Publication highlights: August-October 2022

Prognosis and Oncogenomic Profiling of Patients With Tropomyosin Receptor Kinase Fusion Cancer in the 100,000 Genomes Project

Bridgewater et al., Cancer Treatment and Research Communications 2022

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumour types. Limited data exist on the overall survival of patients with tumours with NTRK gene fusions and on the co-occurrence of NTRK fusions with other oncogenic drivers. This retrospective study included 15,223 patients enrolled in the Genomics England 100,000 Genomes Project who had linked clinical data from UK databases. The results show that the presence or absence of an NTRK gene fusion doesn't statistically impact survival. In addition, the authors suggest that in patients with tumours harbouring an NTRK gene fusion, co-occurrence of other actionable biomarkers is generally uncommon, except for high-MSI and TMB, which were mainly driven by colorectal cancers, supporting the hypothesis that NTRK gene fusions are the primary oncogenic drivers in tumours that harbour them. This highlights the importance of NTRK gene fusions as actionable drug targets and emphasizes the need for widespread adoption of broad panel genomic testing in routine oncology clinical practice. It also underscores the potential clinical benefits of TRK inhibitor therapy for patients with TRK fusion cancer.

A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project

Blakes et al., Genome Medicine 2022

A genetic diagnosis is of immense value to rare disease patients as it provides better understanding of their condition and creates opportunities for tailored treatment and improved genetic counselling. However, diagnostic yields remain below 50%. Here, Blakes et al., attempt to reduce this gap by examining the contribution of splicing variants to rare disease. Variants that disrupt splicing are a known cause of disease, but can be challenging to identify and interpret diagnostically, especially if they occur at non-canonical splice sites. The authors first determine the landscape of splicing variants in WGS data from over 38,688 participants in the 100,000 genomes project and then use this information to identify 35 likely diagnoses for probands with previously unsolved rare disease cases, 6 of which have been confirmed to date. Altogether this study illustrates the contribution of non-canonical slice variants to rare disease and demonstrates the value of investigating them in patients lacking a genetic diagnosis.

Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis

Lemoine et al., American Journal of Human Genetics 2022

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder primarily characterized by formation of numerous cysts on the kidneys. It is the most common inherited kidney disorder, and a progressive condition ultimately requiring renal replacement therapy in most cases. Variants in PKD1 and PKD2 underlie most ADPDK cases, but several other genes, including IFT140, GANAB, DNAJB11, and ALG9 are associated with the disease. Importantly, the genetic causes remain unknown in approximately 7% of affected families. In this study, Lemoine et al, performed whole-exome sequencing on one family lacking a genetic diagnosis and discovered a monoallelic frameshift variant in ALG5. Subsequent, genetic analysis of a large cohort of families with ADPKD like symptoms, and the 100,000 genomes data, identified four additional families with pathogenic variants in ALG5. All 23 affected members presented clinical phenotypes consistent with ADPKD, including progressive development of kidney cysts. The authors further demonstrate that ALG5 is required for normal maturation of PC1, the protein encoded by PKD1. Together, their findings demonstrate that monoallelic variants of ALG5 lead to a ADPKD disorder and shed new light on the genetic origins of this often-fatal kidney disease.

Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Ellingford et al. Genome Medicine 2022

Advances in genomic sequencing have revolutionized our ability to diagnose, understand and treat genetic disease. Indeed, such genetic investigations are now commonplace, but they have tended to focus on variants that occur in protein coding regions or canonical splice sites, leaving many rare disease cases unexplained. The use of WGS has greatly improved our ability to detect a wide range of non-coding variants and to increase diagnostic yield. However, while the role non-coding variants play in human disease is well established, the significance of individual non-coding variants can be challenging to interpret clinically. Here a panel of expert clinical and research scientists produce and discuss a set of extensively tested guidelines on how best to interpret and report variants in non-coding regions. It is hoped that these recommendations will increase our ability to consistently interpret non-coding variants, leading to more accurate diagnoses and an improved understanding of disease mechanisms.

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