Molecular Genetics & Genomic Medicine最新文献

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: 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.

Background: Li-Fraumeni syndrome is a rare autosomal dominant disorder caused by a pathogenic mutation of the tumor suppressor gene TP53. This disease starts at an early age and has been shown to be associated with multiple tumors. The study aims to discuss the clinical and genetic characteristics of Li-Fraumeni syndrome (LFS) and to provide therapeutic experience of LFS.

Materials and methods: We conducted a retrospective analysis of the clinicopathologic features, family history, treatment and follow-up in five LFS patients with germline TP53 (NCBI Gene: 7157, HGNC: 11998, OMIM: 191170) pathogenic/likely pathogenic (P/LP) variants. This research had been approved by the ethics committee and implemented.

Results: Our study involved five LFS patients with germline TP53 P/LP variants, including thyroid cancer, ovarian melanoma, colon cancer, fibrosarcoma, and lung cancer. Among this group of patients, the age at which tumors first appeared was between 24 and 53 years old. Three patients had a family history of tumors, and the other two were probands in the family. Traditional chemotherapy has limited effectiveness in clinical practice and may increase the risk of tumor development. However, immune checkpoint inhibitors (ICIs) have shown unexpected efficacy in patients with high programmed cell death ligand-1 (PD-L1) expression. Next-generation sequencing (NGS) and PD-L1 detection may provide more potential targets for LFS patients to achieve better therapeutic outcomes. In addition, we have added a new TP53 frameshift mutation spectrum, namely c.642_643delTA (p.H214Qfs*7), which belongs to the pathogenic variant. This mutant has not been described in the existing literature.

Conclusion: Patients with LFS may be potential beneficiaries of immune checkpoint inhibitors and targeted therapies.

Background: Williams-Beuren syndrome (WBS; OMIM #194050), caused by 7q11.23 deletions, is well-characterized postnatally, but prenatal manifestations remain poorly defined. This study aims to delineate the prenatal phenotypes, inheritance patterns, and outcomes of 7q11.23 copy number variations (CNVs).

Methods: A retrospective study of 20 prenatal cases with 7q11.23 CNVs diagnosed by SNP array or CNV sequencing (CNV-seq) was conducted. Clinical data, including ultrasound findings, genetic results, and pregnancy outcomes, were analyzed.

Results: Classic 7q11.23 deletions (1.42 Mb median size) were associated with ultrasound anomalies in 100% of cases (11/11), predominantly cardiovascular defects (36.4%, 4/11) and growth restriction (18.2%, 2/11). While 7q11.23 duplications (1.42-3.03 Mb) were associated with anomalies in 50% of cases (3/6), including cleft palate and ventriculomegaly. Inheritance pattern analysis revealed 50% of deletions (6/12) and 42.9% of duplications (3/7) were inherited, either from phenotypically normal or abnormal parents. Termination of pregnancy (TOP) occurred in 76.5% (13/17) of ongoing pregnancies, primarily for de novo CNVs. Four live births involved inherited CNVs.

Conclusion: 7q11.23 CNVs exhibit significant prenatal phenotypic variability and inheritance heterogeneity. Advanced genomic testing and inheritance pattern analysis are critical for accurate diagnosis and counseling.

Objective: Variants of the proto-cadherin 15 (PCDH15) gene are related to Usher syndrome type 1F (USH1F). The purpose of this study was to determine the genetic etiology of a USH1F family in China and to perform a minigene assay for the PCDH15 gene to explore the effect of variation on splicing and determine the pathogenicity of the identified variant.

Methods: Targeted next-generation sequencing of 127 hearing loss-related genes was performed for a 26-year-old proband to identify the candidate variants. Then, multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were performed for all family members to confirm the variants. Further, to verify the pathogenicity of the intronic variant, a minigene splicing assay was performed.

Results: Compound heterozygous PCDH15 EX1_2DEL and c.3717+5G>A variants were identified in the proband. MLPA and Sanger sequencing confirmed these two variants and showed the same genotype of a paternally inherited c.3717+5G>A and a maternally inherited EX1_2DEL variation in both the proband and his affected sister. The minigene assay verified the pathogenicity of c.3717+5G>A and indicated that this variant possibly caused abnormal splicing, resulting in jump of exon 27 and retention of 51 bp at the 5' end of intron 27, leading to the formation of abnormal proteins.

Conclusion: This study reports a novel pathogenic variant c.3717+5G>A of PCDH15 in a proband for the first time. These findings offer evidence for the genetic counseling of USH1F. Minigene splicing assays are considered to be one of the most powerful methods for determining whether intron mutations lead to abnormal splicing.

Introduction: Fanconi anemia (FA) is the most prevalent inherited disorder leading to bone marrow failure, resulting from a rare autosomal recessive genetic condition that affects all three types of blood cells. A key characteristic of FA is the body's heightened sensitivity to DNA-damaging agents, particularly those that induce crosslinking, which serves as an important diagnostic marker. Children at higher risk-such as those with unexplained growth delays, congenital defects, or a family history of FA-can significantly benefit from genetic testing.

Methods: This study involved 140 pediatric patients aged 1 to 18 years who met specific inclusion criteria: unexplained short stature without identifiable endocrine or nutritional causes, congenital anomalies associated with FA (such as skeletal or craniofacial deformities), and a family history suggestive of FA or early-onset blood cancers. The screening and diagnostic approach included a Chromosomal Breakage Test and genetic analysis.

Results: The retrospective analysis revealed that 19 (13.57%) out of the 140 children had previously undiagnosed cases of Fanconi anemia. Among these cases, short stature was noted in 6.7% (5 of 75 patients with short stature), congenital anomalies in 13.3% (4 of 30 patients with congenital anomalies), and positive cases from family screening accounted for 28.6% (10 of 35 patients with positive family history). The findings from the chromosomal breakage test provided valuable insights into the rates of positive, mosaic, and negative outcomes. Notably, mutations in the FANCA gene were found to be the most common among confirmed cases.

Conclusion: Early genetic screening for Fanconi anemia in high-risk pediatric populations has proven to be an effective strategy for ensuring prompt diagnosis and timely management. Incorporating this screening into routine clinical practices could significantly enhance patient outcomes, reduce healthcare costs, and alleviate the impact of this serious genetic condition.