Risk of meningomyelocele mediated by the common 22q11.2 deletion.

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.

Incidence of Acute Rejection Compared With Endomyocardial Biopsy Complications for Heart Transplant Patients in the Contemporary Era.

BACKGROUND: The reference standard of detecting acute rejection (AR) in adult heart transplant (HTx) patients is an endomyocardial biopsy (EMB). The majority of EMBs are performed in asymptomatic patients. However, the incidence of treated AR compared with EMB complications has not been compared in the contemporary era (2010-current). METHODS: The authors retrospectively analyzed 2769 EMBs obtained in 326 consecutive HTx patients between August 2019 and August 2022. Variables included surveillance versus for-cause indication, recipient and donor characteristics, EMB procedural data and pathological grades, treatment for AR, and clinical outcomes. RESULTS: The overall EMB complications rate was 1.6%. EMBs performed within 1 mo after HTx compared with after 1 mo from HTx showed significantly increased complications (OR, 12.74, P < 0.001). The treated AR rate was 14.2% in the for-cause EMBs and 1.2% in the surveillance EMBs. We found the incidence of AR versus EMB complications was significantly lower in the surveillance compared with the for-cause EMB group (OR, 0.05, P < 0.001). We also found the incidence of EMB complications was higher than treated AR in surveillance EMBs. CONCLUSIONS: The yield of surveillance EMBs has declined in the contemporary era, with a higher incidence of EMB complications compared with detected AR. The risk of EMB complications was highest within 1 mo after HTx. Surveillance EMB protocols in the contemporary era may need to be reevaluated.

Benefit versus Risk of Endomyocardial Biopsy for Heart Transplant Patients in the Contemporary Era.

Background: The reference standard of detecting acute rejection (AR) in adult heart transplant (HTx) patients is an endomyocardial biopsy (EMB). The majority of EMBs are performed in asymptomatic patients. However, the benefit of diagnosing and treating AR compared to the risk of EMB complications has not been compared in the contemporary era (2010-current). Methods: The authors retrospectively analyzed 2,769 EMB obtained in 326 consecutive HTx patients between August 2019 and August 2022. Variables included surveillance versus for cause indication, recipient and donor characteristics, EMB procedural data and pathologic grades, treatment for AR, and clinical outcomes. Results: The overall EMB complication rate was 1.6%. EMBs performed within 1 month after HTx compared to after 1 month from HTx showed significantly increased complications (OR = 12.74, p < 0.001). The treated AR rate was 14.2% in the for cause EMBs and 1.2% in the surveillance EMBs. We found the benefit/risk ratio was significantly lower in the surveillance compared to the for cause EMB group (OR = 0.05, p < 0.001). We also found the benefit to be lower than risk in surveillance EMBs. Conclusions: The yield of surveillance EMBs has declined, while for cause EMBs continued to demonstrate a high benefit/risk ratio. The risk of EMB complications was highest within 1 month after HTx. Surveillance EMB protocols in the contemporary era may need to be re-evaluated.

Comparison of two donor-derived cell-free DNA tests and a blood gene-expression profile test in heart transplantation.

BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) testing is an emerging screening modality for noninvasive detection of acute rejection (AR). This study compared the testing accuracy for AR of two commercially available dd-cfDNA and gene-expression profiling (GEP) testing in heart transplant (HTx) recipients. METHODS: This is a retrospective, observational study of HTx only patients who underwent standard and expanded single nucleotide polymorphism (SNP) dd-cfDNA between October 2020 to January 2022. Comparison with GEP was also performed. Assays were compared for correlation, accurate classification, and prediction for AR. RESULTS: A total of 428 samples from 112 unique HTx patients were used for the study. A positive standard SNP correlated with the expanded SNP assay (p < .001). Both standard and expanded SNP tests showed low sensitivity (39%, p = 1.0) but high specificity (82% and 84%, p = 1.0) for AR. GEP did not improve sensitivity and showed worse specificity (p < .001) compared to standard dd-cfDNA. CONCLUSION: We found no significant difference between standard and expanded SNP assays in detecting AR. We show improved specificity without change in sensitivity using dd-cfDNA in place of GEP testing. Prospective controlled studies to address how to best implement dd-cfDNA testing into clinical practice are needed.