scholarly journals Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Chenxi Yu ◽  
Bobo Xie ◽  
Zhengye Zhao ◽  
Sen Zhao ◽  
Lian Liu ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
Hormone Deficiency ◽  
Clinical Criteria ◽  
Mutational Burden ◽  
Group I ◽  
Whole Exome

PurposeCongenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis.MethodsWe retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis.ResultsIn 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients.ConclusionOur study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.

scholarly journals Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management

2021 ◽  
Vol 9 (1) ◽  
pp. 2
Author(s):  
Laura Pezzoli ◽  
Lidia Pezzani ◽  
Ezio Bonanomi ◽  
Chiara Marrone ◽  
Agnese Scatigno ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
Clinical Management ◽  
Genetic Diagnosis ◽  
Family Management ◽  
Whole Exome ◽  
Time To Diagnosis ◽  
The Mean ◽  
Mean Time

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient’s critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients’ clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.

scholarly journals Analysis of tumor mutational burden: correlation of five large gene panels with whole exome sequencing

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Carina Heydt ◽  
Jan Rehker ◽  
Roberto Pappesch ◽  
Theresa Buhl ◽  
Markus Ball ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Large Gene ◽  
Mutational Burden ◽  
Whole Exome ◽  
Tumor Mutational Burden ◽  
Gene Panels

scholarly journals Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity

2020 ◽  
Vol 8 (2) ◽  
pp. e001199
Author(s):  
Tae Hee Hong ◽  
Hongui Cha ◽  
Joon Ho Shim ◽  
Boram Lee ◽  
Jongsuk Chung ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Predictive Ability ◽  
Progression Free Survival ◽  
Superior Performance ◽  
Enhanced Sensitivity ◽  
Mutational Burden ◽  
Tumor Purity ◽  
Whole Exome ◽  
Tumor Mutational Burden

BackgroundTumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.MethodsWe comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker’s predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).ResultsLow tumor purity was common (range 30%–45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p<0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016).ConclusionsOur data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.

scholarly journals Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders

2018 ◽  
Vol 55 (5) ◽  
pp. 316-321 ◽  
Author(s):  
Rebekah Jobling ◽  
Dimitri James Stavropoulos ◽  
Christian R Marshall ◽  
Cheryl Cytrynbaum ◽  
Michelle M Axford ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Clinical Manifestations ◽  
Rare Condition ◽  
Hormone Deficiency ◽  
Truncated Protein ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
And Inversion

BackgroundChitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified.Methods and resultsWe identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion.ConclusionsChitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.

Sign in / Sign up

Export Citation Format

Share Document