NPJ Genomic Medicine最新文献

Many congenital anomaly patients lack genetic diagnoses because there are many disease genes as yet to be discovered. We applied a gene burden test incorporating de novo predicted-loss-of-function (pLoF) and likely damaging missense variants together with inherited pLoF variants to a collection of congenital heart defect (CHD) and orofacial cleft (OFC) parent-offspring trio cohorts (n = 3835 and 1844, respectively). We identified 17 novel candidate CHD genes and 8 novel candidate OFC genes, of which many were known developmental disorder genes. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OFC, respectively. In total, 30 affected children had a de novo missense variant in a DNA binding domain of a known CHD, OFC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OFC and their potentially pleiotropic effects in other developmental disorders.

Common genetic variation detected by genome-wide association studies (GWAS) partially explains variability in the spectrum of cardiac phenotypes. In this work, we explore genetic correlations among 58 cardiac-related traits/diseases, detecting novel ones. We subsequently employ multi-trait analysis of GWAS (MTAG), which meta-analyzes genetically correlated traits, to improve genomic loci discovery and prediction in atrial fibrillation (AF), coronary artery disease (CAD), and heart failure (HF). We identify 19 novel loci specific for AF, 131 for CAD, and 141 for HF. Polygenic scores (PGS) in 15,177 Canadian individuals show similar results when PGS are derived from conventional GWAS versus MTAG summary statistics, although MTAG-PGS improve prediction and discrimination of CAD in females [∆R² 1.735% (95% Confidence Interval (CI): 0.609-2.856); Net reclassification index 0.208 (95%CI: 0.139-0.277)]. This work describes new relevant genetic correlations among cardiac-related traits/diseases and supports MTAG to improve loci discovery in common cardiovascular diseases and potentially improve the prediction of CAD in females.

Gamma-butyrobetaine hydroxylase (BBOX1) catalyses the last step of carnitine biosynthesis, converting γ-butyrobetaine (γ-BB) into L-carnitine. Here we show, for the first time, that biallelic variants in BBOX1 are associated with decreased levels of L-carnitine and increased plasma levels of γ-BB in three patients from two unrelated families presenting with myopathic, neurodevelopmental, and late-onset psychiatric manifestations. Using a knockout C. elegans model of BBOX1 homolog, gbh-1, and strains harboring patient-derived variants (gbh-1(D72G) for p.Asp59Gly, gbh-1(G283R) for p.Gly263Arg, and gbh-1(G247Vfs6) for p.Gly227Valfs*6), we show very low L-carnitine levels and significantly elevated γ-BB in c.675delA and c.787G>A mutants, and moderately elevated γ-BB in c.176A>G. Furthermore, we observed a lethal embryonic phenotype for the gbh-1 loss-of-function strains, which was rescued upon L-carnitine supplementation. Our study provides novel insights into the clinical and biochemical consequences of BBOX1-related L-carnitine biosynthesis deficiency and establishes C. elegans as a model to study the effects of BBOX1 deficiency.

Personalized precision dosing remains an unmet clinical need. This study used population pharmacokinetic (PopPK) modeling to evaluate transitioning lacosamide (LCM) in children with epilepsy from body weight (BW)-based (mg/kg) to simplified BW-band or fixed-dose (mg) regimens. Real-world data from 190 patients were analyzed using nonlinear mixed-effects modeling program, comparing a BW-based model (Model I) and a genotype-guided model (Model II); the latter showed superior predictive performance. Monte Carlo simulations confirmed comparable LCM exposure across regimens, with >78% target attainment in external validation. A fixed 100 mg dose for patients ≥10 kg achieved equivalent exposure to BW-adjusted dosing, with consistent results in 1-4 years and obese patients. These findings enabled BW-band dosing as a clinically viable alternative to mg/kg regimens, while CYP2C19 genotyping further enhanced precision. This PopPK-based strategy simplifies LCM therapy without compromising efficacy, offering a practical approach to personalized epilepsy management in children.

Short-read genome sequencing (GS) is a powerful technique for investigating the genetic etiologies of rare diseases, capturing diverse genetic variations that are challenging to approach with exome sequencing (ES). We performed GS on 260 families with intellectual disability/developmental delay. GS detected potentially disease-related variants in 55 of the 260 families, with structural resolution by long-read sequencing or optical genome mapping, and functional assessment by RNA sequencing. Excluding 31 theoretically ES-resolvable cases, GS yielded likely pathogenic variants in 17 of 229 as well as variants of unknown significance in 7 of 229, totaling 10.5%. These variants implicated several new etiological mechanisms: a microduplication syndrome involving ATP6V0C; disturbed interactions of TBL1XR1 and NR2F1 with putative cis-regulatory elements by chromosomal rearrangements; and a CCG repeat expansion near the CHD3 transcription start site. This study highlights the critical role of GS in clinical diagnostics and its potential to advance understanding of genetic disorders.

Genotype plays a central role in the comprehensive management of pheochromocytomas and paragangliomas, highlighting the critical need for specific in vivo genetic models. Yet, animal models fall short of fully recapitulating the biological complexity of these tumours. We generated first-generation loss-of-function zebrafish models for sdhb, a canonical PPGL-associated gene, using CRISPR/Cas9. Sdhb-CRISPants exhibit increased heart rates, reduced swimming activity and premature death. In whole fish extracts, normetanephrine (NM), metanephrine (MN), and dopamine (DA) levels were about three times higher in sdhb CRISPants than in control larvae. In the bathing medium, NM and MN were also significantly elevated, along with 3-MT. Complementary metabolic and transcriptomic profiling revealed that sdhb CRISPants exhibit a clear signature of Complex II dysfunction and upregulation of genes involved in the hypoxia response, angiogenesis, stress response, and glycolysis. Our work validates the relevance of CRISPant zebrafish models to study the pathogenicity of PPGL-causing genetic variants in vivo.

Pathogenicity assessment of genetic variants is the cornerstone of genetic counselling. Copy gains of exons are challenging, as pathogenicity depends on the localization of the additional exons. Eight patients form six families carried copy gains of BRCA1 exons 8-20. For appropriate characterization, long-read sequencing aligned on three distinct reference genome assemblies, optical genomic mapping, short-read and long-read RNA sequencing were performed. All patients shared the same pathogenic structural variant, involving a large segment located downstream in the genome. One breakpoint occurred in a region incorrectly annotated in GRCh37/hg19 and GRCh38/hg38. Alignment to the T2T-CHM13/hs1 assembly was therefore necessary for accurate characterization. This rearrangement caused various BRCA1 transcriptomic abnormalities: back-splicing, forward genomic strand transcription by insertion of an ectopic promoter, fusion transcripts with the "Next to BRCA1" gene 1 (NBR1). Our findings underscore the need to combine advanced technologies with the latest genome references to resolve complex rearrangements with significant medical implications.

The German National Strategy for Genomic Medicine (genomDE) aims to integrate genome sequencing into standard healthcare. However, integrating genomics data from research and healthcare remains challenging. This study analyzed how the genomDE dataset could be mapped to international standards: the Genomics Reporting Fast Healthcare Interoperability Resources® (FHIR®) Implementation Guide (IG) 2.0.0, the Global Alliance for Genomics and Health (GA4GH)'s Phenopacket Schema, and the German national molecular genomics report IG of the Medical Informatics Initiative (MII). Sample FHIR® bundles and necessary search queries were created and validated. Most dataset elements could be represented using existing FHIR profiles, while unmapped elements were addressed through profiling and extensions. The study highlights that the genomDE dataset can largely be mapped to existing international standards, with the potential to extend these standards to accommodate missing elements, thereby improving genomic data interoperability in healthcare.

Despite advanced diagnostic tools, early detection of rare genetic conditions like Noonan syndrome (NS) remains challenging. We evaluated a deep learning model's real-world performance in identifying potential NS cases using electronic health record (EHR) data, validated through genetic sequencing and clinical assessment. The model analyzed 92,428 patients, identifying 171 high-risk individuals (score > 0.8) who underwent comprehensive review. Among these, 86 had prior genetic diagnoses, including three NS cases diagnosed during the study period. Genetic sequencing of remaining patients identified two additional NS cases with pathogenic variants. The model achieved 2.92% precision and 99.82% specificity. While precision was lower than prior validation (33.3%), this reflected expected differences in disease prevalence rather than model degradation. NS-associated phenotypes were enriched among high-risk patients, and trajectory analysis showed potential for earlier identification, highlighting both promise and limitations of EHR-based computational screening tools.