congenital adrenal hyperplasia or other metabolic disorders. Whole-exome sequencing revealed compound heterozygous mutations in the SCNN1B gene: a splice-site variant (c.585+2T>C) inherited from the mother and a missense variant (c.1544T>C, p.Ile515Thr) from the father. Both mutations are novel and were confirmed by Sanger sequencing. Diagnosis of systemic PHA1B2 was established. Treatment with oral sodium chloride, sodium citrate, and potassium-binding resins led to gradual correction of electrolyte imbalance and clinical stabilization.

Conclusion: These are the first reported Chinese cases of neonatal-onset PHA1B due to novel compound heterozygous SCNN1B mutations. This report broadens the mutational spectrum of SCNN1B and underscores the importance of early genetic testing in refractory neonatal electrolyte disturbances.

Background: Nephrolithiasis is a common urological disorder and has become a significant global public health issue. Aldehyde dehydrogenase 2 (ALDH2), an important endogenous antioxidant enzyme involved in alcohol metabolism, has been shown to exert protective effects in various diseases. However, the specific role of ALDH2 gene polymorphisms in kidney stone formation, particularly in relation to alcohol consumption, remains poorly understood.

Methods: In this study, 979 nephrolithiasis patients and 1,009 healthy controls, matched for sex, age, and ethnicity, were enrolled. Genotyping of single nucleotide polymorphisms (SNPs) was performed, and a nephrolithiasis mouse model with Aldh2 deficiency was established to assess the susceptibility to kidney stone formation under Aldh2-deficient conditions.

Results: The ALDH2 rs671 polymorphism and three nearby SNPs (rs3782886, rs4766566, and rs2188380) were significantly associated with nephrolithiasis. Moreover, in the ethylene glycol (EG)-induced nephrolithiasis model, pathological examination of kidney sections from Aldh2 knockout mice exposed to alcohol revealed a significantly higher calcium oxalate crystal deposition score, accompanied by elevated levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA), compared with that in wild-type mice.

Conclusion: ALDH2 deficiency was significantly associated with an increased risk of nephrolithiasis, and this risk was further exacerbated by alcohol consumption. These findings enhance our understanding of the role of ALDH2 in kidney stone pathogenesis and may inform the development of novel strategies for the prevention and treatment of nephrolithiasis.

Background: While carrier screening is crucial for preventing birth defects, a significant gap exists between comprehensive screening guidelines and the practical barriers-cost, complexity, and compliance-faced by community healthcare in China. This study evaluates the real-world feasibility and clinical effectiveness of a targeted screening program for thalassemia, hereditary deafness, and spinal muscular atrophy in community health settings in China.

Methods: A total of 7068 pregnant women attending the prenatal clinic at Wenzhou Central Hospital underwent genetic carrier screening from February 2020 to June 2024. The screening focused on hotspot variants using NMPA-approved kits. A two-tiered counseling model was implemented, and clinical effectiveness was assessed via a four-year follow-up using hospital and birth defect registries.

Results: The screening program identified 1067 carriers, with an overall carrier rate of 15.1%. Among 72 couples with pathogenic variants in the same gene, 12 fetuses were found to be at "abnormal risk." Crucially, the four-year follow-up revealed no false-negative cases for the targeted severe conditions, demonstrating high clinical effectiveness and a robust negative predictive value.

Conclusion: This targeted screening program is a clinically effective, cost-conscious, and regulatively compliant framework for preventing severe genetic disorders in China. By strategically balancing clinical impact with economic and logistical realities, this model provides a valuable, replicable approach to improving maternal and child health.

Background: Pharmacogenomics (PGx) enables precision medicine by improving efficacy and reducing adverse drug reactions, but implementation is limited by testing burden and ethnic variability. With whole-exome sequencing (WES) increasingly applied in Taiwan, we evaluated its feasibility for PGx analysis.

Methods: We analyzed WES data from 3562 individuals at a tertiary medical center. PGx calling was performed on 17 pharmacogenomic loci using Aldy, and HLA typing was inferred using the high-quality dictionary (HLA-HD). Phenotypes were annotated using the Pharmacogenomics Clinical Annotation Tool (PharmCAT).

Results: After comparison with WGS and sequencing-based HLA typing data, 14 pharmacogenomic loci were found to be suitable for PGx calling from WES. On average, each individual carried approximately 2.4 actionable phenotypes across 14 genes. Compared with East Asian and European populations, the Taiwanese population has a greater frequency of actionable pharmacogenomic phenotypes for G6PD deficiency (2%) and HLA-B*58:01 (21%). Additionally, the CYP2C19, CYP3A5, NUDT15, and HLA-B*15:02 actionable phenotypes occur at frequencies similar to those of East Asians but are more frequent than those in Europeans. Our WES findings are generally consistent with previous Taiwanese WGS and array data.

Conclusions: Ethnic differences in PGx variants underscore the need for population-specific data. The high prevalence of actionable phenotypes in Taiwanese individuals supports the use of WES, which effectively captures certain key pharmacogenes for routine PGx testing.

Background: Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes mellitus (T2DM) and a leading cause of blindness worldwide. Recent evidence suggests a potential role of vitamin D deficiency in the development of DR.

Objective: To systematically evaluate the association between vitamin D deficiency and DR risk in T2DM patients through a meta-analysis of observational studies.

Methods: A systematic literature search was conducted across major databases up to December 2024. Observational studies assessing serum 25(OH)D levels and DR risk were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models depending on heterogeneity. Subgroup analyses, sensitivity analyses, and publication bias assessments were performed.

Results: Twenty studies encompassing 22,408 T2DM patients were included. Vitamin D deficiency was significantly associated with increased DR risk (pooled OR = 1.17, 95% CI: 1.08-1.27, p < 0.001). Heterogeneity was moderate (I² = 52%). Subgroup and sensitivity analyses confirmed robustness. No significant publication bias was observed.

Conclusion: Vitamin D deficiency (25[OH]D < 20 ng/mL) is associated with increased DR risk. Monitoring and correcting vitamin D status may aid in DR prevention. Future studies are needed to determine causality and evaluate the benefits of supplementation.

Background: Hemoglobinopathies are genetic disorders characterized by structural or quantitative hemoglobin abnormalities. We report the first documented case globally of a novel alpha1 (α1)-variant (HBA1:c.-35T>C) co-occurring with Hb M-Saskatoon (HBB:c.190C>T), the latter being identified for the first time in the Chinese population.

Methods: Peripheral blood samples were obtained from a 3-year-old Chinese girl presenting with persistent cyanosis, including complete blood count, hemoglobin electrophoresis, and degenerative globin body testing. Hemoglobin variants detected were subsequently characterized through DNA sequencing.

Results: The research subject was diagnosed with different types of abnormal Hb. Hematological analysis revealed normocytic normochromic erythrocytes with mild anemia (Hb 111 g/L, reference 112-149 g/L). Electrophoretic analysis detected abnormal hemoglobin fractions: abnormal Hb bands in zone I and s in the E zone near the position of Hb A₂. Targeted sequencing demonstrated compound heterozygosity for α1-variant (HBA1:c.-35T>C) with Hb M-Saskatoon (HBB:c.190C>T).

Conclusion: We confirmed Hb M-Saskatoon (HBB:c.190C>T) co-occurring with a globally unreported α1-variant (HBA1:c.-35T>C) in a Chinese proband. This dual variant expands the global hemoglobinopathy registry and provides critical insights for diagnosing atypical cases, particularly in populations with understudied genetic diversity. This finding elucidates novel genotype-phenotype correlations in complex hemoglobinopathies and underscores the imperative of genetic testing for atypical presentations.

Background: Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by congenital melanocytic nevus of the skin with melanocytic deposits in the central nervous system. Patients with neurological symptoms have a poor prognosis and may die within years of symptom onset.

Case report: A fetus was found to have diffuse enhancement of cerebellar hemispheric echo at 23 weeks of gestation and amniocentesis was performed at 25 weeks of gestation. Fetal DNA was extracted from amniotic fluid for copy number variation sequencing (CNV-seq) and Trio-total whole-exome sequencing (Trio-WES). However, genetic tests did not reveal pathogenic mutations associated with this case phenotype. At 29 weeks of pregnancy, a fetoscopy examination was performed, and multiple scattered pigmentation spots were found on the skin of the fetus's back. At 31 weeks of pregnancy, the pregnant woman requested an induced abortion to terminate the pregnancy. Multiple areas of pigmentation can be seen on the skin of a stillborn fetus. Pathological examination confirmed a large amount of melanin deposition in the cerebellum tissue of the stillborn fetus.

Conclusions: We reported a rare case of prenatal NCM, but no known pathogenic mutations, such as NRAS gene mutations, were found. This confirmed that there might be no definite pathogenic mutations in the NCM case, providing important data support for the prenatal identification and diagnosis of NCM. We reported a rare case of prenatal NCM, but no known pathogenic mutations, such as NARS gene mutations, were found. This confirmed that there might be no definite pathogenic mutations in the NCM case, providing important data support for the prenatal identification and diagnosis of NCM.

Background: Bernard-Soulier syndrome (BSS) is a rare bleeding disorder caused by defects in the GPIb-IX-V complex, which is essential for platelet adhesion. We report a novel case of BSS in a Mauritanian patient with a history of chronic bleeding since childhood, accompanied by thrombocytopenia and macroplatelets.

Methods: Diagnosis was confirmed by flow cytometry and molecular analysis. The variant identified in the GP1BB gene (glycoprotein Ib platelet subunit beta, HGNC:4440, OMIM:138720; 22q11.21). The variant identified was annotated according to HGVS nomenclature.

Results: Genetic analysis identified a duplication of the GC dinucleotide in the GP1BB gene at genomic coordinates AF006988.1:g.13373_13374dupGC (transcript reference: NM_000407.4), resulting in a frameshift starting at amino acid residue 115 and generating a premature stop codon after 16 amino acids (p.Ala115Profs16). Flow cytometry demonstrated a significant reduction in GPIb and GPIX expression, explaining the platelet adhesion defect. Clinically, the patient's anemia worsened during adolescence with the onset of menstruation, requiring multiple transfusions that subsequently induced alloimmunization and transfusion incompatibility. Over an 18 years follow-up, the patient exhibited a persistent hemorrhagic syndrome and chronic iron-deficiency anemia, exacerbated by limited access to phenotyped blood in Mauritania. The variant alters the hydrophobicity and stability of the GPIbβ protein, impairing membrane integration and disrupting assembly of the GPIb-IX-V complex.

Conclusion: This case highlights the importance of molecular diagnosis and genetic counseling in at-risk populations. In the absence of curative treatment, management relies on transfusions, antifibrinolytics, and avoidance of antiplatelet agents.