Jul 2026· American Journal of Kidney Diseases· 0 citations· 19 references
Medicine
TL;DR
The ease of use of MPS increasingly tempts non-specialized genetic laboratories to perform broad analyses of numerous diseases, which in specific cases may worsen the quality of investigations, i.e. for the relatively frequent ADPKD.
Abstract
A certain proportion of patients with Mendelian diseases are overlooked, although substantial technical advances in molecular genetics have been achieved. Massively parallel sequencing (MPS) increasingly identifies genetic variants of unknown significance, which may remain clinically unhelpful. Furthermore, difficult niches in the genome exist, which cannot be solved by standard MPS. In the reported family autosomal dominant kidney disease leading to renal failure in middle adulthood runs through the maternal and paternal family. Comprehensive genetic analyses and customized functional evaluation solved the genetic etiologies: autosomal dominant polycystic kidney disease (ADPKD-PKD1, maternal) and autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD, paternal), with the index patient suffering from both diseases. The pathogenic variant in PKD1 (c.2180T>C, p.(Leu727Pro)) was not identified by exome sequencing (ES) but was unveiled by traditional long-range amplification protocols and whole genome sequencing. The ease of use of MPS increasingly tempts non-specialized genetic laboratories to perform broad analyses of numerous diseases, which in specific cases may worsen the quality of investigations, i.e. for the relatively frequent ADPKD.
Underused Drosophila melanogaster offers high genomic and pathway conservation, a wealth of genetic tools, and rapid generation times, making it a reliable and sustainable model for mechanistic, genome-wide, and precision medicine studies.
Jay Deloriea, Cody Casey, Lexee Shearer et al.· Journal of Developmental Bio...· 0 citations
In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history, and provide a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap.
Emma Ehn, H. Thonberg, Inger Nennesmo et al.· Human Molecular Genetics· 0 citations
This study provides the first systematic, mutational-level characterization of a Cypriot Mendelian disease cohort, establishing a local baseline diagnostic yield and revealing a high proportion of novel variants that reflect the underrepresentation of Eastern Mediterranean populations in global databases.
A. Theodosiou, L. Kousoulidou, Ioannis Papaevripidou et al.· Genes· 0 citations
De novo mutations (DNMs) are an important source of congenital diseases. With delayed parenthood and assisted reproductive technology (ART) use increasing, it is essential to elucidate how these reproductive factors influence DNMs and whether resulting mutations influence offspring health. Here we performed whole-genome sequencing of 24,030 individuals from 7,851 parent-offspring families, identifying 390,924 de novo single-nucleotide variants (dnSNVs). Paternal and maternal aging exhibited distinct mutational patterns, with maternal DNM accumulation accelerating at advanced ages. Increased paternal dnSNVs partially accounted for the association between advanced parental age and shorter gestational duration. Moreover, ART showed age-independent, procedure-specific effects: intracytoplasmic sperm injection (ICSI) and ovarian stimulation were associated with increased paternal and maternal dnSNVs, respectively, and ICSI-associated paternal dnSNVs also partially accounted for the association between ICSI and shorter gestational duration. In vitro embryo manipulation was associated with increased early post-zygotic mosaic mutations, particularly C > A substitutions linked to delayed neurocognitive development at 1 year. Collectively, these findings advance understanding of the determinants and consequences of de novo mutagenesis.
N. Qin, Juncheng Dai, Yue Jiang et al.· Nature Medicine· 0 citations
Primary mitochondrial diseases (PMDs) are one of the most common genetic disorders with an estimated prevalence of 1 in 4300. This review article summarises the latest updates in the field of mitochondrial medicine over the last decade. The availability of exome and genome sequencing in clinical practice has empowered clinicians to unravel the phenotypic heterogeneity of PMD and to end the diagnostic odyssey experienced by many patients and families. In unresolved cases, the detection of variant(s) of unknown significance by next-generation sequencing creates diagnostic and clinical uncertainties, and integrating a multi-omics approach can improve diagnostic yield. Alongside breakthroughs in genomic technologies, there is growing interest in using fluid biomarkers to guide diagnosis, monitor disease progression, and potentially serve as clinical trial endpoints. However, the clinical application of these fluid biomarkers in unselected patient cohorts with different disease onset and phenotypes would require more robust evidence. Natural history studies derived from national and international collaborations have provided insights into genotype–phenotype relationships and prognostic factors across several genotypes, including m.3243A>G, MT-ATP6, POLG, and TK2. Advances in therapeutic discoveries and clinical trials are challenging the obsolete dogma that PMDs are untreatable and bringing hope to patients; four compounds have been licensed, and many trials are in progress. Many barriers and challenges to translating laboratory discoveries into clinical therapy in PMD remain, including preclinical models for efficacy and safety testing, sample size, trial design, and the selection of outcome measures and trial endpoints.
A. Lim, Aye Moe, R. Stefanetti et al.· Genes· 0 citations
The genetic architecture of early-onset chronic kidney disease (CKD) is caused by more than 200 monogenic genes, where their common diagnostic classes include congenital anomalies of the kidney and urinary tract, steroid-resistant nephrotic syndrome, nephronophthisis-related ciliopathies, chronic glomerulonephritis, and urinary stone disease. While advancements in whole-exome and whole-genome sequencing have enabled identification of disease-causing variants, their rates of classification have remained unknown. Likewise, the molecular effects of these pathogenic variants remain unresolved, which is essential for improving personalized treatment approaches. In this study, we collected clinical and biophysical data from 117,373 genetic variants across 129 monogenic genes causing early-onset CKD. This data established the NephVar registry, which aims to be a molecular dictionary for nephrologists to classify variants and resolve their unique molecular effects. Through NephVar, we estimated 1-15% of alleles are reclassified and the time to reclassification per variant is 2-12 years in early-onset CKD. Furthermore, NephVar identified the molecular effects of all variant types, emphasizing missense variants. Our analyses indicate that intrinsically disordered regions of proteins are protective against disease-causing missense alleles across most diagnostic classes, but often occur through a buried loss-of-function (LoF) mechanism. Additionally, we show that the mode of inheritance for these monogenic genes influences clustering patterns of genetic variants, where autosomal dominant (AD) genes are more clustered than those of autosomal recessive (AR) genes. This data accurately predicted the non-LoF effects in INF2, PAX2, GATA3, ACTN4, and LMX1B causing inherited nephrotic syndromes. We demonstrate that variant effect prediction is effective for downgrading variants of unknown significance and classifying AR genes, but challenging for pathogenic alleles in AD genes. Lastly, we propose standards and guidelines for determining non-LoF effects, including gain-of-function and dominant negative, in inherited nephrotic syndrome. Overall, the NephVar renal registry has important implications for defining the molecular architecture and estimating the progress of molecular diagnostics for early-onset CKD.