In three published studies from this month, researchers used our genetic analysis software to investigate diverse and challenging genetic questions: identifying potential ovarian cancer susceptibility linked to germline ATRIP variants, expanding the clinical and molecular understanding of VPS35L-related Ritscher–Schinzel syndrome, and exploring the genomic landscape of early-onset oral tongue squamous cell carcinoma in a patient without traditional risk factors. Together, these studies highlight how advanced genomic analysis tools can support variant discovery, genotype–phenotype correlation, and translational research across a wide range of clinical applications.
Title: Germline ATRIP Variants and the Risk of Ovarian Cancer
Background: Ovarian cancer has a strong inherited genetic component, with genes such as BRCA1 and BRCA2 accounting for a substantial portion of hereditary risk, although many cases remain unexplained. Because known susceptibility genes explain only part of inherited risk, researchers are continuing to investigate additional genes that may contribute to ovarian cancer development.
Objective: This study explored whether variants in ATRIP, previously identified as a potential breast cancer susceptibility gene, may also increase ovarian cancer risk. The researchers analyzed ATRIP variants in ovarian cancer patients from Poland and Canada who lacked mutations in known ovarian cancer genes, comparing them with healthy control groups to evaluate a possible association with disease susceptibility.
Subjects and Methods: Researchers analyzed large patient and control cohorts from Poland and Canada using targeted genotyping, next-generation sequencing, and confirmatory Sanger sequencing to identify rare loss-of-function ATRIP variants, while statistical analyses compared their frequency between ovarian cancer patients and cancer-free controls.
Additional tumor analyses evaluated loss of the normal ATRIP allele and markers of homologous recombination deficiency (HRD), a genomic instability pattern linked to impaired DNA repair. Together, these methods aimed to determine whether pathogenic ATRIP variants contribute to hereditary ovarian cancer susceptibility and tumor development.
Results: The study found rare loss-of-function variants in ATRIP among ovarian cancer patients in both Polish and Canadian cohorts, although the individual cohorts alone did not reach statistical significance. When the datasets were combined, carriers of ATRIP variants showed a significantly increased risk of Ovarian cancer, with an estimated 2.5-fold higher risk compared with controls. Tumor analyses from two patients with ATRIP variants did not show loss of the normal ATRIP allele or evidence of homologous recombination deficiency (HRD), suggesting that the biological mechanism linking ATRIP variants to ovarian cancer risk may differ from classic HRD-associated cancer pathways.
Conclusion: Together with previous findings linking ATRIP to breast cancer risk, the results suggest that ATRIP may play a broader role in hereditary cancer predisposition through its function in DNA damage repair and genomic stability.
How SVS Was Used: Regions with at least 20× depth of coverage were used for calling variants, and a different nucleotide from the reference sequence seen in at least 20% of the reads aligned to a given position was called as a variant. The SNP and Variation Suite (Golden Helix, Inc., Bozeman, MT) was used for annotating called variants. We focused on LoF variants (frameshift insertions/deletions, stop-codon gain, essential splicing site, and start codon loss variants) with a minor allele frequency of ≤1% reported in gnomAD and 1000 Genomes Project databases. Finally, all the identified LoF variants were assessed using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for variant classification, and only those classified as pathogenic or likely pathogenic were used for the association analyses.
Citation: Zamani, N. et al. (2026). Germline atrip variants and the risk of ovarian cancer. Genetics in Medicine. https://doi.org/10.1016/j.gim.2026.102547
Title: VPS35L-related Ritscher-Schinzel syndrome: Expanding genotype–phenotype correlations
Background: Ritscher–Schinzel syndrome (RTSC or 3C syndrome) is an ultra-rare neurodevelopmental disorder caused by mutations in several genes, many of which disrupt the endosomal recycling pathway that is essential for normal cellular function and development. One form, RTSC3, is caused by biallelic variants in VPS35L and is associated with craniofacial abnormalities, developmental delay, growth failure, hypotonia, limb anomalies, and characteristic brain MRI findings.
Objective: The purpose of this study was to examine a patient with RTSC in order to better understand the pathogenicity of a VPS35L missense variant.
Subjects and Methods: The study evaluated a patient with suspected Ritscher–Schinzel syndrome using trio-based exome sequencing and detailed clinical review. Genetic variants were identified and interpreted using standard sequencing pipelines, ACMG guidelines, population-frequency filtering, and family segregation analysis to prioritize potentially disease-causing changes in VPS35L.
Results: Genetic testing identified a previously unreported homozygous VPS35L missense variant inherited from both parents, supporting an autosomal recessive RTSC3 diagnosis. Computational and structural modeling predicted that the variant destabilizes the VPS35L protein and disrupts Retriever complex function, while splicing analyses suggested the mutation primarily acts through a damaging missense effect rather than altered RNA splicing.
Conclusions: Patients with VPS35L-related Ritscher–Schinzel syndrome (RTSC3) share a recognizable set of core features, although the severity and range of neurological, skeletal, metabolic, and systemic symptoms can vary widely. This newly reported patient expands the known clinical and genetic spectrum of RTSC3 and highlights the importance of comparing genetic findings with patient features to better understand the disorder. Overall, the evidence supports RTSC3 as an endosomal recycling disorder caused by distinct VPS35L variants, with broad effects on neurological development and multiple organ systems.
How VarSeq Was Used: Library preparation was performed using the SureSelect Human All Exon V8 kit (Agilent Technologies, Santa Clara, CA, USA), followed by 150-bp paired-end sequencing on an Illumina NextSeq 2000 platform (Illumina, San Diego, CA, USA). Sequencing reads were aligned to the GRCh37/hg19 reference genome using BWA, and variant calling was performed with the DRAGEN software suite in accordance with Genome Analysis Toolkit (GATK) best-practice recommendations. Copy number variant (CNV) analysis was conducted using VarSeq software (Golden Helix, Inc., Bozeman, MT) and refined by Circular Binary Segmentation.
Citation: Ilaria Carelli. et al. (2026) VPS35L-related Ritscher-Schinzel syndrome: Expanding genotype–phenotype correlations. European Journal of Medical Genetics, Volume 82, 105085, https://doi.org/10.1016/j.ejmg.2026.105085
Title: Early-Onset Oral Tongue Squamous Cell Carcinoma in the Absence of Traditional Risk Factors: A Case Report with Whole-Exome Sequencing Analysis
Background: Oral squamous cell carcinoma is the most common type of oral cancer and typically affects older adults with established risk factors such as tobacco, alcohol use, and HPV infection. However, an increasing number of cases are being reported in younger patients who lack these traditional exposures, suggesting that alternative biological and genetic mechanisms may contribute to disease development.
Objective: This study focuses on a young, non-smoking, non-drinking patient with tongue OSCC and uses whole-exome sequencing to explore the tumor’s genetic profile. The findings highlight a pathogenic TP53 mutation along with additional somatic alterations, supporting the idea that OSCC in this subgroup is genetically heterogeneous and may arise through non-classical tumorigenic pathways.
Subjects and Methods: A 33-year-old woman with no tobacco, alcohol, HPV exposure, or other known risk factors presented with a persistent lesion on the left lateral tongue that progressed from leukoplakia to invasive oral cancer. Initial biopsy underestimated the lesion, but repeat evaluation confirmed moderately to poorly differentiated Oral squamous cell carcinoma, and imaging showed a localized but infiltrative tumor without clear nodal metastasis. Whole-exome and targeted genetic testing of tumor and blood samples identified key molecular alterations (including a TP53 mutation), with extensive genomic profiling performed to better characterize this rare, early-onset OSCC case lacking traditional risk factors.
Results: Genomic analysis of the tumor identified a high number of somatic mutations, with deep sequencing coverage supporting reliable variant detection and evidence of intratumor heterogeneity. A key finding was a somatic pathogenic stop-gain mutation in TP53, along with additional likely pathogenic variants in several other genes, while no clearly pathogenic germline cancer predisposition mutations were identified. Some variants of uncertain significance were also detected, and one high-allele-frequency variant may represent a possible germline change but could not be confirmed. Overall, the results suggest a genetically complex tumor driven primarily by somatic alterations rather than an inherited cancer syndrome.
Conclusions: This case shows that Oral squamous cell carcinoma in a young patient without smoking, alcohol, or HPV exposure can arise through distinct molecular mechanisms. A somatic TP53 mutation was identified as the main driver, along with additional genetic alterations that may contribute to tumor development through alternative pathways.
Overall, the findings suggest that OSCC in young, non–traditional-risk patients may represent a biologically distinct subtype, and they highlight the importance of genomic profiling for improving understanding, risk assessment, and personalized treatment strategies.
How VarSeq Was Used: Variant annotation and filtering were performed using VarSeq 2.5 (Golden Helix, Inc., Bozeman, MT, USA). Variants were filtered based on sequencing quality metrics (Variant Allele Frequency (VAF), read depth), allele frequency according to population databases, and clinical relevance (ClinVar, COSMIC), and classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines [23]. The following in silico tools were used for the prediction of the effect of the point mutations (single nucleotide variants (SNVs), small deletions, insertions, indels) like: SIFT, Polyphen2, MutationTaster, MutationAssesso, FATHMM, VEST3 score, LRT score for missense mutations and GeneSplicer, MaxEntScan, NNSplice, PWM, Ada score and RF score for splice site variants.
Citation: Aleksiev, E., Kachakova-Yordanova, D. L., Mitev, V., Georgiev, M. M., & Mihaylova, Z. (2026). Early-Onset Oral Tongue Squamous Cell Carcinoma in the Absence of Traditional Risk Factors: A Case Report with Whole-Exome Sequencing Analysis. Reports, 9(2), 130. https://doi.org/10.3390/reports9020130
