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PubMed2025

Long-Read Sequencing of the MUC1 VNTR: Genomic Variation, Mutational Landscape, and Its Impact on ADTKD Diagnosis and Progression.

BACKGROUND: ADTKD-MUC1 is caused by frameshift mutations in MUC1 gene that produce a frameshifted protein (MUC1fs) toxic to kidney cells. The gene's variable number of tandem repeats (VNTR), with high GC content, makes it largely inaccessible to standard sequencing. As a result, both the reference sequence and natural variation in this region remain poorly defined, complicating mutation detection and data interpretation. Standard methods also fail to pinpoint the exact VNTR unit affected, limiting insight into mutation mechanisms and genotype-phenotype correlations. METHODS: We employed Single Molecule, Real-Time (SMRT) sequencing and characterized the genomic sequence of MUC1 in 300 individuals including 279 individuals from 143 families suspected of having ADTKD-MUC1. We compared these results to those obtained using the CLIA-approved mass spectrometry-based probe extension (PE) assay, which specifically detect the most prevalent 59dupC mutation. We correlated the structural features of the MUC1 VNTR with the rate of kidney function decline in affected individuals. RESULTS: We identified MUC1 consensus sequences for 205 unique VNTR alleles, with 9 distinct types of frameshift mutations present on 52 distinct mutated VNTR alleles. MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD, comprising 135 genetically affected individuals (48%). The SMRT assay exhibited complete concordance and revealed that the PE assay is capable of detecting frameshift mutations in approximately 85% of affected families. The constellation of VNTR structures supports a genotype-progression model, in which fast progressors exhibit a significantly lower number of repeat units on the wild-type allele and a higher number of repeats on the mutation-bearing allele, including an increased number of frameshifted repeat units. CONCLUSIONS: SMRT sequencing outperforms current diagnostic methods for ADTKD-MUC1 and reveals the prognostic value of VNTR structures. Although their contribution to disease progression is modest (~6% variance explained), it remains biologically and clinically meaningful.

Autosomal Dominant Tubulointerstitial Kidney Disea↗
PubMed2026

Chromosome-level genome assembly of a cosmopolitan marine harmful algal bloom diatom species Chaetoceros socialis (Chaetocerotaceae).

Chaetoceros socialis is a cosmopolitan diatom species that is crucial for maintaining marine ecosystem structure and driving elemental cycles. C. socialis can form harmful algal blooms (HABs) that may cause a negative impact on the marine ecosystems. Whole-genome information for C. socialis is still unavailable, which may hinder more targeted studies on its ecological adaptive responses and evolutionary drivers. To address this gap, we employed cutting-edge genomic technologies including PacBio single-molecule real-time (SMRT) sequencing and high-throughput chromatin conformation capture (Hi-C) to achieve the first chromosome-level genome assembly of C. socialis. The assembled genome is 60.22 Mb in size with a scaffold N50 of 7.81 Mb and has been anchored to eight pseudochromosomes. A total of 13,378 protein-coding genes were predicted, of which 12,069 (90.22%) were functionally annotated. This high-quality genomic resource provides a fundamental data platform for systematically elucidating the ecological adaptation mechanisms of C. socialis.

Chromosomes↗
PubMed2026

Patterns of Drug Resistance, Drug Resistance Conferring Mutations and Genomic DNA Methylation Revealed in Mycobacterium tuberculosis From South Africa.

Tuberculosis remains a major public health threat globally, with drug-resistant strains undermining treatment efficacy. We analyzed 126 Mycobacterium tuberculosis (M. tuberculosis) isolates with diverse drug resistance spectra and selected 35 for whole genome sequencing (WGS) using Illumina NextSeq, SMRT PacBio Onso and SMRT PacBio Revio sequencing platforms. The study aimed to characterize drug resistance profiles, compare short- and long-read sequencing performance, identify lineages among South African isolates, detect known drug resistance mutations and their lineage-specific patterns, and utilize long-read SMRT platforms for epigenetic profiling. Multiple drug resistance mutations were identified, some lineage-specific, and notably, East-African-Indian (EAI) Lineage 1 isolates often considered less pathogenic, showed significant potential for multidrug-resistance development, including higher fluoroquinolone resistance as compared to other lineages. Three DNA motifs with methylated adenines, namely CACGCaG, CtCCaG and GaTNNNNRtAC, were detected, with methylation patterns varying by lineage and strain due to mutations in the corresponding methyltransferases (MTases). A particularly notable finding was the stable maintenance of a genetic heterogeneity in the mamB MTase, performing methylation at CACGCaG motifs. These results highlight the combined role of genetic and epigenetic variation in M. tuberculosis adaptive evolution and underscore the value of integrating long-read sequencing into TB surveillance and research.

Mycobacterium tuberculosis↗
PubMed2025

Different mutations in TBL1XR1 lead to diverse phenotypes of neurodevelopmental disorder: two case reports.

The TBL1XR1 gene (Transducin beta-like 1X-linked receptor 1) is responsible for encoding the TBL1XR1 protein, an important component of the NCoR and SMRT corepressor complexes. 48 missense variants of the TBL1XR1 gene have been reported, which are associated with various phenotypes of neurodevelopmental disorders, including West syndrome, Pierpont syndrome, and others. However, given the important role of TBL1XR1 in neurological diseases, it is still necessary to further explore the variation of TBL1XR1. In this study, we present two patients with distinct variants and phenotypes. Patient 1 exhibits global developmental delay, intellectual disability, delayed language development, and seizures. While patient 2 displays mild facial dysmorphism, significant developmental delay, feeding difficulties, and increased muscle tone. Through trio whole-exome sequencing, two novel pathogenic variants in the TBL1XR1 gene were identified: A heterozygous NM_024665.6:c.940G > T (p.Val314Phe) variant in patient 1 and a heterozygous NM_024665.6:c.1387G > T (p.Asp463Tyr) in patient 2. Discovery of these two novel variant sites expands the mutation spectrum associated with the TBL1XR1 gene.

Child↗