Multiplex testing of driver mutations in non-small cell lung cancer (NSCLCs) of African-American (AA) patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7561-7561
Author(s):  
Shirish M. Gadgeel ◽  
Michele L Cote ◽  
Ann G. Schwartz ◽  
Aliccia Bollig-Fischer ◽  
Susan Land ◽  
...  
Keyword(s):  
Smoking Status ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Therapeutic Interventions ◽  
Driver Mutations ◽  
Specific Gene ◽  
Kras Mutations ◽  
Institutional Review ◽  
Multiplex Testing ◽  
White Patients

7561 Background: Recently driver genetic alterations have been identified in NSCLC that can be targeted for therapeutic interventions. Previous reports have suggested that rates of certain mutations may vary according to ethnic background. We conducted multiplex testing of NSCLCs of AA and white patients to assess variability in the mutation rates by race. Methods: We identified tumor tissues of 136 AA and 320 white NSCLC patients collected as part of three different institutional review board approved studies. Using the Sequenom MassArray system and a multiplexed panel, we analyzed tumor DNA for 214 oncogenic mutations in 26 genes previously identified in NSCLC. Estimated risk (Odds Ratios (OR)) of any mutation and specific gene mutations among AA patients compared to white patients were calculated after adjusting for age, sex, smoking status and histology (adenocarcinoma versus non-adenocarcinoma). Information on smoking status was unavailable on 46 patients and was not included in calculations of ORs for some genes (ORª). Results: The median age at diagnosis was 60 vs 66 years in AA vs white patients; 43% of AA patients and 66% of white patients were males; 69% of AA patients and 52% of white patients had adenocarcinoma; 66% of AA patients and 85% of white patients had stage I/II NSCLC and 10% of AA patients and 6% of white patients were never smokers. 43% of the AA patients and 47% of white patients had at least one mutation detected (OR = 0.78; 0.5-1.2). 19% of AA patients and 6% of white patients had more than 1 mutation detected (OR 2.3; 1.1-4.9). AA patients were more likely to harbor mutations in STK11 (LKB1) (OR=8.4; 3.2-21.8) and NOTCH1 (ORª=8.1; 2.2-30.8), and they were less likely to have MET mutations (ORª= 0.12; 0.02-0.9) then white patients. While not statistically significant, AA had lower prevalence of Kras mutations (OR=0.64, 0.3-1.4) and p53 mutations (OR= 0.82; 0.4-1.6). Conclusions: Our analysis of NSCLCs shows that AAs were more likely to have multiple genetic mutations than whites and the mutation profile differs by race.

Genetic Alterations in Chinese Resected Lung Cancer with Invasive Mucinous Adenocarcinoma: Genomic Profiling and Prognostic Value Analysis

2021 ◽  
Author(s):  
James D. Klingensmith
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Kras Mutations ◽  
Genetic Characteristics ◽  
Value Analysis ◽  
Invasive Mucinous Adenocarcinoma

Lung invasive mucinous adenocarcinoma (IMA) is a unique histological subtype with different clinical and pathological characteristics. Despite prior genomic investigations on lung IMA, little is known about the genetic features and prognosis-related biomarkers in Chinese surgically resected lung IMA. IMA showed a distinct genetic profile, with more diversified driver mutations and co-occurrence of tumor drivers/suppressors than non-IMA. From non-IMA to mixed-IMA to pure-IMA, the frequency of EGFR (72.0 percent vs. 40.0 percent vs. 23.1 percent, p=0.002) and ALK (undetected vs. 20.0 percent vs. 26.9%, p=0.015) changes exhibited a trend of steady decline and rise, respectively. KRAS mutations were more common in pure-IMA than in mixed-IMA, however the difference was statistically insignificant (23.1 percent vs. 4.0 percent, p=0.10). Pure-IMA had a lower rate of TP53 mutation than mixed-IMA and non-IMA (23.1 percent vs. 52.0 percent vs. 56.0 percent, p=0.03). Furthermore, IMA had fewer arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, with a steady drop in amplification and rise in deletion frequency from non-IMA to mixed-IMA to pure-IMA, respectively. Patients with EGFR mutations (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway mutations (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) had longer DFS than patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or KRAS mutations (mDFS=13 KRAS mutations, PI3K pathway changes, and tumor differentiation status were all shown to be independent predictors with statistically significant effects on IMA patients' clinical outcomes in multivariate analysis. Our research shed light on the genomics of Chinese lung IMA that had been surgically removed. In IMA patients with stage III illness, we also discovered many genetic characteristics that might be used as indicators for postoperative recurrence.

scholarly journals Aberrant Signaling Pathways in Sinonasal Intestinal-Type Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5022
Author(s):  
Cristina Riobello ◽  
Paula Sánchez-Fernández ◽  
Virginia N. Cabal ◽  
Rocío García-Marín ◽  
Laura Suárez-Fernández ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Wide Spectrum ◽  
Tumor Development ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Activity Level ◽  
Intestinal Type ◽  
Specific Gene ◽  
Intestinal Type Adenocarcinoma

Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene mutations and their relation to clinical features. We applied whole exome sequencing of 120 cancer-related genes in 50 ITACs and analyzed the signaling activity of four specific pathways frequently affected by mutations. Genes involved in DNA damage response showed somatic mutations in 30% of cases, including four tumors that also harbored germline mutations. Genes in Wnt, MAPK and PI3K pathways harbored mutations in 20%, 20% and 24% of cases, respectively. Mutations and copy number gains in receptor tyrosine kinases possibly affecting MAPK and PI3K pathways occurred in 44% of cases. Expression of key pathway proteins showed no correlation to mutations in these pathways, except for nuclear β-catenin and APC/CTNNB1 mutation. No specific gene mutation, mutated pathway, nor pathway activity level showed correlation to clinical data or survival. In addition, a similar mutational profile was observed among histological subtypes. The wide spectrum of gene mutations suggests that ITAC is a genetically heterogeneous without specific characterizing gene mutations.

Multiple Myeloma Sequencing Reveals Subclonality and Timing of Genetic Alterations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2897-2897
Author(s):  
Jens Lohr ◽  
Petar Stojanov ◽  
Michael S Lawrence ◽  
Daniel Auclair ◽  
Scott Carter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Time Course ◽  
Somatic Mutations ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Classification Systems ◽  
Driver Mutations ◽  
Kras Mutations

Abstract Abstract 2897 Multiple myeloma is considered to be a homogenous disease within a given patient, and current classification systems and treatment algorithms are based on this assumption. We have asked if there is genetic heterogeneity of multiple myeloma within a patient and if this heterogeneity can be quantified. To address this question, we have used massively parallel whole exome and whole genome sequencing of tumors and matched normal controls of 64 patients with multiple myeloma. We present an analytic strategy to distinguish potential driver mutations based on their clonality. We demonstrate that in some patients there are many somatic mutations that are only present in a subclonal fraction of the malignant plasma cells, and the subclonal fraction comprises up to 50%. These mutations are therefore less likely to confer a selective clonal advantage and are less attractive therapeutic targets because they only affect a small fraction of the myeloma cells. As an example, we found KRAS to be one of the most prevalent mutated genes in multiple myeloma, and KRAS mutations are significantly more likely clonal than subclonal, while other mutations in other genes are predominantly subclonal. We also used this approach to investigate how copy number variations are related to somatic mutations, i.e. to define the temporal sequence of these events. This question is particularly relevant for hyperdiploidy in multiple myeloma, since this is associated with trisomies of odd numbered chromosomes. However, these trisomies do not occur with the same frequency in all odd numbered chromosomes and some hyperdiploid samples are also associated with trisomies of various even numbered chromosomes. It is unclear if these trisomies occur as a single catastrophic event, or rather in a sequential fashion. By assuming a constant rate of somatic mutations and utilizing this rate as a “timer” for chromosomal duplications we demonstrate that trisomies of odd-numbered chromosomes appear to occur early in a distinct order, whereas trisomies of even-numbered chromosomes and chromosome 1q occur late. Our analyses allow us to determine which somatic mutations occurred before chromosomal duplication and may therefore give insight in the time course of pathogenic genetic alterations in multiple myeloma. Our work may also play an important role in prioritizing somatic mutations for therapeutic targeting in multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 47
Author(s):  
Cristina Birzu ◽  
Pim French ◽  
Mario Caccese ◽  
Giulia Cerretti ◽  
Ahmed Idbaih ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Recurrent Glioblastoma ◽  
Molecular Characteristics ◽  
Specific Gene ◽  
Primary Tumors ◽  
First Line Therapy

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.

Somatic mutation spectrum of non-small cell lung cancers (NSCLCs) from African Americans (AAs).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6038-6038
Author(s):  
Philip Edward Lammers ◽  
Velmalia Matthews-Smith ◽  
Ya-Lin Yun ◽  
Yumei Pan ◽  
Snjezana Zaja-Milatovic ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
North American Population ◽  
Molecular Testing ◽  
Chi Square ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ffpe Tumor

6038 Background: In the AA population, previous studies have presented conflicting data on the frequency of EGFR mutations (Reinersman JTO 2011;Leidner JCO 2009), while frequencies of other gene mutations and translocations, including anaplastic lymphoma kinase (ALK), have not been described. Methods: 161 archival FFPE tumor specimens from self reported AA patients with any stage NSCLC from 1997-2010 were collected from 3 sites in Tennessee (132 samples) and one site in Michigan (29 samples). Samples were evaluated for known recurrent driver mutations in EGFR, KRAS, BRAF, NRAS, AKT1, PI3KCA, PTEN, HER-2, MEK1 by standard SNaPshot/sizing assays, and translocations in ALK by FISH. Clinical data was collected on 119 patients. Chi-square was used to compare the frequency of mutations in subgroups and Kaplan-Meier and log rank were used to calculate and compare PFS between groups. Results: 5.0% of tumors had EGFR mutations, 14.9% had KRAS mutations, 0.6% had a BRAF, AKT1, PI3KCA, or HER2 mutation, and 0% had NRAS, PTEN, or MEK1 mutations. Of 35 ‘pan-negative’ non-squamous specimens, 0 had ALK translocations. PFS was the same in those with and without KRAS mutation (p=0.74) and showed a trend towards improvement in those with EGFR mutation (p=0.08). The frequency of EGFR mutations was higher in samples from Detroit versus those from Tennessee (17% vs 2.3%, p<0.01), as was the frequency of adenocarcinoma (62% vs 44%, p<0.05). The frequency of EGFR mutations in never smokers was higher in the samples from Detroit versus Tennessee (83% vs 7.1%, p<0.01). Conclusions: In the largest tumor mutational profiling study of NSCLC from AAs to date, EGFR mutations occurred less frequently than would be expected from a North American population. We noted a regional difference, with fewer EGFR mutations in Tennessee than in Michigan, a finding that may have been the result of more adenocarcinoma samples from Michigan. The rates of other mutations and translocations including ALK were low. While lung cancer tumors should continue to undergo routine molecular testing to prioritize therapy, future comprehensive genotyping efforts should focus on identifying novel driver mutations in this population. Funding: 5RC1CA162260 R01CA060691 R01CA87895.

Multiplex testing for driver mutations in squamous cell carcinomas of the lung.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7505-7505 ◽  
Author(s):  
Paul K. Paik ◽  
Adnan Hasanovic ◽  
Lu Wang ◽  
Natasha Rekhtman ◽  
Marc Ladanyi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell ◽  
Tumor Suppressors ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Personalized Care ◽  
Pik3ca Mutations ◽  
Pten Loss ◽  
Institutional Review ◽  
Multiplex Testing

7505 Background: While the majority of lung adenocarcinomas (ADCL) harbor an identifiable driver mutation, targeted therapies for squamous cell lung carcinomas (SQCLC) have lagged in development due to a paucity of druggable oncogenic events. Three targets, which together occur in up to 50% of SQCLC, have been recently identified (FGFR1 amplification, DDR2 mutations, PIK3CA mutations/PTEN loss). Comprehensive molecular analysis of SQCLC tumors by The Cancer Genome Atlas is ongoing, with new therapeutic targets on the horizon. Methods: We have instituted prospective, multiplex testing of SQCLC tumors (Squamous Cell Lung Cancer Mutation Analysis Program, “SQ-MAP”). Tests include FISH for FGFR1 amplification (defined as FGFR1:CEP8 ≥ 2 in >10% of cells), IHC for loss of PTEN expression, and Sequenom MassARRAY for PIK3CA mutations (and others, below). We are also incorporating targeted exon sequencing (Agilent SureSelect/Ion Torrent) of a panel of over 80 lung cancer oncogenes and tumor suppressors in preparation for future studies. All tests were performed on formalin-fixed paraffin-embedded samples and with Institutional Review Board/Biospecimen Utilization Committee approval. Results: 40 SQCLC patient specimens have been processed through SQ-MAP over 3 months. 8 samples were excluded (insufficient tissue in 4, reclassification to ADCL in 4). Data are available for 28 patients. PTEN IHC was performed on 15 samples to date. Molecular results are summarized in the table. Events were non-overlapping. Results for the ≥80 gene sequencing component will be described. Based on SQ-MAP, accrual to 2 approved clinical trials (FGFR1 inhibition; PI3K inhibition) has begun, with a third planned (DDR2 mutations). Conclusions: Actionable defects were detected in 60% (95% CI: 37-75%) of SQCLC specimens. Mutation data for ≥80 other oncogenes and tumor suppressors will be available shortly (including DDR2). SQ-MAP serves as a platform supporting both personalized care and research. [Table: see text]

Main driver genes and BRCA mutation in Chinese patients with pancreatic adenocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15741-e15741
Author(s):  
Jiangfang Tian ◽  
Du He ◽  
Zhixi Huang ◽  
Bole Tian ◽  
Dan Cao
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Driver Mutations ◽  
Driver Gene ◽  
Brca Mutations ◽  
Main Driver

e15741 Background: Data on pathogenic genetic alterations in Chinese patients with pancreatic adenocarcinoma (PAC) are limited. Especially, as BRCA mutations may become potential biomarkers guiding therapy for PAC patients, the prevalence of BRCA mutations in Chinese patients remains largely unknown.We performed the study to analyze genes mutational landscape and determine the prevalence of BRCA mutations in Chinese PAC patients. Methods: We reviewed clinical characteristics and genes mutations of 134 patients with a pathologically confirmed PAC from West China Hospital of Sichuan University between May 2016 and November 2018. All of them underwent gene-testing and genes variant evaluation with a panel of 381 genes by next-generation sequencing (NGS). The test samples were mainly from primary pancreatic lesions, other were from peripheral blood and metastatic sites. All main driver gene mutations and clinical stages were measured to determine associations of driver gene mutations, the number of altered genes, the level of CA199 with clinical stage. Results: Of the 134 patients, 73 (54.5%) were men with a median age of 58 (range from 34 to 82) years. The major driver mutations were KRAS (89.6%), TP53 (71.6%), CDKN2A (26.9%), SMAD4 (18.7%) and ARID1A (10.4%). The majority of patients (76.9%) had 2 genes or more genes mutations, KRAS/TP53 and KRAS/TP53/CDKN2A were the most frequently combinate types. Stages of PAC was relevant to numbers of altered genes (p = 0.040) and the level of CA199 (p = 0.002). Five (3.7%) patients with BRCA mutations were identified, two patients had somatic BRCA2 variants, one patient had somatic BRCA1 mutation and the other two patients had germline BRCA2 mutation. Two patients with germline BRCA2 mutations received olaparib and keep stable disease for 4 months and more than 8 months. Our finding revealed patients with PAC had a low TMB (median 3.81 per Mb (range 0.81-9 per Mb)) and PD-L1 expression (16/36, 44.4%), nearly all of them were MSS (50/51,98.0%), just three patients with dMMR (3/134,2.2%). Conclusions: The PAC patient commonly harbored two or more number of five major driver mutations including KRAS, TP53, CDKN2A, SMAD4 and ARID1A. The frequency of BRCA1/2 mutations in Chinese patients with PAC was 3.7%. Olaparib may be effective for PAC patients with BRCA mutations. The PAC may be poor response to immunotherapy.

Mutation Mechanisms of Breast Cancer among the Female Population in China

2020 ◽  
Vol 15 (3) ◽  
pp. 253-259
Author(s):  
Asmaa Amer ◽  
Ahmed Nagah ◽  
Tianhai Tian ◽  
Xinan Zhang
Keyword(s):  
Breast Cancer ◽  
Gene Mutations ◽  
Driver Mutations ◽  
Human Breast ◽  
Breast Epithelium ◽  
Female Population ◽  
Multistage Model ◽  
The Usa ◽  
Intermediate Cells ◽  
Mutation Mechanisms

Background: Cancer is a genetic disease caused by the accumulation of gene mutations. It is important to derive the number of driver mutations that are needed for the development of human breast cancer, which may provide insights into the tumor diagnosis and therapy. Objective: This work is designed to investigate whether there is any difference for the mutation mechanism of breast cancer between the patients in the USA and those in China. We study the mechanisms of breast cancer development in China, and then compare these mechanisms with those in the USA. Methods: This work designed a multistage model including both gene mutation and clonal expansion of intermediate cells to fit the dataset of breast cancer in China from 2004 to 2009. Results: Our simulation results show that the maximum number of driver mutations for breast epithelium stem cells of females in China is 13 which is less than the 14 driver mutations of females in the USA. In addition, the two-hit model is the optimal one for the tumorigenesis of females in China, which is also different from the three-hit model that was predicted as the optimal model for the tumorigenesis of females in the USA. Conclusion: The differences of the mutation mechanisms between China and the USA reflect a variety of lifestyle, genetic influences, environmental exposure, and the availability of mammography screening.

scholarly journals Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

2013 ◽  
Vol 98 (2) ◽  
pp. E364-E369 ◽  
Author(s):  
Nishant Agrawal ◽  
Yuchen Jiao ◽  
Mark Sausen ◽  
Rebecca Leary ◽  
Chetan Bettegowda ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Somatic Mutations ◽  
Medullary Thyroid Cancer ◽  
Driver Mutations ◽  
High Confidence ◽  
Kras Mutations ◽  
Protein Coding ◽  
Medullary Thyroid ◽  
Oncogenic Mutations ◽  
Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

scholarly journals The identification of novel gene mutations for degenerative lumbar spinal stenosis using whole-exome sequencing in a Chinese cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xin Jiang ◽  
Dong Chen
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Spinal Stenosis ◽  
Lumbar Spinal Stenosis ◽  
Gene Mutations ◽  
Specific Gene ◽  
Single Nucleotide ◽  
Degenerative Lumbar Spinal Stenosis ◽  
Whole Exome ◽  
Lumbar Spinal

Abstract Background Degenerative lumbar spinal stenosis (DLSS) is a common lumbar disease that requires surgery. Previous studies have indicated that genetic mutations are implicated in DLSS. However, studies on specific gene mutations are scarce. Whole-exome sequencing (WES) is a valuable research tool that identifies disease-causing genes and could become an effective strategy to investigate DLSS pathogenesis. Methods From January 2016 to December 2017, we recruited 50 unrelated patients with symptoms consistent with DLSS and 25 unrelated healthy controls. We conducted WES and exome data analysis to identify susceptible genes. Allele mutations firstly identified potential DLSS variants in controls to the patients’ group. We conducted a site-based association analysis to identify pathogenic variants using PolyPhen2, SIFT, Mutation Taster, Combined Annotation Dependent Depletion, and Phenolyzer algorithms. Potential variants were further confirmed using manual curation and validated using Sanger sequencing. Results In this cohort, the major classification variant was missense_mutation, the major variant type was single nucleotide polymorphism (SNP), and the major single nucleotide variation was C > T. Multiple SNPs in 34 genes were identified when filtered allele mutations in controls to retain only patient mutations. Pathway enrichment analyses revealed that mutated genes were mainly enriched for immune response-related signaling pathways. Using the Novegene database, site-based associations revealed several novel variants, including HLA-DRB1, PARK2, ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205 genes, etc., were DLSS related. Conclusions Our study revealed that deleterious mutations in several genes might contribute to DLSS etiology. By screening and confirming susceptibility genes using WES, we provided more information on disease pathogenesis. Further WES studies incorporating larger DLSS patient cohorts are required to comprehend the genetic landscape of DLSS pathophysiology fully.

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