Clinical characteristics and genetic analysis of two children with Autosomal dominant mental retardation type 21 due to variants of CTCF gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of two children with developmental delay.@*METHODS@#Two children who had presented at the Children's Hospital Affiliated to Shandong University on August 18, 2021 were enrolled as the study subjects. Clinical and laboratory examination, chromosomal karyotyping and high-throughput sequencing were carried out for both children.@*RESULTS@#Both children had a 46,XX karyotype. High-throughput sequencing showed that they have respectively carried a c.489delG (p.Q165Rfs*14) and a c.1157_1158delAT (p.Y386Cfs*22) frameshifting variant of the CTCF gene, both had a de novo origin and were unreported previously.@*CONCLUSION@#The CTCF gene variants probably underlay the development delay in the two children. Above discovery has enriched the mutational spectrum of the CTCF gene and has important implications for revealing the genotype-phenotype correlation for similar patients.

Diagnosis of a case with Hermansky-Pudlak syndrome type 5 through high-throughput sequencing and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a patient with Hermansky-Pudlak syndrome type 5 (HPS-5).@*METHODS@#A child with HPS-5 who had attended the Children's Hospital Affiliated to Shandong University on October 3, 2019 was selected as the study subject. Clinical data of the child were collected. Genetic variant was analyzed through high-throughput sequencing. A literature review was also carried out.@*RESULTS@#The child, a 1-year-and-5-month-old girl, had nystagmus since childhood, lost of retinal pigmentation by fundus examination and easy bruising. High-throughput sequencing revealed that she has harbored compound heterozygous variants of the HPS5 gene, namely c.1562_1563delAA (p.F521Sfs*27) and c.1404C>A (p.C468X), which were inherited from his father and mother, respectively. Based on the guidelines from the American College for Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS+PM2_Supporting+PM3+PP4). Among 18 previously reported HPS-5 patients, all had had eye problems, and most of them had tendency for bleeding. Eight cases had carried compound heterozygous variants of the HPS5 gene, 8 carried homozygous variants, 2 carried double homozygous variants, and most of them were null mutations.@*CONCLUSION@#The c.1562_1563delAA(p.F521Sfs*27) and c.1404C>A (p.C468X) compound heterozygous variants of the HPS5 gene probably underlay the HPS-5 in this child. High-throughput sequencing has provided an important tool for the diagnosis. HSP-5 patients usually have typical ocular albinism and/or oculocutaneous albinism and tendency of bleeding, which are commonly caused by compound heterozygous and homozygous variants of the HPS5 gene, though serious complications have been rare.

Clinical and ASS1 gene variant analysis of three Chinese pedigrees affected with Citrullinemia type I / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical and genetic characteristics of three Chinese pedigrees affected with Citrullinemia type I (CTLN1).@*METHODS@#Three children diagnosed at the Children's Hospital Affiliated to Shandong University from 2017 to 2020 were selected as the study subjects. Genomic DNA was extracted from peripheral blood samples of the probands and their parents. Next generation sequencing (NGS) was carried out to detect pathological variants of the probands. Sanger sequencing was used for validating the candidate variant among the pedigrees.@*RESULTS@#The probands have respectively carried compound heterozygous variants of c.207_209delGGA and c.1168G>A, c.349G>A and c.364-1G>A, c.470G>A and c.970G>A of the ASS1 gene, which were respectively inherited from their parents.@*CONCLUSION@#The newly discovered c.207_209delGGA and c.364-1G>A variants have enriched the mutational spectrum of the ASS1 gene. And the mutation spectrum of Chinese CTLN1 patients is heterogeneous.

Analysis of ADNP gene variant in a child with Helsmoortel-van der Aa syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child manifesting with intellectual disability, language delay and autism spectrum disorder.@*METHODS@#Genomic DNA was extracted from peripheral blood samples of the child and his family members, and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing and interpreted according to the guidelines of the American College of Medical Genetics and Genomics.@*RESULTS@#The child was found to harbor a heterozygous c.568C>T (p.Q190X) nonsense variant of the ADNP gene, which was not detected in either parent by Sanger sequencing.@*CONCLUSION@#The clinical and genetic testing both suggested that the child has Helsmoortel-van der Aa syndrome due to ADNP gene mutation, which is extremely rare in China.

Clinical and genetic analysis of a child with ZTTK syndrome due to heterozygous variant of SON gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a small-for-date infant with gastrointestinal bleeding, developmental delay and thrombocytopenia (Zhu-Tokita-Takenouchi-Kim syndrome).@*METHODS@#Clinical and laboratory examinations were carried out for the patient. Next-generation sequencing (NGS) was used to detect potential variant associated with the disease. Candidate variant was verified by Sanger sequencing of the child and her parents.@*RESULTS@#NGS revealed that the child has carried a heterozygous c.5751_5754del variant of the SON gene, which resulted in a frameshift p.V1918Efs*87. The same variant was detected in neither parent.@*CONCLUSION@#The heterozygous variant of SON gene probably underlay the ZTTK syndrome in this child. Above finding has enriched the mutational spectrum of the SON gene and provides a basis for genetic counseling and clinical decision-making.

Identification of a GNB1 gene variant in a child with autosomal dominant mental retardation 42 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child featuring global developmental delay.@*METHODS@#DNA was extracted from peripheral blood sample taken from the patient and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing of his family members.@*RESULTS@#A heterozygous c.239T>C (p.Ile80Thr) variant of the GNB1 gene was detected in the proband, which was a verified to be de novo in origin.@*CONCLUSION@#The heterozygous c.239T>C (p.Ile80Thr) variant of the GNB1 gene probably underlay the disease in this child.

Surveillance of drug resistance of clinically isolated fungi strains from 46 hospitals in Shandong Province / 中华临床感染病杂志

Objective:To analyze the distribution of clinically isolated fungal strains and their resistance to common antifungal drugs in Shandong province.Methods:Through the Shandong Children’s Bacterial & Fungal Drug Resistance Surveillance and Research Collaborative Network, a total of 1 030 fungi were collected in 46 hospitals of Shandong province from January 1 to December 31, 2018. The source and type of strains were analyzed, and antifungal drug sensitivity tests were performed by using the micro-dilution method. Whonet 5.6 and SPSS 22.0 were applied to analyze the data.Results:The overall main strains were Candida albicans (38.74%, 399/1 030), Candida tropicalis (16.99%, 175/1 030) and Candida parapsilosis (16.41%, 169/1 030); the main fungi strains in child patients were C. albicans (52.50%, 63/120), C. parapsilosis (12.50%, 15/120) and C. tropicalis (9.17%, 11/120); the main fungi strains in adult patients were C. albicans (36.37%, 331/910), C. tropicalis (17.03%, 155/910) and C. parapsilosis (15.27%, 139/910). The isolation rate of main Candida strains from January to March and August to December was much higher than that of other months. The drug resistance rates of C. albicans to fluconazole and voriconazole were 7.14% and 7.43%, respectively, and the drug resistance rates to itraconazole were 50.44%. The resistance rates of C. tropicalis to fluconazole, voriconazole and itraconazole were 29.05%, 23.29% and 48.65%, respectively. The sensitivity rates of C. parapsilosi to fluconazole, voriconazole and itraconazole were 93.06%, 93.75% and 94.44%, respectively. Candida glabrata showed a dose-dependent sensitivity rate of 2.33% to fluconazole. Analysis of 244 blood fungi strains showed that non-candida albicans bacteremia accounted for 70.08%. In the pathogen spectrum covering 92.22%, fluconazole was sensitive to 64.65% of the pathogens, voriconazole was 68.88%, and amphotericin B was 88.75%. After quantification, the effective rates of fluconazole, voriconazole and amphotericin B in the clinical treatment of fungal bacteremia were 70.10%, 74.69% and 96.23%, respectively. Among them, the sensitivity rate of voriconazole to C. tropicalis was lower than that of fluconazole. Conclusions:Candida is the main clinical fungus isolates in hospitals of Shandong province. The resistance rate of C. tropicalis to azole antifungal drugs is on the rise, and the sensitivity of other Candida species to clinically used antifungal drugs is basically stable.

Abnormal Upregulation of Cardiovascular Disease Biomarker PLA2G7 Induced by Proinflammatory Macrophages in COVID-19 patients

BACKGROUNDCoronavirus disease 2019 (COVID-19) triggers distinct patterns of pneumonia progression with multiorgan disease, calling for cell- and/or tissue-type specific host injury markers. METHODSAn integrated hypothesis-free single biomarker analysis framework was performed on nasal swabs (n = 484) from patients with COVID-19 in GSE152075. The origin of candidate biomarker was assessed in single-cell RNA data (GSE145926). The candidate biomarker was validated in a cross-sectional cohort (n = 564) at both nucleotide and protein levels. RESULTSPhospholipase A2 group VII (PLA2G7) was identified as a candidate biomarker in COVID-19. PLA2G7 was predominantly expressed by proinflammatory macrophages in lungs emerging with progression of COVID-19. In the validation stage, PLA2G7 was found in patients with COVID-19 and pneumonia, especially in severe pneumonia, rather than patients suffered mild H1N1 influenza infection. Up to 100% positive rates of PLA2G7 were positively correlated with not only viral loads in patients with COVID-19 but also severity of pneumonia in non-COVID-19 patients. Although Ct values of PLA2G7 in severe pneumonia was significantly lower than that in moderate pneumonia (P = 7.2e-11), no differences were observed in moderate pneumonia with COVID-19 between severe pneumonia without COVID-19 (P = 0.81). Serum protein levels of PLA2G7, also known as lipoprotein-associated phospholipase A2 (Lp-PLA2), were further found to be elevated and beyond the upper limit of normal in patients with COVID-19, especially among the re-positive patients. CONCLUSIONSWe firstly identified and validated PLA2G7, a biomarker for cardiovascular diseases (CVDs), was abnormally enhanced in COVID-19 patients at both nucleotide and protein aspects. These findings provided indications into the prevalence of cardiovascular involvements seen in COVID-19 patients. PLA2G7 could be a hallmark of COVID-19 for monitoring disease progress and therapeutic response. FUNDINGThis study was supported by grants from China Mega-Projects for Infectious Disease (2018ZX10711001), National Natural Science Foundation of China (82041023).

Genome-wide variations of SARS-CoV-2 infer evolution relationship and transmission route

The authors have withdrawn this manuscript (Genome-wide variations of SARS-CoV-2 infer evolution relationship and transmission route) from medRxiv, because it was found that the statistical and analytical methods used in the manuscript had certain controversies after further discussion, so the authors of the manuscipt disclaimed that this conclusion cannot be used as the basis for the origin and evolution of SARS-COV-2, also as information to guide clinical practice and health-related behaviors, it should not be reported as established facts in the news media and "We-Media". No one should do too much extended interpretation of the content of this manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Genetic analysis of a case with Pitt-Hopkins syndrome due to variant of TCF4 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a patient presenting with dysmorphism, intellectual disability, psychomotor delay and hypoplasia of corpus callosum by using next generation sequencing.@*METHODS@#Genomic DNA was extracted from peripheral blood samples of the patient and his family members and subjected to exome sequencing. Suspected variants were verified with Sanger sequencing.@*RESULTS@#The patient was found to carry a heterozygous c.1357delAinsGGA variant in exon 11 of the TCF4 gene, which was verified as de novo by Sanger sequencing. The variant may result in a truncated protein and affect its function.@*CONCLUSION@#The heterozygous c.1357delAinsGGA variant the TCF4 gene probably underlies the disease in the proband.

Clinical and genetic analysis of a patient with periventricular nodular heterotopia 7 caused by NEDD4L gene variant / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a patient featuring global developmental delay, intellectual disability, cleft palate, seizures and hypotonia.@*METHODS@#Clinical examination and laboratory tests were carried out. Peripheral blood samples were obtained from the patient and his parents. Whole genomic DNA was extracted and subjected to next generation sequencing. Candidate variation was analyzed by using bioinformatic software and validated by Sanger sequencing.@*RESULTS@#The proband was found to carry a heterozygous c.2117T>C (p.Leu706Pro) variant of the NEDD4L gene, which was a de novo variant validated by Sanger sequencing and predicted to be likely pathogenic according to the American College of Medical Genetics Guidelines.@*CONCLUSION@#The heterozygous variant of c.2117T>C (p.Leu706Pro) of the NEDD4L gene probably underlies the disorders in the patient.

Clinical and genetic analysis of a case with Nicolaides-Baraitser syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a girl featuring epilepsy, speech delay and mild mental retardation.@*METHODS@#Peripheral blood samples of the child and her parents were collected. Genomic DNA was extracted and subjected to next generation sequencing. Suspected variant was confirmed by Sanger sequencing.@*RESULTS@#The child was found to carry a de novo heterozygous c.3592G>A (p.V1198M) variant of the SMARCA2 gene, which was predicted to be pathogenic by bioinformatic analysis.@*CONCLUSION@#The child was diagnosed with Nicolaides-Baraitser syndrome due to heterozygous variant of the SMARCA2 gene.

Identification of two novel SLC19A3 variants in a Chinese patient with Biotin-thiamine responsive basal ganglia disease / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a neonate featuring global developmental delay.@*METHODS@#Clinical and laboratory tests were carried out for the patient. Peripheral venous blood samples were collected from the neonate and his parents for the extraction of DNA. Potential variant was detected by using targeted capture and next generation sequencing for a panel of genes associated with nervous system diseases. Suspected variant was validated by Sanger sequencing.@*RESULTS@#The nine-month-old boy manifested global developmental delay and was unstable to sit alone and distinguish strangers from acquaintance. Genetic testing revealed two novel variants of the SLC19A3 gene in him, namely c.448G>A and c.169C>T. The amino acids encoded by the two codons are highly conservative, and both variants were predicted to be pathogenic by bioinformatic analysis.@*CONCLUSION@#The compound heterozygous c.448G>A and c.169C>T variants probably underlay the onset of disease in the patient. Above finding also enriched the variant spectrum of SLC19A3 gene underlying Biotin-thiamine responsive basal ganglia disease.

Clinical and genetic analysis of a patient with periventricular nodular heterotopia 7 caused by NEDD4L gene variant / 中华医学遗传学杂志

Objective@#To explore the genetic basis of a patient featuring global developmental delay, intellectual disability, cleft palate, seizures and hypotonia.@*Methods@#Clinical examination and laboratory tests were carried out. Peripheral blood samples were obtained from the patient and his parents. Whole genomic DNA was extracted and subjected to next generation sequencing. Candidate variation was analyzed by using bioinformatic software and validated by Sanger sequencing.@*Results@#The proband was found to carry a heterozygous c. 2117T>C (p.Leu706Pro) variant of the NEDD4L gene, which was a de novo variant validated by Sanger sequencing and predicted to be likely pathogenic according to the American College of Medical Genetics Guidelines.@*Conclusion@#The heterozygous variant of c. 2117T>C (p.Leu706Pro) of the NEDD4L gene probably underlies the disorders in the patient.

Clinical and genetic analysis of an infant with 3-methylglutaconic aciduria type VII / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical and genetic characteristics of an infant girl featuring comprehensive developmental backwardness.@*METHODS@#The patient was subjected to clinical examination, gas chromatography mass spectrometry and next-generation sequencing (NGS).@*RESULTS@#The child was insensitive to sound, could not turn over, raise head, laugh or recognize his mother. Laboratory tests were all normal, but metabolic analysis suggested 3-methylglutaconic aciduria due to elevated 3-methylglutaconic acid and 3-methylglutaric acid. NGS has detected two compound heterozygous CLPB variants in the child, namely c.1085G>A and c.1700A>C, which were respectively inherited from her father and mother. Bioinformatic analysis predicted both variants to be pathogenic. The patient was diagnosed with 3-methylglutaconic aciduria type VII (MGCA7).@*CONCLUSION@#The MGCA7 in the child was probably caused by CLPB gene variants. NGS has provided a powerful diagnostic tool for this rare disorder.

Clinical and genetic analysis of a pedigree affected with cytochrome P450 oxidoreductase deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and molecular basis of a Chinese pedigree with two siblings affected by cytochrome P450 oxidoreductase deficiency (PORD).@*METHODS@#Clinical features of the patients were reviewed, and their genomic DNA was subjected to next generation sequencing (NGS).@*RESULTS@#The two siblings presented peculiar facies, genital hypoplasia and skeletal deformity. NGS revealed that both have carried compound heterozygous variants of the POR gene, namely c.1370G>A and c.517-19_517-10delGGCCCCTGTGinsC, which were respectively inherited from their parents.@*CONCLUSION@#Both siblings were diagnosed with PORD based on sequencing of the POR gene. The newly discovered POR c.517-19_517-10delGGCCCCTGTGinsC has enriched the spectrum of PORD-related genetic variants.

CLPB gene mutations analysis in a case of type 3-methylglutaconic aciduria / 中华医学遗传学杂志

OBJECTIVE@#To validate the diagnosis of an infant with elevated urine 3-methylglutaconic acid (3-MGA) through sequencing of the CLPB gene.@*METHODS@#Genomic DNA of the infant was sequenced by next generation sequencing (NGS), and candidate pathogenic variants were verified by Sanger sequencing and bioinformatics analysis.@*RESULTS@#NGS has revealed that the infant has carried a c.1085G>A (p.Arg362Gln) and a c.1700A>C (p.Tyr567Ser) of the CLPB gene, which were respectively inherited from her parents. Among these, c.1085G>A (p.Arg362Gln) is a novel variant which was unreported previously, and based on the ACMG guidelines, it was predicted to be a possible pathogenic variant.@*CONCLUSION@#Compound heterozygous variants c.1085G>A (p.Arg362Gln) and c.1700A>C (p.Tyr567Ser) of the CLPB gene probably underlay the disease in this infant. Genetic testing has confirmed the diagnosis.

Clinical and genetic analysis of a patient with Angelman syndrome due to a frameshift variant of UBE3A gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese boy featuring developmental delay and epilepsy.@*METHODS@#Clinical data of the patient was collected. Genomic DNA of the patient and his parents was extracted and subjected to high-throughput sequencing. Pathogenicity of the variant was predicted and validated.@*RESULTS@#Sequencing results showed that the patient has carried a de novo c.1470delA (p.V491Ffs*6) variant of the UBE3A gene, which was predicted to be pathogenic.@*CONCLUSION@#The frameshift variant c.1470delA (p.V491Ffs*6) probably underlay the disorders in this child.

Diagnosis of Bainbridge-Ropers syndrome due to de novo ASXL3 variant by high throughput sequencing / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic features of a patient with mental retardation.@*METHODS@#G-Banding chromosomal karyotyping and high-throughput sequencing was carried out for the child. Suspected variant was validated in his family by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The patient was found to carry a de novo heterozygous c.4090G>T (p.Gly1364X) variant of the ASXL3 gene, which was known to predispose to Bainbridge-Ropers syndrome.@*CONCLUSION@#The nonsense c.4090G>T (p.Gly1364X) variant probably accounts for the disease in this patient.

Analysis of a case with Mowat-Wilson syndrome caused by ZEB2 gene variant / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a proband with distinctive facial features, global developmental delay, seizures and hypoplasia of corpus callosum through next generation sequencing (NGS).@*METHODS@#Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Whole exome and flanking sequences were screened by NGS. Suspected variants were verified by Sanger sequencing.@*RESULTS@#The proband was found to carry a heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene, which was verified by Sanger sequencing to be a de novo variant.@*CONCLUSION@#The heterozygous c.2824G>T (p.G942X) variant of the ZEB2 gene probably underlies the Mowat-Wilson syndrome in the proband.