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.

Evaluating human mutation databases for "treatability" using patient-customized therapy.

Genome sequencing in the clinic often allows patients to receive a molecular diagnosis. However, variants are most often evaluated for pathogenicity, neglecting potential treatability and thus often yielding limited clinical benefit. Antisense oligonucleotides (ASOs), among others, offer attractive programmable and relatively safe platforms for customized therapy based upon the causative genetic variant. The landscape of ASO-treatable variants is largely uncharted, with new developments emerging for loss-of-function, haploinsufficient, and gain-of-function effects. ASOs can access the transcriptome to target splice-gain variants, poison exons, untranslated/regulatory regions, and naturally occurring antisense transcripts. Here we assess public variant databases and find that approximately half of pathogenic variants have one or more viable avenues for ASO therapy. The future might see medical teams considering "treatability" when interpreting genomic sequencing results to fully realize benefits for patients.

The performance of different classification criteria for systemic lupus erythematosus in a real-world rheumatology department.

OBJECTIVE: New classification criteria have been proposed to improve classification of systemic lupus erythematosus (SLE). We aimed to evaluate their performance by determining their sensitivity, specificity and accuracy in a real-world rheumatology department. METHODS: SLE patients who were enrolled in the Australian Lupus Registry and Biobank were included and compared with controls recruited from other rheumatology clinics. Clinical and immunological features were reviewed, according to ACR 1997, SLICC 2012, EULAR/ACR 2019, or Systemic Lupus Erythematosus Risk Probability Index (SLERPI). Performance of each set of criteria was evaluated for the overall cohort and in a subgroup of patients with early SLE. RESULTS: The study included 394 SLE and 123 control patients with other rheumatological conditions. Sensitivity was highest using SLICC 2012 or SLERPI 2020 criteria. Specificity was highest using ACR 1997 criteria. The SLICC 2012 criteria had the highest overall accuracy at 94.4% (95% CI: 91.7, 97.1%). In the subgroup analysis of SLE patients with early disease, SLICC 2012 performed similarly well. CONCLUSIONS: The sensitivity and specificity of each set of classification criteria vary slightly, with SLICC 2012 and SLERPI 2020 having the highest sensitivities and the ACR 1997 criteria having the highest specificity in our patient cohort. All classification criteria serve as good instructional aids for clinicians to understand SLE manifestations. For the Australian Lupus Registry and Biobank, we will continue to use the ACR 1997 and/or SLICC 2012 as entry to the observational cohort.