NPJ Genomic Medicine最新文献

Whole genome sequencing has transformed rare disease research; however, 50-80% of rare disease patients remain undiagnosed after such testing. Regular reanalysis can identify new diagnoses, especially in newly discovered disease-gene associations, but efficient tools are required to support clinical interpretation. Exomiser, a phenotype-driven variant prioritisation tool, fulfils this role; within the 100,000 Genomes Project (100kGP), diagnoses were identified after reanalysis in 463 (2%) of 24,015 unsolved patients after previous analysis for variants in known disease genes. However, extensive manual interpretation was required. This led us to develop a reanalysis strategy to efficiently reveal candidates from recent disease gene discoveries or newly designated pathogenic/likely pathogenic variants. Optimal settings to highlight new candidates from Exomiser reanalysis were identified with high recall (82%) and precision (88%) when including Exomiser's automated ACMG/AMP classifier, which correctly converted 92% of variants from unknown significance to pathogenic/likely pathogenic. In conclusion, Exomiser efficiently reinterprets previously unsolved cases.

Long-read sequencing can often overcome the deficiencies in routine microarray or short-read technologies in detecting complex genomic rearrangements. Here we used Pacific Biosciences circular consensus sequencing to resolve complex rearrangements in two patients with rare genetic anomalies. Copy number variants (CNVs) identified by clinical microarray -chr8p deletion and chr8q duplication in patient 1, and interstitial deletions of chr18q in patient 2-were suggestive of underlying rearrangements. Long-read genome sequencing not only confirmed these CNVs but also revealed their genomic structures. In patient 1, we resolved a novel recombinant chromosome 8 (Rec8)-like rearrangement with a 3.43 Mb chr8q terminal duplication that was linked to a 7.25-8.21 Mb chr8p terminal deletion. In patient 2, we uncovered a novel complex rearrangement involving a 1.17 Mb rearranged segment and four interstitial deletions ranging from 9 bp to 12.39 Mb. Our results underscore the diversity of clinically relevant structural rearrangements and the power of long-read sequencing in unraveling their nuanced architectures.

Autism spectrum disorder (ASD) comprises neurodevelopmental disorders with wide variability in genetic causes and phenotypes, making it challenging to pinpoint causal genes. We performed whole exome sequencing on a modest, ancestrally diverse cohort of 195 families, including 754 individuals (222 with ASD), and identified 38,834 novel private variants. In 68 individuals with ASD (~30%), we identified 92 potentially pathogenic variants in 73 known genes, including BCORL1, CDKL5, CHAMP1, KAT6A, MECP2, and SETD1B. Additionally, we identified 158 potentially pathogenic variants in 120 candidate genes, including DLG3, GABRQ, KALRN, KCTD16, and SLC8A3. We also found 34 copy number variants in 31 individuals overlapping known ASD loci. Our work expands the catalog of ASD genetics by identifying hundreds of variants across diverse ancestral backgrounds, highlighting convergence on nervous system development and signal transduction. These findings provide insights into the genetic underpinnings of ASD and inform molecular diagnosis and potential therapeutic targets.

Black women face the highest mortality-to-incidence ratio from high grade serous ovarian cancer (HGSOC). This study investigated biological differences in HGSOC tumors from Black vs. White women. HGSOC from 35 Black and 31 White patients were analyzed by Infinium Methyation-EPIC array and RNA sequencing. 191 CpG sites were differentially methylated (FDR < 0.05, β value change> 10%) and 277 genes were differentially expressed (FDR < 0.05). Gene Ontology identified enriched pathways related to DNA damage response, p53/apoptosis signaling, and cholesterol/lipid metabolism directly connected with genes like INSR, FOXA1 and FOXB1. INSR and FOXA1 knockdown enhanced cisplatin sensitivity and inhibited cell proliferation and colony formation. Tumors from Black patients were infiltrated by fewer CD4+ naïve and regulatory T-cells. Overall, differences in DNA methylation, transcriptomic profiles and immune cell infiltration were detected in tumors from Black vs. White patients. Further investigation is warranted into how these differences may affect treatment response and outcomes in Black women.

Boston Children's Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children's Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.

The global burden of undiagnosed diseases, particularly in adults, is rising due to their significant socioeconomic impact. To address this, we enrolled 232 adult probands with undiagnosed conditions, utilizing bioinformatics tools for genetic analysis. Alongside exome and genome sequencing, repeat-primed PCR and Cas9-mediated nanopore sequencing were applied to suspected short tandem repeat disorders. Probands were classified into probable genetic (n = 128) or uncertain (n = 104) origins. The study found genetic causes in 66 individuals (28.4%) and non-genetic causes in 12 (5.2%), with a longer diagnostic journey for those in the probable genetic group or with pediatric symptom onset, emphasizing the need for increased efforts in these populations. Genetic diagnoses facilitated effective surveillance, cascade screening, drug repurposing, and pregnancy planning. This study demonstrates that integrating sequencing technologies improves diagnostic accuracy, may shorten the time to diagnosis, and enhances personalized management for adults with undiagnosed diseases.

Cancer genetic data from Sub-Saharan African (SSA) are limited. Patients with female breast (fBC), male breast (mBC), and prostate cancer (PC) in Rwanda underwent germline genetic testing and counseling. Demographic and disease-specific information was collected. A multi-cancer gene panel was used to identify germline Pathogenic Variants (PV) and Variants of Uncertain Significance (VUS). 400 patients (201 with BC and 199 with PC) were consented and recruited to the study. Data was available for 342 patients: 180 with BC (175 women and 5 men) and 162 men with PC. PV were observed in 18.3% fBC, 4.3% PC, and 20% mBC. BRCA2 was the most common PV. Among non-PV carriers, 65% had ≥1 VUS: 31.8% in PC and 33.6% in BC (female and male). Our findings highlight the need for germline genetic testing and counseling in cancer management in SSA.

The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). The GWAS confirmed three known WML-associated loci (SH3PXD2A, GFAP, and TRIM47). The lead variant of GFAP was a common missense variant (p.D295N) in East Asians. Meta-GWAS using the publicly available summary statistics of UK Biobank identified one previously unreported locus 6q23.2 (SLC2A12). Integration with expression quantitative trait locus data implied the newly identified locus affects SLC2A12 expression. The effect sizes of 20 lead variants at the WML-associated loci were moderately correlated between JPSC-AD and UK Biobank. These results indicate that the alteration in GFAP protein caused by the common missense variant in East Asians influences the WML volume.

Approximately 200 critically ill infants and children in New Zealand are in high-dependency care, many suspected of having genetic conditions, requiring scalable genomic testing. We adopted an acute care genomics protocol from an accredited laboratory and established a clinical pipeline using Oxford Nanopore Technologies PromethION 2 solo system and Fabric GEM™ software. Benchmarking of the pipeline was performed using Global Alliance for Genomics and Health benchmarking tools and Genome in a Bottle samples (HG002-HG007). Evaluation of single nucleotide variants resulted in a precision and recall of 0.997 and 0.992, respectively. Small indel identification approached a precision of 0.922 and recall of 0.838. Large genomic variations from Coriell Copy Number Variation Reference Panel 1 were reliably detected with ~2 M long reads. Finally, we present results obtained from fourteen trio samples, ten of which were processed in parallel with a clinically accredited short-read rapid genomic testing pipeline (Newborn Genomics Programme; NCT06081075; 2023-10-12).

Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. In this retrospective study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with recessive Jeune syndrome. We detected twelve variants, eight of which were novel, including c.373+91A>G, which led to aberrant splicing. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Analysis of all reported and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.