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Motivation In the modern era of genomic research, the scientific community is witnessing an explosive growth in the volume of published findings. While this abundance of data offers invaluable insights, it also places a pressing responsibility on genetic professionals and researchers to stay informed about the latest findings and their clinical significance. Genomic variant interpretation is currently facing a challenge in identifying the most up-to-date and relevant scientific papers, while also extracting meaningful information to accelerate the process from clinical assessment to reporting. Computer-aided literature search and summarization can play a pivotal role in this context. By synthesizing complex genomic findings into concise, interpretable summaries, this approach facilitates the translation of extensive genomic datasets into clinically relevant insights. Results To bridge this gap, we present VarChat (varchat.engenome.com), an innovative tool based on generative AI, developed to find and summarize the fragmented scientific literature associated with genomic variants into brief yet informative texts. VarChat provides users with a concise description of specific genetic variants, detailing their impact on related proteins and possible effects on human health. In addition, VarChat offers direct links to related scientific trustable sources, and encourages deeper research. Availability and implementation varchat.engenome.com. [ABSTRACT FROM AUTHOR]

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 μM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis. [ABSTRACT FROM AUTHOR]

We analyzed by next-generation sequencing (NGS) 67 epilepsy genes in 19 patients with different types of either isolated or syndromic epileptic disorders and in 15 controls to investigate whether a quick and cheap molecular diagnosis could be provided. The average number of nonsynonymous and splice site mutations per subject was similar in the two cohorts indicating that, even with relatively small targeted platforms, finding the disease gene is not an univocal process. Our diagnostic yield was 47% with nine cases in which we identified a very likely causative mutation. In most of them no interpretation would have been possible in absence of detailed phenotype and familial information. Seven out of 19 patients had a phenotype suggesting the involvement of a specific gene. Disease-causing mutations were found in six of these cases. Among the remaining patients, we could find a probably causative mutation only in three. None of the genes affected in the latter cases had been suspected a priori. Our protocol requires 8-10 weeks including the investigation of the parents with a cost per patient comparable to sequencing of 1-2 medium-to-large-sized genes by conventional techniques. The platform we used, although providing much less information than whole-exome or whole-genome sequencing, has the advantage that can also be run on 'benchtop' sequencers combining rapid turnaround times with higher manageability. [ABSTRACT FROM AUTHOR]

Background: A major obstacle faced by rare disease families is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years, and causal variants are identified in under 50%. The Rare Genomes Project (RGP) is a direct-to-participant research study on the utility of genome sequencing (GS) for diagnosis and gene discovery. Families are consented for sharing of sequence and phenotype data with researchers, allowing development of a Critical Assessment of Genome Interpretation (CAGI) community challenge, placing variant prioritization models head-to-head in a real-life clinical diagnostic setting., Methods: Predictors were provided a dataset of phenotype terms and variant calls from GS of 175 RGP individuals (65 families), including 35 solved training set families, with causal variants specified, and 30 test set families (14 solved, 16 unsolved). The challenge tasked teams with identifying the causal variants in as many test set families as possible. Ranked variant predictions were submitted with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on rank position of true positive causal variants and maximum F-measure, based on precision and recall of causal variants across EPCR thresholds., Results: Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performing teams recalled the causal variants in up to 13 of 14 solved families by prioritizing high quality variant calls that were rare, predicted deleterious, segregating correctly, and consistent with reported phenotype. In unsolved families, newly discovered diagnostic variants were returned to two families following confirmatory RNA sequencing, and two prioritized novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS , identified in trans with a frameshift variant, in an unsolved proband with phenotype overlap with asparagine synthetase deficiency., Conclusions: By objective assessment of variant predictions, we provide insights into current state-of-the-art algorithms and platforms for genome sequencing analysis for rare disease diagnosis and explore areas for future optimization. Identification of diagnostic variants in unsolved families promotes synergy between researchers with clinical and computational expertise as a means of advancing the field of clinical genome interpretation., Competing Interests: Competing interests. Authors S.Z., I.L., E.R., P.M., and R.B., own shares of enGenome srl. Authors F.D.P. and G.N. are employees of enGenome srl. Authors T.J., R.S., S.G.V., N.S., A.R., U.S., N.T., are employees of TCS Ltd. Authors P.J.C., C.K., K.N., and P.S. are employees of Invitae Ltd. H.L.R. receives support from Illumina and Microsoft for rare disease gene discovery and diagnosis. A.O’D-L. is a member of the scientific advisory board for Congenica Inc and the Simons Foundation SPARK for Autism study and co-chairs the clinical advisory board for CAGI. S.E.B receives support at UC Berkeley from a research agreement from TCS. All other authors report no competing interests.