Analysis of clinical phenotype and genetic variants among four Chinese pedigrees affected with Waardenburg syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for four Chinese pedigrees affected with Waardenburg syndrome (WS).@*METHODS@#Four WS probands and their pedigree members who had presented at the First Affiliated Hospital of Zhengzhou University between July 2021 and March 2022 were selected as the study subjects. Proband 1, a 2-year-and-11-month female, had blurred speech for over 2 years. Proband 2, a 10-year-old female, had bilateral hearing loss for 8 years. Proband 3, a 28-year-old male, had right side hearing loss for over 10 years. Proband 4, a 2-year-old male, had left side hearing loss for one year. Clinical data of the four probands and their pedigree members were collected, and auxiliary examinations were carried out. Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Proband 1, with profound bilateral sensorineural hearing loss, blue iris and dystopia canthorum, was found to have harbored a heterozygous c.667C>T (p.Arg223Ter) nonsense variant of the PAX3 gene, which was inherited from her father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+PM2_Supporting+PP4), and the proband was diagnosed with WS type I. Proband 2, with moderate sensorineural hearing loss on the right side and severe sensorineural hearing loss on the left side, has harbored a heterozygous frameshifting c.1018_1022del (p.Val340SerfsTer60) variant of the SOX10 gene. Neither of her parents has harbored the same variant. Based on the ACMG guidelines, it was classified as pathogenic (PVS1+PM2_Supporting+PP4+PM6), and the proband was diagnosed with WS type II. Proband 3, with profound sensorineural hearing loss on the right side, has harbored a heterozygous c.23delC (p.Ser8TrpfsTer5) frameshifting variant of the SOX10 gene. Based on the ACMG guidelines, it was classified as pathogenic (PVS1+PM2_Supporting+PP4), and the proband was diagnosed with WS type II. Proband 4, with profound sensorineural hearing loss on the left side, has harbored a heterozygous c.7G>T (p.Glu3Ter) nonsense variant of the MITF gene which was inherited from his mother. Based on the ACMG guidelines, the variant was classified as pathogenic (PVS1+PM2_Supporting+PP4), and the proband was diagnosed with WS type II.@*CONCLUSION@#By genetic testing, the four probands were all diagnosed with WS. Above finding has facilitated molecular diagnosis and genetic counseling for their pedigrees.

Analysis of phenotype and pathogenic variants in a Chinese pedigree affected with Multiple synostoses syndrome type 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a Chinese pedigree affected with Multiple synostoses syndrome type 1 (SYNS1).@*METHODS@#Clinical data of the proband and her family members were collected. Genomic DNA was extracted from peripheral blood samples. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were carried out for the proband and her parents.@*RESULTS@#The pedigree has comprised of 14 members from three generations, of whom six had manifested hearing loss, with other symptoms including proximal symphalangism, hemicylindrical nose, amblyopia, strabismus, brachydactyly, incomplete syndactyly, which fulfilled the diagnostic criteria for SYNS1. WES had detected no pathogenic single nucleotide variants and insertion-deletion (InDel) in the coding region of the NOG gene, whilst copy number variation (CNV) analysis indicated that there was a heterozygous deletion involving the NOG gene. WGS revealed a heterozygous deletion (54171786_55143998) in 17q22 of the proband. The CNV was classified as pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The heterozygous deletion in 17p22 involving the NOG gene probably underlay the pathogenesis of SYNS1 in this pedigree. Above finding has enriched the mutational spectrum of NOG. CNV should be considered when conventional sequencing has failed to detect any pathogenic variants in such patients.

SARS-CoV-2 infecting the inner ear results in potential hearing damage at the early stage or prognosis of COVID-19 in rodents

ObjectivesIn order to find out the association between the sensorineural hearing loss and COVID-19, we detected the expression ACE2 and TMPRSS2 in the mouse the hamster. DesignUsing the public data from NCBI and GISAID, we assessed the expression of ACE2 and TMPRSS2 at the transcriptomic, DNA, and protein levels of ACE2 in the brain, inner ear, and muscle from the golden Syrian hamster (Mesocricetus auratus) and mouse (Mus musculus). ResultsWe identified ACE2 and TMPRSS2 expressed at different level in the inner ear and brain at DNA and transcriptomic levels of both mouse and the hamster. The protein expression shows a similar pattern of the brain and inner ear, while the expression of ACE2 from the inner ear was relatively higher than it from the muscle. ConclusionSARS-CoV-2 could infect the hearing system potentially and SSNHL could be a characteristic to detect asymptomatic patients of COVID-19.

Binding Ability Prediction between Spike Protein and Human ACE2 Reveals the Adaptive Strategy of SARS-CoV-2 in Humans

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus causing an outbreak of COVID-19 globally in the past six months. A relatively higher divergence on the spike protein of SASR-CoV-2 enables it to transmit across species efficiently. We particularly believe that the adaptive mutations of the receptor-binding domain (RBD) of spike protein in SARS-CoV-2 might be essential to its high transmissibility among humans. Thus here we collected 2,142 high-quality genome sequences of SARS-CoV-2 from 160 regions in over 50 countries and reconstructed their phylogeny, and also analyzed the interaction between the polymorphisms of spike protein and human ACE2 (hACE2). Phylogenetic analysis of SARS-CoV-2 and coronavirus in other hosts show SARS-CoV-2 is highly possible originated from Bat-CoV (RaTG13) found in horseshoe bat and a recombination event may occur on the spike protein of Pangolin-CoV to imbue it the ability to infect humans. Moreover, compared to the S gene of SARS-CoV-2, it is more conserved in the direct-binding sites of RBD and we noticed that spike protein of SARS-CoV-2 may under a consensus evolution to adapt to human hosts better. 3,860 amino acid mutations in spike protein RBD (T333-C525) of SARS-CoV-2 were simulated and their stability and affinity binding to hACE2 (S19-D615) were calculated. Our analysis indicates SARS-CoV-2 could infect humans from different populations with no preference, and a higher divergence in the spike protein of SARS-CoV-2 at the early stage of this pandemic may be a good indicator that could show the pathway of SARS-CoV-2 transmitting from the natural reservoir to human beings.

Implementation of radiotherapy in a tertiary hospital in Zhejiang province during the epidemic of COVID-19 / 中华放射医学与防护杂志

Objective:To explore the clinical practice of delivering radiotherapy during the outbreak of 2019 novel coronavirus disease(COVID-19).Methods:During this epidemic period, available method including but not limited to: strict disinfection, body temperature monitoring and staff training of relevant knowledge, were used to ensure the safety of radiotherapy treatment. Statistical analysis was performed to study the relevant data including proportion of patients receiving radiotherapy for different purposes, time from scanning to the first time of radiation delivery and degree of satisfaction in the view of staffs and patients, respectively.Results:A total of 60 patients received radiation therapy in the department of radiotherapy of Zhejiang Provincial People′s Hospital (2020-02-11). Compared with the same period in 2019 (after the Spring Festival), the total number of patients receiving radiotherapy was decreased from 72 to 60(83.3%). Among them, the number of patients receiving palliative radiation therapy decreased significantly, while the proportion of radical, preoperative and/or postoperative radiotherapy/radiochemotherapy did not significantly decrease. There was significant difference between two years ( χ2=6.967, P<0.05). The median time for newly admitted patients to receive radiotherapy was two days, which was not significantly longer than the interval in 2019 ( P>0.05). Staff and patients were generally satisfied with the current prevention measures. Conclusions:Using a variety of prevention and control method, and taking full account of medical safety and patient benefits, radiation-related activities can be carried out during the epidemic.

Implementation of radiotherapy in a tertiary hospital in Zhejiang province during the epidemic of COVID-19 / 中华放射医学与防护杂志

Objective@#To explore the clinical practice of delivering radiotherapy during the outbreak of 2019 novel coronavirus disease(COVID-19).@*Methods@#During this epidemic period, available methods including but not limited to: strict disinfection, body temperature monitoring, learning relevant knowledge by all staffs to ensure the safety of radiotherapy treatment. Relevant data including proportion of radiotherapy, time from scanning to the first time of radiation delivery and degree of satisfaction in the view of staffs and patients, respectively.@*Results@#A total of 60 patients received radiation therapy in the department of radiotherapy of Zhejiang Provincial People’s Hospital (2020-02-11). Compared with the same period in 2019 (after the Spring Festival), the total number of patients receiving radiotherapy was decreased from 72 to 60(83.3%). Among them, the number of patients receiving palliative radiation therapy decreased significantly, while the proportion of radical, preoperative and/or postoperative radiotherapy/radiochemotherapy did not significantly decrease. There was significant difference between different years (χ2=6.967, P<0.05). The median time for newly admitted patients to receive radiotherapy was two days, which was not significantly longer than the interval in 2019 (P>0.05). Staffs and patients were generally satisfied with the current prevention measures.@*Conclusions@#Using a variety of prevention and control methods, and taking full account of medical safety and patient benefits, radiation-related activities can be carried out during the epidemic.