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.

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.

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.

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.

Clinical and genetic analysis of a patient with slow-channel congenital myasthenic syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a female patient featuring unstable head upright and hypotonia of limbs.@*METHODS@#The child was examined clinically. Peripheral blood samples of the child, her parents and siblings were collected. Genomic DNA was extracted and subjected to next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#DNA sequencing found that the patient has carried a de novo heterozygous c.354C>A (p.N118K) variant of the CHRND gene, which was not found in her parents and sibling. Bioinformatics analysis predicted that the variant was likely to be pathogenic. Literature review suggested that the phenotype of the patient was very similar to previously reported ones.@*CONCLUSION@#The child was diagnosed with slow-channel congenital myasthenic syndrome (SCCMS) type 3A caused by heterozygous variant of the CHRND gene. NGS has provided a powerful tool for the diagnosis of such disorders.

Clinical and genetic analysis of a patient with Gitelman syndrome misdiagnosed as hypokalemic periodic paralysis / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child suspected for hypokalemic periodic paralysis.@*METHODS@#Clinical data of the patient was collected, and venous blood samples were taken from the patient and his parents for the extraction of genomic DNA. Next generation sequencing (NGS) with target capture was carried out to detect potential variants. Suspected variants were validated by Sanger sequencing.@*RESULTS@#The child developed fatigue without obvious reason at the age of 15. Laboratory test revealed hypokalemia but normal serum magnesium. Genetic testing discovered that he has carried two variants in the SLC12A3 gene, namely c.179C>T and c.539C>A. The patient was diagnosed with Gitelman syndrome.@*CONCLUSION@#For children with hypokalemia, genetic testing should be considered for the differential diagnosis of Gitelman syndrome from hypokalemia due to other causes.

A case with autosomal dominant mental retardation type 5 due to de novo SYNGAP1 variant / 中华医学遗传学杂志

OBJECTIVE@#To investigate the clinical and genetic features of a Chinese girl featuring mental retardation, intellectual disability, language development delay and epilepsy.@*METHODS@#G-banded chromosomal karyotyping was carried out for the child. Genomic DNA of the patient and her parents was extracted and subjected to high-throughput sequencing. The results were analyzed with bioinformatic tools and validated by Sanger sequencing.@*RESULTS@#The karyotype of the child was ascertained as 46,XX. Sequencing result showed that she has carried a de novo heterozygous c.1861C>T (p.R621X) variant of the SYNGAP1 gene.@*CONCLUSION@#The nonsense variant c.1861C>T (p.R621X) of the SYNGAP1 gene probably underlies the disease in this child. Above result has enabled genetic diagnosis and counseling for her family.

Variant analysis of CCBE1 gene in a case of Hennekam lymphangiectasia-lymphedema syndrome type 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a child with lymphangiectasia and lymphedema.@*METHODS@#DNA sample of the patient was extracted and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing.@*RESULTS@#The patient was found to carry compound heterozygote variants (c.521G>A and c.472C>T) of the CCBE1 gene, which were respectively inherited from his parents.@*CONCLUSION@#The compound heterozygote variants of the CCBE1 gene probably underlie the disease in this child.

Clinical phenotype and genetic analysis of a Chinese patient featuring X-linked Claes-Jensen type syndromic mental retardation / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a Chinese patient featuring global developmental delay.@*METHODS@#Peripheral venous blood samples from the proband and his parents and sister were taken for the extraction of DNA. Target capture and next generation sequencing was carried out to detect genetic variants associated with the disease. Suspected variant was validated by Sanger sequencing.@*RESULTS@#Genetic testing discovered that the proband has carried hemizygous c.150G>T and c.150+1G>T variants of the KDM5C gene which are inherited from his mother. His younger sister also carried the variants. The c.150+1G>A variant was unreported previously, which has altered a splice site and was predicted to be pathogenic by bioinformatics analysis.@*CONCLUSION@#The hemizygous c.150+1G>T variant of the KDM5C gene, known to underlie X-linked Claes-Jensen type syndromic mental retardation, probably accounts for the disorder in the patient. Identification of this variant has enriched the variant spectrum of the KDM5C gene.

Clinical and genetic analysis of a patient with rare nephronophthisis / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with clinically suspected nephronophthisis (NPHP).@*METHODS@#Peripheral blood samples of the patient and her parents were collected subjected to high-throughput sequencing. Sanger sequencing was used to verify the gene variants.@*RESULTS@#The patient, a 7-year-old girl with congenital blindness, was admitted to a local hospital due to repeated vomiting for 7-8 days and then transferred to author's hospital due to renal failure. Her urine occult bloods (3+) and urine protein (1+) were abnormal. Her blood urea nitrogen and creatinine showed a significant progressive increase. Renal ultrasound showed a mild enlargement in bilateral renal, increased echogenicity, loss of corticomedullary differentiation, and the presence of cysts in both kidneys. No familial genetic history was found in the family of patient and the child was clinically diagnosed with nephronophthisis. The proband was found to harbor compound heterozygous variants of the CEP290 gene, namely c.2587-2A>T and c.2251C>T, which were inherited from her mother and father, respectively. Based on the ACMG guidelines, both variants were predicted to be pathogenic.@*CONCLUSION@#The patient was diagnosed with NPHP type 6 due to variants of the CEP290 gene. Above finding has provided new evidence for the genotype-phenotype correlation of this disease.

Analysis of clinical and genetic characteristics of a child with ring chromosome 4 syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child featuring short stature.@*METHODS@#G-banded karyotyping, chromosomal microarray analysis (CMA) and high-throughput sequencing were carried out on peripheral blood sample from the child.@*RESULTS@#The karyotype of the child was ascertained as 45,XY,-4[3]/46,XY,r(4)(p16q35)[84]/47,XY,-4,r(4)(p16q25)*2[7]/48,XY,-4,r(4)(p16q35)*3[1]/46,XY,dic r(4;4)(p16q35;p16q35)[2]/46,XY,add(4)(p16)[3]. A 647 kb deletion at 4p16.3 was identified by CMA, which encompassed 6 OMIM genes including ZNF141, PIGG, PDE6B, ATP5I, PCGF3 and MYL5. High-throughput sequencing has identified no pathogenic/likely pathogenic variants consistent with the clinical symptoms.@*CONCLUSION@#A rare ring chromosome 4 syndrome was identified by combined chromosomal karyotyping, CMA and high-throughput sequencing. Conventional cytogenetic analysis and genetic testing in combine have enabled the diagnosis in this case.

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 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.