無脾症候群

Variant calling in paralogous genes using short-read sequencing is problematic due to mapping ambiguity between highly similar sequences. Aggregate variant calling, which treats paralogous loci as a single locus by realigning reads to a masked reference genome, can enable variant detection in paralogous genes. We used our informatics tool Parascopy to assess the accuracy of aggregate variant calling in paralogous genes using short-read data. Parascopy achieved significantly higher recall compared to standard variant calling without sacrificing precision. We identified 158 paralogous genes with over 25 percentage points improvement in recall using simulated data, and 118 genes with at least 10 percentage points improvement in recall across GIAB reference samples. Across 1000 Genomes samples, aggregate genotypes in paralogous genes were highly concordant between whole-genome and whole-exome data (r2=0.9998). Using sequence data from population and disease cohorts, we utilized aggregate variant calls to perform population-genetic analysis, case-control association analysis, and haplotype phasing in specific disease-relevant paralogous genes that are inaccessible to standard diploid variant calling. Specifically, in the SMN1 gene, we identified tag-SNPs for two-copy SMN1 haplotypes and showed that specific low-frequency missense variants in African populations occurred exclusively on such haplotypes. For the CFC1 gene-previously implicated in heterotaxy syndrome-association analysis using exome data indicated that loss-of-function variants are unlikely to be associated with heterotaxy in individuals with congenital heart disease. Finally, we utilized aggregate genotypes to perform haplotype phasing for the X-linked gene IKBKG, achieving 99.2% concordance between trio-based and statistical phasing approaches.

Pulmonary overcirculation in single-ventricle physiology often requires early modulation to preserve systemic output while balancing the timing and risk of surgical palliation. We report the first use of a fenestrated balloon-expandable PECA exGraft patch as a modifiable intraluminal pulmonary artery band (IL-PAB). A full-term neonate with heterotaxy syndrome, complex anatomy with borderline left ventricle, ductal-dependent systemic circulation, and primary ciliary dyskinesia developed severe pulmonary overcirculation with respiratory instability, making early surgery prohibitive. Initial transcatheter pulmonary flow restrictor placement achieved hemodynamic stabilization. At 8 weeks of age, during aortic arch repair, a fenestrated PECA exGraft IL-PAB was implanted in the main pulmonary artery. Progressive restriction with somatic growth was subsequently treated by transcatheter balloon dilation of the graft fenestration, resulting in improved oxygenation and reduced gradient. This case demonstrates the feasibility of a staged and catheter-modifiable strategy for pulmonary blood flow regulation using an expandable internal pulmonary artery band in high-risk infants requiring adaptable physiologic control.

OBJECTIVE: To investigate the subtype distribution, clinical characteristics, and genetic causes in a single-center cohort of Fetal Left-right asymmetry anomalies (FLRAA). METHODS: Seventy-nine typical FLRAA cases undergoing prenatal evaluation at Guangzhou Women and Children's Medical Center between January 1, 2011 and June 30, 2025 were included. Genetic analyses including karyotyping, copy number variation (CNV) detection, and gene sequencing were carried out, and genotype-phenotype correlation was explored. This study was approved by the Medical Ethics Committee of Guangzhou Women and Children's Medical Center (Ethics No.: 2015-112). RESULTS: The cohort has included 43 cases of situs inversus totalis (54.4%), 8 cases of situs inversus incompletus/partialis (10.1%), 9 cases of heterotaxy-right isomerism/asplenia (11.4%), 10 cases of heterotaxy-left isomerism/polysplenia (12.7%), and 9 cases (11.4%) of undetermined subtypes prenatally. Among these, isolated FLRAA was observed in 28 cases (35.4%), while non-isolated FLRAA was identified in 51 cases. The non-isolated group included 26 cases (32.9%) with cardiovascular anomalies, 5 cases (6.3%) with extracardiac anomalies, and 20 cases (25.3%) with both cardiovascular and extracardiac anomalies. Genetic testing has revealed chromosomal abnormalities in 5 cases, pathogenic CNV in 1 case, and pathogenic/likely pathogenic monogenic variants in 4 cases. The identified variants involved multiple ciliary motility-related genes including DNAH11, DNAH9, and LRRC56. CONCLUSION: FLRAA may exhibit diverse clinical manifestations and complex etiologies. This study has highlighted the value of integrated genetic testing and expanded the spectrum of pathogenic variants of key FLRAA-related genes. Above findings have provided critical insights for genetic counseling and pregnancy management. Further studies with larger cohorts and functional validation are warranted to elucidate the underlying pathogenic mechanisms.

Autosplenectomy, defined as the spontaneous loss of splenic tissue in the absence of trauma or surgery, is most commonly associated with sickle cell disease and is rarely described in patients with autoimmune conditions. We present a case of a 54-year-old woman with systemic lupus erythematosus (SLE) and Sjögren's overlap syndrome who was incidentally found to have a complete absence of the spleen on computed tomography (CT), despite prior imaging demonstrating a normal splenic anatomy. The patient presented with polyarthralgia, fatigue, and systemic inflammation. Laboratory investigations revealed elevated anti-dsDNA titers, hypocomplementemia, and a positive extractable nuclear antigen (ENA) profile. Imaging confirmed splenic absence, and extensive evaluation excluded infectious, malignant, infiltrative, and hematological causes of splenic agenesis. Serial imaging findings, combined with the presence of an active autoimmune disease, supported the diagnosis of a probable autoimmune-mediated autosplenectomy. This case highlights a rare but clinically significant manifestation of systemic autoimmune diseases. Recognition of asplenia is critical because of the associated risk of overwhelming infection, necessitating vaccination and the implementation of prophylactic strategies. Clinicians should consider splenic dysfunction in patients with autoimmune diseases, particularly when unexplained infections or atypical imaging findings are present.