Progress of Immunotherapy in EGFR-mutated Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC.
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Genomic analysis and biomarker discovery of thymic cancer based on whole exome sequencing: A retrospective cohort study / 中国胸心血管外科临床杂志

@#Objective To examined gene mutations in thymic carcinoma (TC) patients and to explore prognostic correlates and potential targets for therapy. Methods We retrospectively included TC patients in Sichuan Cancer Hospital between January 2015 and Febuary 2021.Whole-exome sequencing was performed on tumor tissues from TC patients and their control peripheral blood samples, and the raw data were subjected to bioinformatics analysis and statistical analysis. Results We finally included 24 TC patients with 16 males and 8 females at a median age of 55 (42-74) years. The highest frequency of single nucleotide mutations in this cohort were in the TTN gene (42%), HSPG2 (29%), and OBSCN (29%). Higher frequency of copy number variations occurred in ZNF276 gene (54%, loss), BEND3 (50%, loss), DHODH (50%, loss), and VAC14 (50%, loss). Microsatellite instability (MSI) phenotype was found in 25% of the patients, and the mean tumor mutation burden (TMB) was 9.86. Conclusion This study is the first comprehensive analysis of the mutation profile of thymic carcinoma in China to date. The mutation frequencies of TTN, OBSCN, and ZNF276 genes were high. The biomarker analysis suggests that patients may benefit from immunotherapy and have a long effective survival.

Clinical and Genetic Study on 48 Children with Short Stature of Unknown Etiology / 中山大学学报(医学科学版)

ObjectiveTo explore the clinical features and causative genes of short stature children with unknown etiology， providing evidence for precise clinical diagnosis and treatment. MethodsThe study recruited children with suspected but undiagnosed short stature from the pediatric endocrinology department in our hospital between January 2018 and August 2022. A retrospective analysis was performed on the clinical manifestations， laboratory test and whole exome sequencing （WES） results. Causative genes were classified and analyzed according to different pathogenic mechanisms. ResultsA total of 48 children （30 boys and 18 girls） were enrolled， aged 7.73 ± 3.97 years， with a height standard deviation score （ HtSDS） of -3.63 ± 1.67. Of the patients， 33 （68.8%） suffered from facial anomalies， 31 （64.6%） from skeletal abnormalities， 26 ［54.2%， 61.5% of whom born small for gestational age （SGA）］ from perinatal abnormalities， 24 ［50.0%， 87.5% of whom with growth hormone （GH） peak concentration below normal］ from endocrine disorders and 21（43.8%） had a family history of short stature. Laboratory tests showed that GH peak concentration following stimulation test was （9.72 ± 7.25） ng/mL， IGF-1 standard deviation score was -0.82 ± 1.42， the difference between bone age and chronological age was -0.93 ± 1.39 years. Of the 25 cases with mutant genes found by WES， 14 （56.0%） had pathogenic mutation， 6 （24.0%） likely pathogenic mutation， and 5 （20.0%） mutation of uncertain significance. Pathogenic and likely pathogenic variants were identified in 14 genes， including 10 affecting intracellular signaling pathways （PTPN11， RAF1， RIT1， ARID1B， ANKRD11， CSNK2A1， SRCAP， CUL7， SMAD4 and FAM111A） and 4 affecting extracellular matrix （ECM） components or functions （ACAN， FBN1， COL10A1 and COMP）. ConclusionsA rare monogenic disease should be considered as the possible etiology for children with severe short stature accompanied by facial anomalies， disproportionate body types， skeletal abnormalities， SGA， GH peak concentration below normal and a family history of short stature. WES played an important role in identifying the monogenic causes of short stature. This study indicated that affecting growth plate cartilage formation through intracellular signaling pathways and ECM components or functions was the main mechanism of causative genes leading to severe short stature in children. Further research may help discover and study new pathogenic variants and gene functions.

Eye diseases associated with developmental abnormality of neural crest / 国际眼科杂志(Guoji Yanke Zazhi)

The neural crest represents a dynamic population of embryonic stem cells, playing a pivotal role in the development of the eye. Through interactions with the surrounding neuroectoderm, superficial ectoderm and mesoderm, the neural crest contributes to the formation of numerous ocular structures, encompassing the corneal stroma and endothelium, trabecular meshwork, iris stroma, ciliary muscle, vitreous and choroidal vessels, and Müller cells. Aberrant migration and development of neural crest cells within the eye can instigate a complex series of ocular diseases. Such diseases include anterior segment like Axenfeld-Rieger syndrome, Peters anomaly, aniridia, primary congenital glaucoma, and Nail-Patella syndrome. Defects that impact the posterior segment may lead to CHARGE syndrome and Branchio-oculo-facial syndrome. Further, rare neurocristopathies such as Waardenburg syndrome, Treacher-Collins syndrome, and Char syndrome can also present with ocular abnormalities. In this review, we explore the ocular diseases that arise from abnormal neural crest cell development, and delve into the related genes involved in neural crest migration and development. We further discuss how mutations and defects in these genes can precipitate ocular diseases.

Correlation of IL36RN and CARD14 mutations with clinical manifestations and laboratory findings in patients with generalised pustular psoriasis

Background: Generalized pustular psoriasis (GPP) is a chronic disease associated with genetic factors related to mutations of the interleukin 36 receptor antagonist gene (IL36RN) and the caspase recruitment domain 14 gene (CARD14). However, the relevance of these mutations to the clinical features and severity of GPP remains unclear. Aims: Our objective was to correlate the presence of IL36RN and CARD14 mutations with the clinical and laboratory findings in patients with GPP. Methods: This cross-sectional descriptive study was conducted in 64 subjects with GPP. Clinical manifestations were recorded and the severity was graded as mild, moderate, or severe. Routine laboratory tests were performed and blood samples were collected for Sanger sequencing. The clinical data of patients were compared among the different mutation groups. Results: The two main variants of IL36RN were c.115+6T > C (p.Arg10ArgfsX1) and c.227C > T (p.Pro76Leu). The major CARD14 mutations were c.2458C > T (p.Arg820Trp), c.1641C > T (p.Arg547Ser), and c.1753G > A transitions. Provocative factors were uncommon in the group with both IL36RN and CARD14 mutations. Drugs (unspecified), especially herbals, were the most common triggers. A history of psoriasis was frequent in patients with only CARD14 mutations, but fever was uncommon. The c.1641C > T mutation was associated with leukocytosis > 15000/mm3 and the c.1753G > A mutation was associated with hypoalbuminemia <3.8g/dL. Both the c.115+6T > C and c.227C > T variants of IL36RN were associated with fever ?38.5°C while the c.115+6T > C variant was also associated with geographic tongue. No gene mutations were associated with the total severity and severity grades. Limitations: Four patients without the two major IL36RN mutations were excluded from the study. Conclusion: The presence of IL36RN and CARD14 mutations were associated with a history of psoriasis, various provocative factors, fever, leukocytosis, hypoalbuminemia, and geographic tongue. Further studies to explore the role of these mutations in therapeutic efficacy and disease outcomes are necessary.

Prognostic Predictive Value of ITPKB Mutation's Variant Allele Frequency in Diffuse Large B-cell Lymphoma / 肿瘤防治研究

Objective To investigate the correlation between ITPKB mutation's variant allele frequency (VAF) and prognosis of diffuse large B-cell lymphoma (DLBCL). Methods This study included 155 patients with DLBCL initially diagnosed in the People's Hospital of Xinjiang Uygur Autonomous Region from June 2014 to December 2020. Paraffin-embedded tumor tissue specimens were obtained, and tumor tissue DNA was extracted. A total of 475 hotspot genes including ITPKB were detected by the next generation sequencing to analyze the relationship of the VAF of high-frequency mutant gene with progression-free survival (PFS) and overall survival (OS). Results The mutation frequency of ITPKB was 18.71%. The PFS was significantly shorter in the patients with ITPKB mutations than in those without mutations (37 months vs. 108 months; HR=1.643, 95%CI: 0.920-2.934, P=0.093). The R-language based web tool was used to find the best VAF cutoff to differentiate prognosis. The patients were divided into two groups (VAF High vs. VAF Low+Wt) according to their VAF values. The optimal VAF threshold for ITPKB was 27.48% (HR=3.480, 95%CI: 1.70-7.13, P=0.00027). Multivariate Cox analysis was conducted using clinical indicators such as age, gender, COO classification, IPI, and LDH, and the results showed that PFS was associated with high ITPKB VAF (≥28%) (HR=3.592, 95%CI: 1.738-7.425, P < 0.001) which was an independent adverse predictor of PFS. Conclusion The high load of ITPKB mutation is an independent risk factor for the PFS of patients with DLBCL, and the VAF of ITPKB mutation has a prognostic predictive value for patients with DLBCL.

Preliminary study of familial nonsyndromic tooth agenesis caused by ectodysplasin A mutation / 口腔疾病防治

Objective@# To explore the pathogenic genes in a Chinese family affected by nonsyndromic tooth agenesis so as to study the pathogenesis of oligodontia.@*Methods @# Hospital ethical approval and informed consent of the patients and family members were obtained. Clinical data of the proband and close family members were collected, peripheral venous blood was collected, and DNA was extracted. Gene sequencing was performed through whole-exome sequencing, and then the screened pathogenic genes were verified by Sanger sequencing. The three-dimensional structure of the mutant proteins was analyzed and compared with the wild-type using bioinformatics tools.@*Results@#The two patients with congenital majority tooth loss in this family were cousins, and there were no other patients with congenital majority tooth loss in the family. Besides congenital multiple tooth loss, the two patients had no obvious hair abnormalities, finger/toe abnormalities, sweating abnormalities or other abnormal manifestations of ectodermal tissue. We found a mutant gene that in this family by carrying out gene sequencing of the patients and their close family members. A novel EDA (ectodysplasin A) missense mutation c.983C>T (p. Pro328Leu) was identified, which changed the encoded amino acid from proline (Pro) to leucine (Leu). Analysis of the mutation site showed that the site was highly conserved, and three-dimensional structure modeling also found that it changed the structure of EDA. @* Conclusion@#A novel EDA missense variant (c.983C>T, p.Pro328Leu) was first identified in a Chinese family with nonsyndromic tooth agenesis, extending the mutation spectrum of the EDA gene.

Analysis of clinicopathological and molecular abnormalities of angioimmunoblastic T-cell lymphoma / 北京大学学报(医学版)

OBJECTIVE@#To analyze the clinicopathological features, molecular changes and prognostic factors in angioimmunoblastic T-cell lymphoma (AITL).@*METHODS@#Sixty-one cases AITL diagnosed by Department of Pathology of Peking University Cancer Hospital were collected with their clinical data. Morphologically, they were classified as typeⅠ[lymphoid tissue reactive hyperplasia (LRH) like]; typeⅡ[marginal zone lymphoma(MZL)like] and type Ⅲ [peripheral T-cell lymphoma, not specified (PTCL-NOS) like]. Immunohistochemical staining was used to evaluate the presence of follicular helper T-cell (TFH) phenotype, proliferation of extra germinal center (GC) follicular dendritic cells (FDCs), presence of Hodgkin and Reed-Sternberg (HRS)-like cells and large B transformation. The density of Epstein-Barr virus (EBV) + cells was counted with slides stained by Epstein-Barr virus encoded RNA (EBER) in situ hybridization on high power field (HPF). T-cell receptor / immunoglobulin gene (TCR/IG) clonality and targeted exome sequencing (TES) test were performed when necessary. SPSS 22.0 software was used for statistical analysis.@*RESULTS@#Morphological subtype (%): 11.4% (7/61) cases were classified as type Ⅰ; 50.8% (31/61) as type Ⅱ; 37.8% (23/61) as type Ⅲ. 83.6% (51/61) cases showed classical TFH immunophenotype. With variable extra-GC FDC meshwork proliferation (median 20.0%); 23.0% (14/61) had HRS-like cells; 11.5% (7/61) with large B transformation. 42.6% (26/61) of cases with high counts of EBV. 57.9% (11/19) TCR+/IG-, 26.3% (5/19) TCR+/IG+, 10.5% (2/19) were TCR－/IG－, and 5.3% (1/19) TCR－/IG+. Mutation frequencies by TES were 66.7% (20/30) for RHOA, 23.3% (7/30) for IDH2 mutation, 80.0% (24/30) for TET2 mutation, and 33.3% (10/30) DNMT3A mutation. Integrated analysis divided into four groups: (1) IDH2 and RHOA co-mutation group (7 cases): 6 cases were type Ⅱ, 1 case was type Ⅲ; all with typical TFH phenotype; HRS-like cells and large B transformation were not found; (2) RHOA single mutation group (13 cases): 1 case was type Ⅰ, 6 cases were type Ⅱ, 6 cases were type Ⅲ; 5 cases without typical TFH phenotype; 6 cases had HRS-like cells, and 2 cases with large B transformation. Atypically, 1 case showed TCR－/IG－, 1 case with TCR－/IG+, and 1 case with TCR+/IG+; (3) TET2 and/or DNMT3A mutation alone group (7 cases): 3 cases were type Ⅱ, 4 cases were type Ⅲ, all cases were found with typical TFH phenotype; 2 cases had HRS-like cells, 2 cases with large B transformation, and atypically; (4) non-mutation group (3 cases), all were type Ⅱ, with typical TFH phenotype, with significant extra-GC FDC proliferation, without HRS-like cells and large B transformation. Atypically, 1 case was TCR－/IG－. Univariate analysis confirmed that higher density of EBV positive cell was independent adverse prognostic factors for both overall survival (OS) and progression free survival(PFS), (P=0.017 and P=0.046).@*CONCLUSION@#Pathological diagnoses of ALTL cases with HRS-like cells, large B transformation or type Ⅰ are difficult. Although TCR/IG gene rearrangement test is helpful but still with limitation. TES involving RHOA, IDH2, TET2, DNMT3A can robustly assist in the differential diagnosis of those difficult cases. Higher density of EBV positive cells counts in tumor tissue might be an indicator for poor survival.

Gene Mutation Types of Thalassemia in Chongzuo Childbearing-age Population of Guangxi Zhuang Autonomous Region of China / 中国实验血液学杂志

OBJECTIVE@#To investigate the gene mutation and genotype distribution of thalassemia in the population of childbearing age in Chongzuo area of Guangxi.@*METHODS@#Six α-thalassemia and 17 β-thalassemia gene mutations common in Chinese were detected by gap-polymerase chain reaction (gap-PCR) combined with agarose gel eletrophoresis and reserve dot bolt hybridization in 29 266 cases of child-bearing age suspected of thalassemia.@*RESULTS@#A total of 19 128 (65.36%) cases were identified with thalassemia. The detection rate of α-thalassemia, β-thalassemia and α-combining β-thalassemia was 45.25% (13 242/29 266), 15.47% (4 526/29 266) and 4.65% (1 360/29 266), respectively. A total carrying rate of 8 kinds of α-thalassemia gene mutations was 26.74% (15 649/58 532), including 12.51% for --SEA, followed by 5.70% for -α3.7, and 0.24% for --Thai. Among 32 α-thalassemia genotypes, the most common five were --SEA/αα, -α3.7/αα, αCSα/αα, -α4.2/αα and αWSα/αα, accounting for 47.27%, 18.31%, 8.56%, 8.52% and 7.91%, respectively, as well as 0.97% for --Thai/αα. A total carrying rate of 13 kinds of β-thalassemia gene mutations was 10.07% (5 897/58 532), including 3.63% for CD41-42, followed by 2.55% for CD17, and 0.003% for -50 (G>A). Among 17 β-thalassemia genotypes, the most common six were CD41-42/N, CD17/N, CD71-72/N, CD26/N, 28/N and IVSI-1/N, accounting for 36.15%, 25.81%, 9.43%, 8.18%, 8.09% and 7.75%. The homozygous genotype CD26/CD26 [hemoglobin (Hb): 121 g/L] and -28/-28 (Hb: 56 g/L) were respectively detected in one case, and double heterozygous genotype were detected in 5 cases, including 3 cases of CD41-42/CD26 (Hb: 41 g/L, 51 g/L, 63 g/L, respectively), 1 case of -28/IVSI-1 (Hb: 53 g/L), and 1 case of CD71-72/CD26 (Hb: 89 g/L), in which patients with moderate or severe anemia had a history of blood transfusion. Among 104 α-combining β-thalassemia genotypes, the most common were --SEA/αα, -α3.7/αα combining CD41-42/N and --SEA/αα combining CD17/N, accounting for 12.13%, 9.63% and 9.26%, respectively. In addition, 1 case of --SEA/-α3.7 combining -28/IVSI-1 (Hb: 83 g/L) and 1 case of -α3.7/αα combining CD41-42/ CD41-42 (Hb: 110 g/L) were detected without history of blood transfusion, while 1 case of αWSα/αα combining CD41-42/CD17 (Hb: 79 g/L) and 1 case of --SEA/αα combining CD17/-28 (Hb: 46 g/L) were detected with history.@*CONCLUSIONS@#The detection rate of thalassemia genes is high and the mutations are diverse in the population of childbearing age in Chongzuo area of Guangxi. The common deletion genotype is --SEA/αα in α-thalassemia and CD41-42/N in β-thalassemia, and deletion genotype --Thai is not rare. There is a certain incidence of intermediate and severe β-thalassemia, and most patients require transfusion therapy. The results are beneficial for genetic consultation and intervention of thalassemia.

Correlation of gene mutations and microsatellite instability in colorectal cancer tissues with clinicopathological features of patients / 肿瘤研究与临床

Objective:To explore KRAS, NRAS, BRAF gene mutations and microsatellite instability(MSI) in colorectal cancer tissues as well as their correlation with the clinicopathological characteristics of patients.Methods:The clinicopathological data of 473 colorectal cancer patients in Shanxi Province Cancer Hospital from October 2020 to May 2021 were retrospectively analyzed. The mutation status of KRAS, NRAS and BRAF gene in the paraffin tissues were detected by using amplification refractory mutation system (ARMS) method. Polymerase chain reaction (PCR)-capillary electrophoresis was used to analyze MSI status, and the correlation of the clinicopathological characteristics of patients with gene mutations and MSI status was analyzed.Results:The mutation rates of KRAS, NRAS and BRAF were 45.03% (213/473), 2.96% (14/473) and 5.50% (26/473), respectively in 473 patients with colorectal cancer. No case harbored both 2 gene mutations was detected. The mutation rate of KRAS gene in well differentiated adenocarcinoma was higher than that in poorly differentiated adenocarcinoma [47.4% (175/369) vs. 36.5% (38/104), χ2 = 3.89, P = 0.049]. NRAS mutation rate in female was higher than that in male [5.0% (10/202) vs. 1.5% (4/271), χ2 = 4.86, P = 0.027], and the NRAS mutation rate in patients with tumor diameter ≤ 3 cm was higher than that in those with tumor diameter >3 cm [7.1% (7/98) vs. 1.9% (7/375), P = 0.013]. BRAF mutation rate of tumors located in colon was higher than that in rectum [11.7% (20/171) vs.2.0% (6/302), χ2 = 19.81, P < 0.001]; BRAF mutation rate in poorly differentiated tumor was higher than that in well differentiated tumor [10.6% (11/104) vs. 4.1% (15/369), χ2 = 6.62, P = 0.010]; BRAF mutation rate in patients with mucus was higher than that in those without mucus [10.9% (11/101) vs. 4.0% (15/372), χ2 = 7.19, P = 0.007]; BRAF mutation rate in patients with lymphatic metastasis was higher than that in patients without lymphatic metastasis [8.2% (15/182) vs.3.8% (11/291), χ2 = 4.29, P = 0.038]. The incidence of high frequency MSI (MSI-H) in 473 colorectal cancer tissues was 7.19% (34/473). The incidence of MSI-H in colon was higher than that in rectum [14.0% (24/171) vs. 3.3% (10/302), χ2 = 18.82, P < 0.001]; the incidence of MSI-H in patient with poor differentiated tumor was higher than that in those with well differentiated tumor [17.3% (18/104) vs. 4.3% (16/369), χ2 = 20.46, P < 0.001]; the incidence of MSI-H in patients with mucus was higher than that in those without mucus [11.9% (12/101) vs. 5.9% (22/372), χ2 = 4.24, P = 0.039]; and the incidence of MSI-H in patients without lymphatic metastasis was higher than that in patients with lymphatic metastasis [10.0% (29/291) vs. 2.7% (5/182), χ2 = 8.75, P = 0.003]. In addition, the incidence of MSI-H was on the rise in patients with BRAF mutation ( P < 0.001). Conclusions:KRAS, NRAS, BRAF gene mutations and MSI status are correlated with the clinicopathological characteristics of patients with colorectal cancer; there is a close relationship between MSI-H and BRAF mutation.

Laboratory and clinical characteristics of patients with different SF3B1 genotypes in myelodysplastic syndromes / 中华检验医学杂志

Objective:To analyze the distribution of different SF3B1 genotypes in patients with myelodysplastic syndromes (MDS) and its prognostic value.Methods:Totally, 377MDS patients who were initially diagnosed in the First Affiliated Hospital of Nanjing Medical University from January 2014 to January 2022 were included in the retrospective analysis.The patients were divided into three different groups according to mutation stcote of SF3B1, including 317 patients with SF3B1 wild type (SF3B1 WT) (214 males and 103 females, 63(49, 71) years old),39 patients with SF3B1 K700E mutation(SF3B1 K700E(17 males and 22 females, 65(52, 73)years old)) and 21 patients with SF3B1 non-K700E mutation(SF3B1 non-K700E)(13 males and 8 females, 67(63, 73) years old). MDS-related 20 gene mutations were detected using targeted sequencing technology; Survival curves were constructed by the Kaplan-Meier method; Cox proportional hazards model was established to evaluate different factors at diagnosis on survival by univariate and multivariate analyses.. Results:Compared with SF3B1 non-K700E patients, SF3B1 K700E patients had a higher median absolute neutrophil count ( P=0.002) and were likely to be in the low/int-1 International Prognostic Scoring System (IPSS) categories ( P=0.023). A 20-gene targeted sequencing analysis showed that, compared with SF3B1 WT patients, SF3B1 K700E patients were associated with lower frequency of ASXL1 and U2AF1 mutations ( P=0.018 and P=0.003); while compared with SF3B1 non-K700E patients, the frequency of ASXL1 mutation was significantly lower in SF3B1 K700E cases ( P=0.029). Patients with SF3B1 K700E had better overall survival (OS) in comparison with SF3B1 WT and SF3B1 non-K700E in MDS patients ( P<0.001 and P=0.045, respectively). In comparison with SF3B1 WT patients, SF3B1 MUT patients had more favorable OS and progression-free survival (PFS) in MDS without excess blasts ( P<0.001 and P<0.001, respectively), but no significant difference was found in MDS with excess blasts ( P>0.05). Compared with SF3B1 WT patients, SF3B1 K700E patients had superior OS and PFS in the int-1 IPSS category ( P=0.010 and P=0.013, respectively). By multivariable analysis, the presence of SF3B1 K700Ewas an independent predictor of superior OS ( HR=0.461,95% CI 0.262-0.811, P=0.007). Conclusion:SF3B1 K700E and SF3B1 non-K700E patients had significantly improved OS in comparison with SF3B1 WT MDS patients. Furthermore, SF3B1 K700E patients were associated with a better OS compared with SF3B1 non-K700E MDS patients. SF3B1 mutation could not overcome the poor prognostic effect of excess blasts, which highlights the importance of the SF3B1 mutation subtype in risk assessment of MDS without excess blasts.

Clinical features, gene analysis and prenatal diagnosis with NDP gene mutation in a family / 中华眼底病杂志

Objective:To observe and determine the gene mutation site and clinical phenotype of a NDP gene mutant family, and provide a basis for the prenatal diagnosis of offspring. Methods:A pedigree investigation study. Two patients and 6 family members of a third-generation Han family with NDP gene mutation who were admitted to the Maternal and Child Health Hospital of Gansu Province from July 2019 to December 2021 were included in the study. The patients and their parents underwent the examination of pupil light reflex, strip light imaging, visual acuity evaluation, fundus color photography, and wide-field fluorescein fundus angiography (FFA). Peripheral blood of all the subjects was collected, the pathogenic genes were screened by whole exome sequencing, and NDP genes were detected by amplification of multiple ligated probes. DNA prenatal diagnosis was performed by amniocentesis at 19th weeks of the mother's third gestation. Results:Proband (Ⅲ1), male, 4 years old, full term natural delivery. At about 40 days after birth, B-mode ultrasonography indicated total retinal detachment in both eyes. Normal hearing and intelligence. Fundus examination was not performed. First sibling of proband (Ⅲ2, big younger brother), ophthalmologic examination 30 days after birth, retinal detachment in both eyes. Proband's mother (Ⅱ2) had unvascularized peripheral temporal retina in both eyes. Wide-angle FFA examination showed no vascularization of the peripheral temporal retina in both eyes, and slight leakage of peripheral vascular fluorescein. The proband's second sibling (Ⅲ3, little younger brother) was screened for neonatal eye disease 1 day after birth. No abnormalities were observed outside both eyes. Cornea and lens transparent. No abnormalities were observed in the optic disc and macula in both eyes. No vascular curvature was observed in the peripheral retina. The results of gene detection showed that there was hemizygote deletion in exon 2 of NDP gene of the proband (Ⅲ1) and its big younger brother (Ⅲ2). His mother (Ⅱ2) had heterozygosity deletion in exon 2 of NDP gene. The phenotype and genetic test results of the proband's father (Ⅱ1), uncle (Ⅱ3), maternal grandfather (Ⅰ1) and maternal grandmother (Ⅰ2) were not abnormal. Conclusions:The hemizygote deletion in exon 2 of NDP gene is a pathogenic variation in the native family. The clinical phenotypes of different genders are different. Prenatal diagnosis is an effective way to block hereditary diseases in families.

Analysis of ocular clinical features in 13 children with methylmalonic acidemia / 中华眼底病杂志

Objective:To observe the clinical features of eyes in children with methylmalonic acidemia (MMA).Methods:A retrospective clinical case study. From June 2019 to June 2022, 13 children with MMA visited on the Department of Ophthalmology of Henan Children's Hospital were included in the study. The anterior segment and fundus were examined under surface or general anesthesia. Best corrected visual acuity (BCVA) and refraction were performed in 9 cases; fluorescein fundus angiography (FFA) was performed in 3 cases; flash electroretinogram (FERG) was performed in 6 cases; flash visual evoked potential (FVEP) was detected in 6 cases; optical coherence tomography (OCT) was performed in 3 cases.Results:Among the 13 pediatric patients with methylmalonic acidemia, 6 cases were male and 7 cases were female. The average age at first visit was 45 months. All cases suffered from hyperhomocysteinemia; 9 cases were with epilepsy; 2 cases were with infantile spasms; 11 cases were with stunting, 13 cases were with repeated pulmonary infection during growth period; 4 cases were with hydrocephalus; 1 cases was with hypertension and renal insufficiency. Genetic dectection results of 8 cases were recorded, MMACHC:c.609G>A:p.W203* mutation site was found in all cases. One case was accompanied by corneal ulcer. There were 10 cases with nystagmus, 4 cases with macular degeneration, 3 cases with hyperopic refractive error and esotropia. Nine cases underwent BCVA examination, BCVA was light perception-0.6. In OCT, 2 cases of 3 cases showed retinal thinning and photoreceptor cell layer atrophy in the macular area. In FFA, 2 cases of 3 cases showed circular transparent fluorescence in the macular area. Five cases of 6 cases who with FVEP had different degrees of P100 peak time delay and decreased amplitude, and 4 cases of 6 cases with FERG had decrease of a and b wave in light and dark adaptation. Conclusions:The clinical phenotypes of eyes in children with MMA are various and the severity was different; most of them are accompanied by nystagmus, and the fundus lesions are common in the characteristic bovine eye like macular region. Those with macular disease have severe visual impairment.

Clinical manifestations and gene mutation of X-linked adrenoleukodystrophy: case analysis / 中华内分泌代谢杂志

The clinical manifestations, biochemical parameters and imaging examination, genetic test results, and treatment of 3 cases of X-linked adrenoleukodystrophy(X-ALD) patients were reviewed and analyzed, and the structure of adrenoleukodystrophy protein(ALDP) was analyzed. All 3 patients were male. Patients 1 and 2 were childhood cerebral ALD(CCALD), patients 3 was adrenomyeloneuropathy(AMN), and all of them were misdiagnosed at early stage. Brain magnetic resonance imaging(MRI), and hematologic examinations showed the neurological demyelination of X-ALD, adrenocortical insufficiency, and accumulation of very long chain fatty acids(VLCFAs). Sequencing of ABCD1 gene revealed 3 new pathogenic mutations[c.910delins22(p.A304delins8), c. 887A>C(p.Y296S), and c. 1451_1481del(p.P484fs)], which affected the key structure of ALDP and led to the disease. Patients 1 and 2 received hematopoietic stem cell transplantation, and their condition continued to progress after surgery. Patient 3 was in stable condition. The misdiagnosis rate of X-ALD is high, clinicians should be vigilant. In this study, 3 new mutations were found, which expanded the ABCD1 gene mutation spectrum in patients with X-ALD. It is important to note that early identification and early diagnosis of X-ALD should be made to reduce misdiagnosis and mistreatment.

A case of mitochondrial diabetes mellitus complicated with hypopituitarism and literature review / 中华内分泌代谢杂志

The clinical data of a patient with mitochondrial diabetes mellitus complicated with hypopituitarism were analyzed, the patient′s mitochondrial gene was detected by microarray capture high-throughput sequencing, and the related domestic and foreign literature was reviewed and analyzed. The results showed that the patient had m. 3243 A>G variant on MT-TL1 gene and the clinical features were consistent with mitochondrial diabetes mellitus and hypopituitarism.

Clinical and genetic analysis of five pedigree with maturity-onset diabetes of the young type 2 / 中华内分泌代谢杂志

Objective:To explore the clinical and molecular genetic characteristics of patients with maturity-onset diabetes of the young type 2(MODY2).Methods:Clinical data and laboratory results were collected from five MODY2 patients and their family members diagnosed in the Department of Endocrinology, Genetics, and Metabolism of Xi ′an Children′s Hospital in the recent two years. Whole exome sequencing was carried out on every proband to identify potential variants, then the suspected variants were verified with Sanger sequencing in family numbers.Results:Among the 5 probands, except for proband 4 who presented with polydipsia and polyuria, hyperglycemia in the rest of the children was accidentally identified. Urine routine, urinary protein, and blood lipid of the five probands were all normal, and HbA 1C was between 5.96% and 8.15%. Moreover, an important discovery in this study was that proband 5 had insulin resistance(IRS), which was different from previous studies. It was confirmed by genetic analysis that a glucokinase(GCK) gene variant existed in every MODY2 pedigree. There were four GCK variants in this study, including c. 146C>T(p.T49I), c. 1237T>G(p.Y413D), c. 683C>T(p.T228M) and c. 952G>T(p.G318W), among which the C. 1237T>G(P.y413d) and C. 952G>T(P.G318W) had not been reported till now. All probands received lifestyle intervention, and the blood glucose control was relatively stable. Conclusion:There is MODY2 patient complicated with IRS. MODY2 patients can be controlled well by lifestyle interventions. In addition, we discovered two novel variants of GCK, which extend the mutation spectrum of this gene.

Genetic profiles of phenylalanine hydroxylase gene mutations in neonates with phenylketonuria in Xinjiang / 中国新生儿科杂志

Objective:To study the genetic profiles of phenylalanine hydroxylase (PAH) gene mutations in neonates with phenylketonuria (PKU) in Xinjiang.Methods:From January 2015 to December 2021,neonates born and genetically diagnosed with PKU in our region were retrospectively included. The genetic profiles of different ethnic groups were analyzed and compared with PKU patients from central, northwest and northern regions of China.Results:A total of 131 neonates with PKU were enrolled, including 82 Han, 25 Hui and 20 Uyghur patients, 4 cases of other ethnic groups. 46, 20 and 14 types of pathogenic variants were detected in each ethnic group with detection rates of 95.1% (156/164), 66.0% (33/50), and 60.0% (24/40), respectively. The variants were mainly missense mutations and located in exons 2, 3, 6,7 and 11. The most common loci in Hui patients were c.158G>A (18.2%), c.728G>A (18.2%) and c.898G>T (9.1%). The most common loci in Uyghur patients were c.158G>A (33.3%), c.355C>T (12.5%) and c.1068C>A (8.3%). c. 898G>T might be most unique in Hui patients and c.355C>T most unique in Uyghur patients in Xinjiang. A novel variant of PAH gene, c.828G>C (p.M276I) in exon 7 was identified. Compared with northern, central and northwestern regions of China, PKU patients in Xinjiang had significantly higher incidence of c.158G>A mutation and lower incidence of c.728G>A mutation ( P<0.05). Conclusions:Missense mutations of PAH gene are common in some regions of Xinjiang. The compositions of PAH gene variations are similar to northwest and northern China with significant differences in hotspots of mutations.

Familial glucocorticoid deficiency caused by the NNT gene mutation: a case report and literature review / 中华实用儿科临床杂志

The clinical data, diagnose and treatment of a child with familial glucocorticoid deficiency (FGD) caused by the NNT gene mutation who was treated in the Department of Endocrinology, Children′s Hospital Affiliated to Nanjing Medical University in November 2014 were retrospectively analyzed.The female child with 1 year and 5 months old presented with 6 months of skin pigmentation.Laboratory examinations showed decreased cortisol and increased adrenocorticotropic hormone.During the follow-up period, she developed convulsions and precocious puberty.Whole exome sequencing revealed that the patient carried a homozygous mutation c. 1054G > A (p.G352R) in exon 8 of the NNT gene, which was a newly reported gene mutation.Domestic cases of FGD caused by the NNT gene mutation has never been reported yet.Through literature review of a total of 40 reported children with FGD caused by the NNT gene mutation, typical manifestations included skin pigmentation, hypoglycemia and seizures, alongside mineralocorticoid deficiency, precious puberty, abnormal male gonadal development, thyroid diseases and heart diseases.

Relationships between PIK3CA gene status and clinical features and prognosis in triple-negative breast cancer / 国际肿瘤学杂志

Objective:To detect the status of PIK3CA in triple-negative breast cancer (TNBC) , and to analyze the relationships between PIK3CA mutation and clinical features and its impact on prognosis.Methods:From January 1, 2016 to December 31, 2018, 50 patients with primary TNBC admitted to Xinxiang Central Hospital of Henan Province were collected. The PIK3CA mutation status was detected, and the relationships between PIK3CA mutation and clinical characteristics of patients with TNBC and its impact on prognosis were analyzed.Results:PIK3CA gene mutation was detected in 9 of 50 TNBC patients, with a mutation frequency of 18.0%. H1047R mutation was found in 4 cases, E545K mutation in 3 cases and E542K mutation in 2 cases. PIK3CA gene mutation was not associated with age ( χ2=3.55, P=0.060) , tumor location ( χ2=1.01, P=0.315) , tumor size ( χ2<0.01, P>0.999) , lymph node status ( χ2=0.76, P=0.385) , clinical stage ( χ2=0.65, P=0.420) , Ki-67 value ( χ2<0.01, P>0.999) , P53 status ( χ2=0.02, P=0.894) and human epidermal growth factor receptor-2 (HER-2) status ( χ2=1.65, P=0.200) . Prognostic analysis showed that 3-year disease-free survival rates of wild-type PIK3CA patients was significantly higher than that of mutant PIK3CA patients (80.5% vs. 11.1%, χ2=28.23, P<0.001) . Conclusion:The frequency of PIK3CA gene mutation is higher in TNBC patients. There is no correlation between PIK3CA mutation and clinicopathologic features in TNBC patients. PIK3CA gene mutation may be significantly associated with poor prognosis of TNBC patients.

Advances in chloride voltage-gated channel and intellectual disability / 国际儿科学杂志

Chloride voltage-gated channel, as an important ion channel in living organisms, has many important physiological functions.The gene encoding chloride voltage-gated channel protein is CLCN, which has nine members(CLCN1~7, CLCNKa, and CLCNKb).The CLCN gene variants lead to abnormal expression of chloride channel proteins, which affect the biological activities of neuronal signaling, ion homeostasis, intracellular transport, and lysosomal protein degradation, thereby altering ion channel gating properties, interfering with the normal developmental process of the nervous system, and causing the development of intellectual disability.In recent years, further studies of the CLCN gene have found that the variants in some members of this family are closely related to intellectual disability.This review will discuss the correlation between the chloride voltage-gated channel and intellectual disability.