New Mutations In Patients Research Articles

Novel biallelic USH2A variants in a patient with usher syndrome type IIA- a case report

BackgroundUsher Syndrome is the commonest cause of inherited blindness and deafness. The condition is clinically and genetically heterogeneous, with no current treatment. We report a case carrying novel biallelic variants in USH2A causing progressive early adolescent onset visual and hearing impairment consistent with Usher Syndrome Type IIA.Case presentationOur patient presented at age 13 with progressive visual field loss and hearing loss, associated with early onset of cataract in her 40s requiring lens extraction. Now 52 years old, latest best corrected visual acuity (BCVA) stands at Logmar Right Eye (RE) 0.8 and Left Eye (LE) 0.2, with significantly constricted visual fields bilaterally. She was registered partially sighted age 46. Clinical and molecular genetic assessment of the proband was consistent with a diagnosis of Usher Syndrome Type IIA. Genetic testing identified two novel USH2A variants, resulting in the premature termination codon p.Leu30Ter and a missense mutation p.Cys3251Tyr. Segregation analysis confirmed that these variants were biallelic in the affected case. Comprehensive in silico analysis confirmed that these mutations are the probable cause of Usher Syndrome Type IIA in this individual.ConclusionsThe identification of novel mutations in USH2A increases the spectrum of genetic variations that lead to Usher Syndrome, aiding genetic diagnosis, assessment of patient prognosis, and emphasising the importance of genetic testing to identify new mutations in patients with undiagnosed progressive visual loss.

A Review of Drug Therapy in Vestibular Schwannoma.

Vestibular schwannomas (VSs, also known as acoustic neuromas) are benign intracranial tumors commonly managed with observation, surgery, and radiotherapy. There is currently no approved pharmacotherapy for VS patients, which is why we conducted a detailed search of relevant literature from PubMed and Web of Science to explore recent advances and experiences in drug therapy. VSs feature a long course of disease that requires treatment to have minimal long-term side effects. Conventional chemotherapeutic agents are characterized by neurotoxicity or ototoxicity, poor effect on slow-growing tumors, and may induce new mutations in patients who have lost tumor suppressor function, and therefore are unsuitable for treating VSs. Along with the well-investigated molecular pathophysiology of VS and the increasingly accessible technology such as drug repositioning platform, many molecular targeted inhibitors have been identified and shown certain therapeutic effects in preclinical experiments or clinical trials.

Investigating mutation-specific biological activities of small molecules using quantitative structure-activity relationship for epidermal growth factor receptor in cancer

Epidermal Growth Factor Receptor (EGFR) is a potential drug target in cancer therapy. Missense mutations play major roles in influencing the protein function, leading to abnormal cell proliferation and tumorigenesis. A number of EGFR inhibitor molecules targeting ATP binding domain were developed for the past two decades. Unfortunately, they become inactive due to resistance caused by new mutations in patients, and previous studies have also reported noticeable differences in inhibitor binding to distinct known driver mutants as well. Hence, there is a high demand for identification of EGFR mutation-specific inhibitors. In our present study, we derived a set of anti-cancer compounds with biological activities against eight typical EGFR known driver mutations and developed quantitative structure-activity relationship (QSAR) models for each separately. The compounds are grouped based on their functional scaffolds, which enhanced the correlation between compound features and respective biological activities. The models for different mutants performed well with a correlation coefficient, (r) in the range of 0.72–0.91 on jack-knife test. Further, we analyzed the selected features in different models and observed that hydrogen bond and aromaticity-related features play important roles in predicting the biological activity of a compound. This analysis is complimented with docking studies, which showed the binding patterns and interactions of ligands with EGFR mutants that could influence their activities.

Deletions, not duplications or small mutations, are the predominante new mutations in the dystrophin gene.

Examination of the carrier state was performed in 744 unrelated mothers of the Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) probands with identified mutations in the dystrophin gene. Owing to that it was possible to assess frequency and type of new mutations in the gene. Contrary to the Japanese observations of Lee et al. published in this journal, we did not find significant differences in the carrier frequency between mothers of DMD and BMD patients. However, we found that new mutations in patients with deletions were significantly more frequent than in those with duplications and small mutations: of 564 unrelated patients with deletions, 236 (41.8%) carried new mutations, the respective values for duplications and small mutations were 21 of 95 patients (22.1%) and 18 of 85 patients (21.2%)-the differences highly significant (P<0.0001).

Patients with Philadelphia-positive leukemia with Y253H or F359V mutation have a high risk of developing new mutations in the setting of dasatinib resistance

The treatment outcome and development of new mutations in patients with imatinib- and/or nilotinib-failure Philadelphia chromosome positive (Ph+) leukemia with highly nilotinib-resistant mutations (Y253H, E255K/V and F359V/C) were assessed on dasatinib therapy. A total of 111 patients with Ph+ leukemia were grouped into three cohorts by baseline BCR–ABL kinase domain mutation status: no mutation (n = 44), non-nilotinib-resistant mutations (n = 26) or nilotinib-resistant mutations (n = 41). The frequencies of hematological, cytogenetic and molecular responses and clinical resistance to dasatinib were similar among the three cohorts during dasatinib therapy. In dasatinib-resistant patients, new mutations were most frequently observed in the cohort with nilotinib-resistant mutations (p = 0.001). Multivariate analysis revealed that advanced disease and harboring Y253H or F359V mutation before dasatinib were independent predictors of developing new mutations. We conclude that patients with Ph+ leukemia with Y253H or F359V mutation have a high likelihood of developing new mutations in the setting of dasatinib resistance.

Detection of new mutations in patients (pts) with imatinib-resistant chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib.

6516 Background: BCR-ABL transcript levels have been reported to be a predictor of response outcomes, including the detection of new mutations, in pts with imatinib resistance. In this posthoc analysis of the nilotinib phase II study we examined the association between newly detectable BCR-ABL mutations, baseline mutations (BL), resistance, and intolerance to imatinib, and initial molecular response to nilotinib. Methods: CML-CP pts (n = 321) with imatinib resistance (78%) or intolerance (22%) were analyzed. All pts had at least 24 mo follow-up. BCR-ABL transcript levels at 3 mo (≤1%, >1-≤10%, and >10% BCR-ABL [International Scale, IS]) were used to perform a landmark analysis. Results: Newly detectable mutations were observed in 56 of 290 (19%) pts with available BL mutation data, including 51 of 200 (26%) imatinib-resistant and 5 of 90 (6%) imatinib-intolerant pts. Pts with BL mutations and resistance to prior imatinib had a higher probability of detecting new mutations compared with pts without BL mutations (p < 0.0001) and imatinib-intolerant pts (p = 0.0002). BCR-ABL% (IS) at 3 mo did not predict for newly detectable mutations, including less sensitive mutations (Y253H, E255K/V, F359C/V, T315I), in pts with BL mutations or those resistant to imatinib therapy (Table), Molecular response to nilotinib at 3 mo did not predict for newly detectable mutations in pts without BL mutation and those intolerant of imatinib. Conclusions: In this analysis pts with BL mutations and imatinib resistance had a higher probability of detecting new mutations. Molecular response to nilotinib at 3 mo did not correlate with detection of new mutations within 24 mo of nilotinib therapy. Other correlative factors need to be evaluated. Occurrence of newly detectable mutations by 24 mo by BCR-ABL% (IS) at 3 mo on nilotinib BCR-ABL% (IS) at 3 mo p value ≤ 1 > 1 – ≤ 10 > 10 Occurrence of newly detectable mutations by 24 mo (%) Pts with BL mutations, n = 79 21 17 45 0.258a, 0.983b Resistant pts, n = 158 21 14 28 0.146a, 0.532b Occurrence of less sensitive mutations by 24 mo (%) Pts with BL mutations, n = 79 21 17 21 0.983a, 0.919b Resistant pts, n = 158 11 10 16 0.556a, 0.858b a Comparison of > 1 – ≤10 vs > 10. b Comparison of ≤ 1 vs > 1 – ≤ 10. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Merck, Novartis, Wyeth Novartis Bristol-Myers Squibb, Celgene, Merck, Novartis Bristol-Myers Squibb, Genzyme, Novartis, Wyeth

Novel EBP gene mutations in Conradi–Hünermann–Happle syndrome

Conradi-Hünermann-Happle syndrome [X-linked dominant chondrodysplasia punctata type 2 (CDPX2); MIM no. 302960] is an X-linked dominant disorder of cholesterol metabolism that causes a wide spectrum of skeletal abnormalities and linear ichthyosiform skin lesions. Mosaicism is probably responsible for the variability of the phenotype. To describe new mutations in patients with variable manifestations of the disease. We studied three patients with CDPX2. We performed mutation analysis of the EBP (formerly known as CDPX2) gene and gas chromatography-mass spectroscopy on serum of two patients. We found two novel (3G-->T and 419-422delTTCT) and one known mutation in the EBP gene. We demonstrated the presence of increased levels of dehydrocholesterol and 8(9)-cholestenol in the two patients with new mutations, confirming the diagnosis of CDPX2 and strongly suggesting that the mutations are indeed pathogenic. One patient had a very mild phenotype, presenting with linear alopecia and a mild symmetrical epiphyseal dysplasia. X-inactivation studies in peripheral blood of all patients showed skewing in only the most severely affected patient. The strong phenotypic variability in our patients suggests that there is no clear genotype-phenotype correlation.