Resistencia a los inhibidores de la integrasa en niños con el virus de la inmunodeficiencia humana por transmisión vertical: primeros casos en Uruguay / Resistance to integrase inhibitors in children with vertically-transmitted human immunodeficiency virus: First cases in Uruguay

La resistencia a los antirretrovirales (ARV) es un problema de salud pública. Con el uso de inhibidores de la integrasa (INSTI) en pediatría, también comienzan a aparecer resistencias. El objetivo de esta comunicación es describir 3 casos con resistencia a los INSTI. Se describen 3 pacientes pediátricos con transmisión vertical del virus de la inmunodeficiencia humana (VIH). Iniciaron ARV de lactantes y preescolares, con mala adherencia al tratamiento, cursaron con diferentes planes secundarios a comorbilidades asociadas y fallas virológicas por resistencia. Los 3 casos clínicos describen la rápida aparición de resistencia frente a la falla virológica y el compromiso de los INSTI. La adherencia debe ser supervisada para detectar precozmente el aumento de la viremia. La falla virológica en un paciente tratado con raltegravir obliga a un rápido cambio de esquema ARV, ya que continuar utilizándolo podría favorecer nuevas mutaciones y resistencia a los INSTI de segunda generación.

Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.

CLCA1 is Poorly Expressed in Stomach Adenocarcinoma and Correlates with Immune Infiltration / CLCA1 se Expresa Deficientemente en el Adenocarcinoma de Estómago y se Correlaciona con la Infiltración Inmune

SUMMARY: Calcium-activated chloride channel regulator 1 (CLCA1) is associated with cancer progression. The expression and immunologic function of CLCA1 in stomach adenocarcinoma (STAD) remain unclear. In this investigation, the expression of CLCA1 in STAD tissues and its involvement in the progression and immune response of STAD were examined using databases such as cBioPortal, TISIDB, and UALCAN. In order to validate the expression level of CLCA1 protein in gastric adenocarcinoma, thirty clinical tissue specimens were gathered for immunohistochemical staining. The findings indicated a downregulation of CLCA1 in STAD patients, which was correlated with race, age, cancer grade, Helicobacter pylori infection, and molecular subtype. Through the examination of survival analysis, it was identified that diminished levels of CLCA1 within gastric cancer cases were linked to decreased periods of post-progression survival (PPS), overall survival (OS), and first progression (FP) (P<0.05). The CLCA1 mutation rate was lower in STAD, but the survival rate was higher in the variant group. The correlation between the expression level of CLCA1 and the levels of immune infiltrating cells in STAD, as well as the immune activating molecules, immunosuppressive molecules, MHC molecules, chemokines, and their receptor molecules, was observed. Gene enrichment analysis revealed that CLCA1 may be involved in STAD progression through systemic lupus erythematosus (SLE), proteasome, cell cycle, pancreatic secretion, and PPAR signaling pathways. In summary, CLCA1 is anticipated to function as a prognostic marker for patients with STAD and is linked to the immunization of STAD.

El regulador 1 del canal de cloruro activado por calcio (CLCA1) está asociado con la progresión del cáncer. La expresión y la función inmunológica de CLCA1 en el adenocarcinoma de estómago (STAD) aún no están claras. En esta investigación, se examinó la expresión de CLCA1 en tejidos STAD y su participación en la progresión y respuesta inmune de STAD utilizando bases de datos como cBioPortal, TISIDB y UALCAN. Para validar el nivel de expresión de la proteína CLCA1 en el adenocarcinoma gástrico, se recolectaron treinta muestras de tejido clínico para tinción inmunohistoquímica. Los hallazgos indicaron una regulación negativa de CLCA1 en pacientes con STAD, que se correlacionó con la raza, la edad, el grado del cáncer, la infección por Helicobacter pylori y el subtipo molecular. Mediante el examen del análisis de supervivencia, se identificó que los niveles reducidos de CLCA1 en los casos de cáncer gástrico estaban relacionados con períodos reducidos de supervivencia posterior a la progresión (PPS), supervivencia general (OS) y primera progresión (FP) (P <0,05). La tasa de mutación CLCA1 fue menor en STAD, pero la tasa de supervivencia fue mayor en el grupo variante. Se observó la correlación entre el nivel de expresión de CLCA1 y los niveles de células inmunes infiltrantes en STAD, así como las moléculas activadoras inmunes, moléculas inmunosupresoras, moléculas MHC, quimiocinas y sus moléculas receptoras. El análisis de enriquecimiento genético reveló que CLCA1 puede estar involucrado en la progresión de STAD a través del lupus eritematoso sistémico (LES), el proteasoma, el ciclo celular, la secreción pancreática y las vías de señalización de PPAR. En resumen, se prevé que CLCA1 funcione como un marcador de pronóstico para pacientes con STAD y está vinculado a la inmunización de STAD.

Resistencia transmitida de VIH-1 en pacientes sin exposición a tratamiento antirretroviral: Guatemala / Transmitted HIV-1 resistance in patients without exposure to antiretroviral treatment: Guatemala / Resistência transmitida ao HIV-1 em pacientes sem exposição ao tratamento antirretroviral: Guatemala

El objetivo del estudio fue describir los niveles de resistencia transmitida de VIH-1 en adultos atendidos en Unidades de Atención Integral de Guatemala. El estudio incluyó registros de 185 pacientes adultos VIH-1 positivo, de reciente diagnóstico sin antecedente de uso de TAR, de noviembre del 2019 a noviembre del 2020. El análisis se realizó en el software DeepChek® v2.0, para la clasificación de la resistencia se siguió el algoritmo de Stanford HIVdb (v9.4 - 07/12/2022). Se encontró 18.4% (IC 95% 13.1 - 24.7%) de resistencia general a alguna familia de ARVs. Se evidenció 15.1% (IC 95% 10.3 - 21.1%) de resistencia individual a la familia de INNTR afectando principalmente a NVP y EFV; 2.2% (IC 95% 0.6 - 5.4%) de resistencia a INTR, mayormente a FTC/3TC; y 2.7% (IC 95% 0.9 - 6.2%) de resistencia intermedia y baja los IP NFV y LPV/r. Tres casos presentaron resistencia múltiple a los INTR + INNTR. Las mutaciones más frecuentemente encontradas fueron K103N (41.2%), M184V/I (8.8%) y M46I (5.9%). La elevada resistencia transmitida del VIH-1 en pacientes atendidos en distintas Unidades de Atención Integral del VIH, demuestra la importancia de analizar periódicamente la tendencia de la resistencia en personas que no han estado expuestas a ARVs, lo cual a su vez es un marcador indirecto de presencia de resistencia adquirida en el país, datos que evidencian la necesidad de acciones e intervenciones prontas y efectivas dado su impacto en la salud pública.

The objective of this study was to describe the levels of transmitted HIV-1 resistance in patients with a recent HIV diagnosis before starting ART, treated in Comprehensive Care Units in Guatemala during the years 2019 and 2020. The study included records of 185 HIV-positive adult patients, recently diagnosed with HIV without a history of ART use. The analysis was carried out in the DeepChek® v2.0 software, the Stanford HIVdb algorithm (v9.4 - 07/12/2022) was followed to classify resistance. 18.4% (95% CI 13.1 - 24.7%) of general resistance to some family of ARVs was found. There was evidence of 15.1% (95% CI 10.3 - 21.1%) of individual resistance to the NNRTI family, mainly affecting NVP and EFV; 2.2% (95% CI 0.6 - 5.4%) resistance to INTR, mostly to FTC/3TC; and 2.7% (95% CI 0.9 - 6.2%) of intermediate and low resistance IP NFV and LPV/r. Three cases presented multiple resistance to NRTIs + NNRTIs. The most frequently found mutations were K103N (41.2%), M184V/I (8.8%) and M46I (5.9%). The high transmitted resistance of HIV-1 in patients treated in different Comprehensive HIV Care Units demonstrates the importance of periodically analyzing the trend of resistance in people who have not been exposed to ARVs, which in turn is an indirect marker. of the presence of acquired resistance in the country, data that demonstrate the need for prompt and effective actions and interventions given its impact on public health.

O objetivo deste estudo foi descrever os níveis de resistência transmitida ao HIV-1 em adultos tratados em Unidades de Cuidados Integrais na Guatemala. O estudo incluiu prontuários de 185 pacientes adultos HIV-1 positivos, recentemente diagnosticados sem histórico de uso de TARV, no período de novembro de 2019 a novembro de 2020. A análise foi realizada no software DeepChek® v2.0, para classificação da resistência, O algoritmo Stanford HIVdb (v9.4 - 07/12/2022) foi seguido. Foi encontrada 18.4% (IC 95% 13.1 - 24.7%) de resistência geral a alguma família de ARVs. Houve evidência de 15.1% (IC 95% 10.3 - 21.1%) de resistência individual à família de NNRTI, afetando principalmente NVP e EFV; 2.2% (IC 95% 0.6 - 5.4%) resistência ao INTR, principalmente ao FTC/3TC; e 2.7% (IC 95% 0.9 - 6.2%) de resistência intermediária e baixa ao IP NFV e LPV/r. Três casos apresentaram resistência múltipla a NRTIs + NNRTIs. As mutações mais frequentemente encontradas foram K103N (41.2%), M184V/I (8.8%) e M46I (5.9%). A elevada resistência transmitida do HIV-1 em pacientes atendidos em diferentes Unidades de Cuidados Integrados ao HIV demonstra a importância de analisar periodicamente a tendência de resistência em pessoas que não foram expostas aos ARVs, o que por sua vez é um marcador indireto da presença de ARVs adquiridos. resistência no país, dados que demonstram a necessidade de ações e intervenções rápidas e eficazes dado o seu impacto na saúde pública.

Progress of BRAF Gene Alteration in Non-small Cell Lung Cancer / 中国肺癌杂志

V-Raf murine sarcoma viral oncogene homolog B (BRAF) alteration is one of the most essential driver genes of non-small cell lung cancer (NSCLC). BRAF encodes serine/threonine protein kinases, and its mutations typically lead to protein compositional activation, thereby activating the mitogen-activated protein kinase kinase (MEK) signaling pathway. A promising new approach for the treatment of mutated BRAF and/or downstream MEK may provide customized treatment opportunities for BRAF driven NSCLC patients. However, combination therapy is necessary to overcome the difficulties such as short duration of benefit, poor therapeutic effect of non-V600 BRAF mutations and susceptibility to drug resistance. This article reviewed the progress in structural characteristics, related signaling pathways, mutation types of BRAF gene, and the clinical pathological relationship between BRAF mutations and NSCLC, as well as the therapy, in order to provide more evidences for clinical doctors to make treatment decisions.
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Hypothesis of Genetic Diversity Selection in the Occurrence and Development of Lung Cancer: Molecular Evolution and Clinical Significance / 中国肺癌杂志

So far, the monoclonal hypothesis of tumor occurrence and development cannot be justified. The genetic diversity selection hypothesis for the occurrence and development of lung cancer links Mendelian genetics with Darwin's theory of evolution, suggesting that the genetic diversity of tumor cell populations with polyclonal origins-monoclonal selection-subclonal expansion is the result of selection pressure. Normal cells acquire mutations in oncogenic driver genes and have a selective advantage over other cells, becoming tumor initiating cells; In the interaction with the tumor microenvironment (TME), the vast majority of initiating cells are recognized and killed by the human immune system. If immune escape occurs, the incidence of malignant tumors will greatly increase, and subclonal expansion, intratumour heterogeneity, etc. will occur. This article proposed the hypothesis of genetic diversity selection and analyzed its clinical significance.
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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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Zellweger syndrome caused by PEX6 gene variation in 2 cases and literature review / 中华儿科杂志

Objective: To summarize the clinical features and genetic characteristics of Zellweger spectrum disorder caused by PEX6 gene variation. Methods: This was a case series research. Clinical date and genetic results of 2 neonatal cases of Zellweger syndrome caused by PEX6 gene variation in Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology and Affiliated Hospital of Guangdong Medical University from July 2021 to July 2022 were retrospectively collected and analyzed. Literature up to August 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of "Zellweger syndrome" "Zellweger spectrum disorder", and "PEX6 gene" both in Chinese and English. The main clinical features and genetic characteristics of Zellweger spectrum disorder caused by PEX6 gene variation were summarized. Results: The 2 male neonates both developed clinical manifestations as dyspnea, hypotonia, feeding difficulties, enlarged fontanelle, and high palatine arch after birth. Biochemical parameters indicated elevated bile acids, and the cranial ultrasound showed the enlarged bilateral ventricles and subependymal cyst in both 2 neonates. Zellweger syndrome was confirmed by whole exome sequencing, and the results revealed PEX6 gene variation in the 2 neonates, including compound heterozygous variants c.315G>A and c.2095-3T>G, and homozygous variant c.506_507del. Case 1 was hospitalized for 5 days, and case 2 for 32 days; they both died shortly after being discharged (the specific time is unknown). Literature review found 26 patients, including 2 neonates in this study, with Zellweger spectrum disorder caused by PEX6 gene defect reported in 1 Chinese article and 11 English articles. Clinical features included hearing loss (19 cases), developmental delay (19 cases), vision impairment (19 cases), elevated very long chain fatty acids (17 cases), brain malformations (15 cases), hypotonia (12 cases), hepatic insufficiency (12 cases), distinctive facies (10 cases), and dental impairment (9 cases). Compound heterozygous variations dominated the variation types (15 cases), and the frameshift variations (16 cases) were the main pathogenic variations. Conclusions: Zellweger spectrum disorder should be considered when neonates show hypotonia, feeding difficulty, distinctive facial appearance, brain malformations and failure of hearing screening, or when older children show retinitis pigmentosa, sensorineural hearing loss, amelogenesis imperfecta and developmental delays. Detection of genetic variation in the PEX gene is crucial for definitive diagnosis.

Reappraisals of biological behaviors of PDGFRA mutant gastrointestinal stromal tumor / 中华病理学杂志

Objective: To investigate the biological behavior spectrum of platelet-derived growth factor alpha receptor (PDGFRA)-mutant gastrointestinal stromal tumor (GIST), and to compare the clinical values of the Zhongshan method of benign and malignant evaluation with the modified National Institutes of Health (NIH) risk stratification. Methods: A total of 119 cases of GIST with PDGFRA mutation who underwent surgical resection at Zhongshan Hospital, Fudan University from 2009 to 2020 were collected. The clinicopathological data, follow-up records, and subsequent treatment were reviewed and analyzed statistically. Results: There were 79 males and 40 females. The patients ranged in age from 25 to 80 years, with a median age of 60 years. Among them, 115 patients were followed up for 1-154 months, and 13 patients progressed to disease. The 5-year disease-free survival (DFS) and overall survival (OS) were 90.1% and 94.1%, respectively. According to the modified NIH risk stratification, 8 cases, 32 cases, 38 cases, and 35 cases were very-low risk, low risk, intermediate risk, and high risk, and 5-year DFS were 100.0%, 95.6%, 94.3%, and 80.5%, respectively. There was no significant difference in prognosis among the non-high risk groups, only the difference between high risk and non-high risk groups was significant (P=0.029). However, the 5-year OS was 100.0%, 100.0%, 95.0% and 89.0%, and there was no difference (P=0.221). According to the benign and malignant evaluation Zhongshan method, 43 cases were non-malignant (37.4%), 56 cases were low-grade malignant (48.7%), 9 cases were moderately malignant (7.8%), and 7 cases were highly malignant (6.1%). The 5-year DFS were 100.0%, 91.7%, 77.8%, 38.1%, and the difference was significant (P<0.001). The 5-year OS were 100.0%, 97.5%, 77.8%, 66.7%, the difference was significant (P<0.001). Conclusions: GIST with PDGFRA gene mutation shows a broad range of biological behavior, ranging from benign to highly malignant. According to the Zhongshan method, non-malignant and low-grade malignant tumors are common, the prognosis after surgery is good, while the fewer medium-high malignant tumors showed poor prognosis after surgical resection. The overall biological behavior of this type of GIST is relatively inert, which is due to the low proportion of medium-high malignant GIST. The modified NIH risk stratification may not be effective in risk stratification for PDGFRA mutant GIST.

Mutation characteristics of angioimmunoblastic T-cell lymphoma: an analysis of 75 cases / 中华病理学杂志

Objective: To investigate the characteristics of gene mutations in angioimmunoblastic T-cell lymphoma (AITL). Methods: Seventy-five AITL cases diagnosed at the Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from June 2021 to June 2023 were included. Their formalin-fixed and paraffin-embedded or fresh tissues were subject to targeted next generation sequencing (NGS). The sequencing data was collected, and the distribution and type of gene mutations were analyzed. Results: 492 potential driver mutations were identified in 74 out of the 84 genes. Targeted sequencing data for the 75 AITL patients showed that the genes with mutation frequencies of ≥10% were TET2 (89.3%), RHOA (57.3%), IDH2 (37.3%), DNMT3A (36.0%), KMT2C (21.3%), PLCG1 (12.0%), and KDM6B (10.7%). There were significant co-occurrence relationships between TET2 and RHOA, TET2 and IDH2, and RHOA and IDH2 gene mutations (P<0.05), respectively, while TET2 and KDM6B gene mutations were mutually exclusive (P<0.05). Conclusions: The study reveals the mutational characteristics of AITL patients using NGS technology, which would provide insights for molecular diagnosis and targeted therapy of AITL.

Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report / 临床耳鼻咽喉头颈外科杂志

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.

Long-term auditory monitoring in children with Alport syndrome based on different degrees of renal injury / 临床耳鼻咽喉头颈外科杂志

Objective:To investigate long-term auditory changes and characteristics of Alport syndrome（AS） patients with different degrees of renal injury. Methods:Retrospectively analyzing clinical data of patients diagnosed AS from January 2007 to September 2022, including renal pathology, genetic detection and hearing examination. A long-term follow-up focusing on hearing and renal function was conducted. Results:This study included 70 AS patients, of which 33（25 males, 8 females, aged 3.4-27.8 years） were followed up, resulting in a loss rate of 52.9%.The follow-up period ranged from 1.1to 15.8 years, with 16 patients followed-up for over 10 years. During the follow-up, 10 patients presenting with hearing abnormalities at the time of diagnosis of AS had progressive hearing loss, and 3 patients with new hearing abnormalities were followed up, which appeared at 5-6 years of disease course. All of which were sensorineural deafness. While only 3 patients with hearing abnormalities among 13 patients received hearing aid intervention. Of these patients,7 developed end-stage renal disease（ESRD）, predominantly males （6/7）. The rate of long-term hearing loss was significantly different between ESRD group and non-ESRD group（P=0.013）. There was no correlation between the progression of renal disease and long-term hearing level（P>0.05）. kidney biopsies from 28 patients revealed varying degrees of podocyte lesion and uneven thickness of basement membrane. The severity of podocyte lesion was correlated with the rate of long-term hearing loss（P=0.048）, and there was no correlation with the severity of hearing loss（P>0.05）. Among 11 cases, theCOL4A5mutationwas most common （8 out of 11）, but there was no significant correlation between the mutation type and hearing phenotype（P>0.05）. Conclusion:AS patients exhibit progressive hearing loss with significant heterogeneity over the long-term.. THearing loss is more likely to occur 5-6 years into the disease course. Hearing abnormalities are closely related to renal disease status, kidney tissue pathology, and gene mutations, emphasizing the need for vigilant long-term hearing follow-up and early intervention.

Genetic and phenotypic analysis of MYO15A rare variants associated with autosomal recessive hearing loss / 临床耳鼻咽喉头颈外科杂志

Objective:To analyze the phenotype and genotype characteristics of autosomal recessive hearing loss caused by MYO15A gene variants, and to provide genetic diagnosis and genetic counseling for patients and their families. Methods:Identification of MYO15A gene variants by next generation sequencing in two sporadic cases of hearing loss at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The sequence variants were verified by Sanger sequencing.The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics（ACMG） variant classification guidelines, in conjuction with clinical data. Results:The probands of the two families have bilateral,severe or complete hearing loss.Four variants of MYO15A were identified, including one pathogenic variant that has been reported, two likely pathogenic variants,and one splicing variant of uncertain significance. Patient I carries c. 3524dupA（p. Ser1176Valfs*14）, a reported pathogenic variant, and a splicing variant c. 10082+3G>A of uncertain significance according to the ACMG guidelines. Patient I was treated with bilateral hearing aids with satisfactory effect, demonstrated average hearing thresholds of 37.5 dB in the right ear and 33.75 dB in the left ear. Patient Ⅱ carries c. 7441_7442del（p. Leu2481Glufs*86） and c. 10250_10252del（p. Ser3417del）,a pair of as likely pathogenic variants according to the ACMG guidelines. Patient Ⅱ, who underwent right cochlear implantation eight years ago, achieved scores of 9 on the Categorical Auditory Performance-Ⅱ（CAP-Ⅱ） and 5 on the Speech Intelligibility Rating（SIR）. Conclusion:This study's discovery of the rare c. 7441_7442del variant and the splicing variant c. 10082+3G>A in the MYO15A gene is closely associated with autosomal recessive hearing loss, expanding the MYO15A variant spectrum. Additionally, the pathogenicity assessment of the splicing variant facilitates classification of splicing variations.

Splicing mutations of GSDME cause late-onset non-syndromic hearing loss / 临床耳鼻咽喉头颈外科杂志

Objective:To dentify the genetic and audiological characteristics of families affected by late-onset hearing loss due to GSDMEgene mutations, aiming to explore clinical characteristics and pathogenic mechanisms for providing genetic counseling and intervention guidance. Methods:Six families with late-onset hearing loss from the Chinese Deafness Genome Project were included. Audiological tests, including pure-tone audiometry, acoustic immittance, speech recognition scores, auditory brainstem response, and distortion product otoacoustic emission, were applied to evaluate the hearing levels of patients. Combining with medical history and physical examination to analyze the phenotypic differences between the probands and their family members. Next-generation sequencing was used to identify pathogenic genes in probands, and validations were performed on their relatives by Sanger sequencing. Pathogenicity analysis was performed according to the American College of Medical Genetics and Genomics Guidelines. Meanwhile, the pathogenic mechanisms of GSDME-related hearing loss were explored combining with domestic and international research progress. Results:Among the six families with late-onset hearing loss, a total of 30 individuals performed hearing loss. The onset of hearing loss in these families ranged from 10 to 50 years（mean age: 27.88±9.74 years）. In the study, four splicing mutations of the GSDME were identified, including two novel variants: c. 991－7C>G and c. 1183+1G>T. Significantly, the c. 991－7C>G was a de novo variant. The others were previously reported variants: c. 991-1G>C and c. 991-15_991-13del, the latter was identified in three families. Genotype-phenotype correlation analysis revealed that probands with the c. 991－7C>G and c. 1183+1G>T performed a predominantly high-frequency hearing loss. The three families carrying the same mutation exhibited varying degrees of hearing loss, with an annual rate of hearing deterioration exceeding 0.94 dB HL/year. Furthermore, follow-up of interventions showed that four of six probands received intervention（66.67%）, but the results of intervention varied. Conclusion:The study analyzed six families with late-onset non-syndromic hearing loss linked to GSDME mutations, identifying four splicing variants. Notably, c. 991－7C>G is the first reported de novo variant of GSDME globally. Audiological analysis revealed that the age of onset generally exceeded 10 years,with variable effectiveness of interventions.

Distribution characteristics and correlation analysis of GJB2 variation in patients with auditory neuropathy / 临床耳鼻咽喉头颈外科杂志

Objective:To elucidate the correlation between the GJB2 gene and auditory neuropathy, aiming to provide valuable insights for genetic counseling of affected individuals and their families. Methods:The general information, audiological data（including pure tone audiometry, distorted otoacoustic emission, auditory brainstem response, electrocochlography）, imaging data and genetic test data of 117 auditory neuropathy patients, and the patients with GJB2 gene mutation were screened out for the correlation analysis of auditory neuropathy. Results:Total of 16 patients were found to have GJB2 gene mutations, all of which were pathogenic or likely pathogenic.was Among them, one patient had compound heterozygous variants GJB2[c. 427C>T][c. 358_360del], exhibiting total deafness. One was GJB2[c. 299_300delAT][c. 35_36insG]compound heterozygous variants, the audiological findings were severe hearing loss.The remaining 14 patients with GJB2 gene variants exhibited typical auditory neuropathy. Conclusion:In this study, the relationship between GJB2 gene and auditory neuropathy was preliminarily analyzed,and explained the possible pathogenic mechanism of GJB2 gene variants that may be related to auditory neuropathy.

Genetic characteristic analysis of slight-to-moderate sensorineural hearing loss in children / 临床耳鼻咽喉头颈外科杂志

Objective:To analyze genetic factors and phenotype characteristics in pediatric population with slight-to-moderate sensorineural hearing loss. Methods:Children with slight-to-moderate sensorineural hearing loss of and their parents, enrolled from the Chinese Deafness Genome Project, were studied. Hearing levels were assessed using pure tone audiometry, behavioral audiometry, auditory steady state response（ASSR）, auditory brainstem response（ABR） thresholds, and deformed partial otoacoustic emission（DPOAE）. Classification of hearing loss is according to the 2022 American College of Medical Genetics and Genomics（ACMG） Clinical Practice Guidelines for Hearing Loss. Whole exome sequencing（WES） and deafness gene Panel testing were performed on peripheral venous blood from probands and validations were performed on their parents by Sanger sequencing. Results:All 134 patients had childhood onset, exhibiting bilateral symmetrical slight-to-moderate sensorineural hearing loss, as indicated by audiological examinations. Of the 134 patients, 29（21.6%） had a family history of hearing loss, and the rest were sporadic patients. Genetic causative genes were identified in 66（49.3%） patients. A total of 11 causative genes were detected, of which GJB2 was causative in 34 cases（51.5%）, STRC in 10 cases（15.1%）, MPZL2 gene in six cases（9.1%）, and USH2A in five cases（7.6%）.The most common gene detected in slight-to-moderate hearing loss was GJB2, with c. 109G>A homozygous mutation found in 16 cases（47.1%） and c. 109G>A compound heterozygous mutation in 9 cases（26.5%）. Conclusion:This study provides a crucial genetic theory reference for early screening and detection of mild to moderate hearing loss in children, highlighting the predominance of recessive inheritance and the significance of gene like GJB2, STRC, MPZL2, USH2A.

Increased yield performance of mutation induced Soybean genotypes at varied agro-ecological conditions / Aumento no desempenho de rendimento de genótipos de soja induzidos por mutação em condições agroecológicas variadas

Abstract In soybean breeding program, continuous selection pressure on traits response to yield created a genetic bottleneck for improvements of soybean through hybridization breeding technique. Therefore an initiative was taken to developed high yielding soybean variety applying mutation breeding techniques at Plant Breeding Division, Bangladesh Institute of Nuclear Agriculture (BINA), Bangladesh. Locally available popular cultivar BARI Soybean-5 was used as a parent material and subjected to five different doses of Gamma ray using Co60. In respect to seed yield and yield attributing characters, twelve true breed mutants were selected from M4 generation. High values of heritability and genetic advance with high genotypic coefficient of variance (GCV) for plant height, branch number and pod number were considered as favorable attributes for soybean improvement that ensure expected yield. The mutant SBM-18 obtained from 250Gy provided stable yield performance at diversified environments. It provided maximum seed yield of 3056 kg ha-1 with highest number of pods plant-1 (56). The National Seed Board of Bangladesh (NSB) eventually approved SBM-18 and registered it as a new soybean variety named 'Binasoybean-5' for large-scale planting because of its superior stability in various agro-ecological zones and consistent yield performance.

Resumo No programa de melhoramento da soja, a pressão pela seleção contínua para a resposta das características de rendimento criou um gargalo genético para melhorias da soja por meio da técnica de melhoramento por hibridação. Portanto, foi desenvolvida uma variedade de soja de alto rendimento, aplicando técnicas de reprodução por mutação, na Divisão de Melhoramento de Plantas, no Instituto de Agricultura Nuclear de Bangladesh (BINA), em Bangladesh. A cultivar popular BARI Soybean-5, disponível localmente, foi usada como material original e submetida a cinco doses diferentes de raios gama usando Co60. Em relação ao rendimento de sementes e às características de atribuição de rendimento, 12 mutantes genuínos foram selecionados a partir da geração M4. Altos valores de herdabilidade e avanço genético com alto coeficiente de variância genotípico (GCV) para altura da planta, número de ramos e número de vagens foram considerados atributos favoráveis ​​ao melhoramento da soja, garantindo, assim, a produtividade esperada. O mutante SBM-18, obtido a partir de 250Gy, proporcionou desempenho de rendimento estável em ambientes diversificados e produtividade máxima de sementes de 3.056 kg ha-1 com o maior número de vagens planta-1 (56). O Conselho Nacional de Sementes de Bangladesh (NSB) finalmente aprovou o SBM-18 e o registrou como uma nova variedade de soja, chamada 'Binasoybean-5', para plantio em larga escala por causa de sua estabilidade superior em várias zonas agroecológicas e desempenho de rendimento consistente.

Mutations in the bone morphogenetic protein 15 gene causing defective protein secretion in Cholistani infertile sheep / Mutações no gene da proteína morfogenética óssea 15 causadoras de defeitos na secreção proteica em ovelhas inférteis Cholistani

Naturally occurring mutations in morphogenetic protein 15 (BMP15) are associated with decreased ovulation rate (OR), litter size (LS), and sterility. It is of a great interest to elucidate BMP15 gene in Cholistani sheep breed to uplift socio-economic status and the knowledge of Cholistani sheep breeding in Southern Punjab, Pakistan. In our study, a total of 50 infertile Cholistani sheep aged between 2-6 years and having no blood relation were screened for BMP15 mutations. For this purpose, a high-quality DNA was extracted from the blood of sheep followed by primer designing, Polymerase Chain Reaction (PCR) amplification, DNA sequencing, and in silico analyses. Out of total 50 samples, 9 samples including case 1 (T3), case 2 (T8), case 3 (T17), case 4 (T22), case 5 (T25), case 6 (T33), case 7 (T40), case 8 (T44), and case 9 (T47) were found positive for a variety of already reported and novel BMP15 mutations. Further in silico analyses of the observed mutations have shown the functional impact of these mutations on different characteristics (molecular weight, theoretical PI, estimated half-life, instability index, sub-cellular localization, and 3D confirmation) of the encoded proteins, possibly altering the normal functionality. In a nutshell, findings of this study have confirmed the possible essential role of the BMP15 mutations in the infertility of the Cholistani sheep.

Mutações de ocorrência natural na proteína morfogenética 15 (BMP15) estão associadas à diminuição da taxa de ovulação (TO), tamanho da ninhada (TN) e esterilidade. Estudar a BMP15 na raça Cholistani para elevar o status socioeconômico e o conhecimento da criação de ovinos Cholistani no sul de Punjab, Paquistão. Em nosso estudo, 50 ovelhas Cholistani inférteis sem parentesco sanguíneo foram rastreadas para mutações BMP15. Para tanto, um DNA de alta qualidade foi extraído do sangue dessas ovelhas, seguido de concepção do primer, amplificação da reação em cadeia da polimerase (PCR), sequenciamento de DNA e análises in silico. Do total de 50 amostras, 9, incluindo caso 1 (T3), caso 2 (T8), caso 3 (T17), caso 4 (T22), caso 5 (T25), caso 6 (T33), caso 7 (T40), caso 8 (T44) e caso 9 (T47), foram consideradas positivas para uma variedade de mutações BMP15 novas e já relatadas. Mais análises in silico das mutações observadas mostraram o impacto funcional dessas mutações em diferentes características (peso molecular, PI teórico, meia-vida estimada, índice de instabilidade, localização subcelular e confirmação 3D) das proteínas codificadas, possivelmente alterando a funcionalidade normal. Nossos achados confirmaram o possível papel essencial das mutações BMP15 na infertilidade de ovelhas Cholistani.

Advance of research on Hereditary spastic paraplegia type 4 / 中华医学遗传学杂志

Spastic paraplegia type 4 (SPG4) is the most common type of autosomally inherited spastic paraplegia. Its main clinical features include typical simple hereditary spastic paraplegia, with neurological impairments limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation, without accompanying features such as nerve atrophy, ataxia, cognitive impairment, seizures, and muscle tone disorders. SPAST is the main pathogenic gene underlying SPG4, and various pathogenic SPAST variants have been discovered. This disease has featured a high degree of clinical heterogeneity, and the same pathogenic variant can have different age of onset and severity among different patients and even within the same family. There is a lack of systematic research on the correlation between the genotype and phenotype of SPG4, and the pathogenic mechanism has remained controversial. This article has provided a review for the clinical characteristics, pathogenic gene characteristics, correlation between the genotype and phenotype, and pathogenic mechanism of this disease, with an aim to provide reference for its clinical diagnosis and treatment.

Clinical and genetic analysis of a patient with Desminopathy manifesting initially with myalgia after lower limb activity / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic variant of a patient with desminopathy manifesting with atypical symptoms.@*METHODS@#A patient who was admitted to the Department of Neurology of Jing'an District Central Hospital on February 24, 2021 was selected as the study subject. Clinical data, laboratory tests, muscle pathology, muscle magnetic resonance imaging (MRI) and genetic testing of the patient were retrospectively analyzed.@*RESULTS@#The patient had developed myalgia after lower limb activity, and gradually developed asymmetrical muscle weakness and atrophy of the lower limbs. Cardiac examination revealed atrioventricular block and decreased left ventricular diastolic function. Muscle MRI showed that semitendinosus, sartorius, gracilis, fibula, gastronemius and supinator muscles were selectively involved at the early stage. Muscle biopsy confirmed pathological changes of desmin positive myofibrils. Genetic testing revealed that the patient has harbored a c.1024A>G (p.n342d) missense variant in exon 6 of the DES gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PS4_moderate+PM2_supporting+PP3_moderate+PP1).@*CONCLUSION@#Desmin disease has a great clinical heterogeneity. Postexercise myalgia of lower limbs is a rare clinical phenotype. For patients harboring the c.1024A>G (p.n342d) variant of the DES gene, in addition to semitendinosus and fibula, Cardiac involvement is relatively insidious and easy to be ignored in clinic. Timely muscle MRI, muscle biopsy and gene detection will help the early diagnosis of the disease.

Clinical phenotype and genetic analysis of a fetus with Cardiac valvular dysplasia type 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with Cardiac valvular dysplasia type 1 (CVDP1).@*METHODS@#A CVDP1 fetus identified at the Ningbo Women and Children's Hospital on July 7, 2022 was selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were subjected to trio-whole exome sequencing (trio-WES), and candidate variants were verified by Sanger sequencing.@*RESULTS@#The fetus had exhibited generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes. Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene, namely c.2977C>T (p.R993*) and c.1460G>A (p.W487*), which were respectively inherited from its father and mother. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2977C>T (p.R993*) variant was evaluated to be likely pathogenic (PVS1_Moderate+PM2_Supporting+PM3+PP4), whilst the c.1460G>A (p.W487*) variant was evaluated to be pathogenic (PVS1+PM2_Supporting+PP4).@*CONCLUSION@#The c.2977C>T (p.R993*) and c.1460G>A (p.W487*) compound heterozygous variants of the PLD1 gene probably underlay the CVDP1 in the fetus. Above discovery has enriched the mutational spectrum of the PLD1 gene and provided a guidance for genetic counseling and prenatal diagnosis in this family.