Objective:To explore the genetic basis for a girl with primary microcephaly and growth retardation.Methods:A girl who was admitted to Guangdong Maternal and Child Health Care Hospital in was selected as the study subject. Peripheral blood samples were collected from the child and her parents. Trio whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing and bioinformatic analysis. This study was approved by the Medical Ethnics Committee of Guangdong Maternal and Child Health Care Hospital (Ethics No. 202201278).Results:DNA sequencing revealed that the child has harbored compound heterozygous variants of the WDR62 gene, including a frameshifting c. 2963delC (p.Pro988Argfs*80) variant in exon 24 which was inherited from the unaffected father, and a nonsense c.3163G>T (p.Glu1055*) variant in exon 26, which was inherited from her unaffected mother. Both variants were predicted to affect the reading frame of the WDR62 gene. Conclusion:Based on the clinical manifestations, results of genetic testing and pedigree analysis, the compound heterozygous variants were predicted to underlay the pathogenesis of microcephaly and growth retardation in this child. Above discovery has expanded the mutational spectrum for WDR62-associated Primary microcephaly type 2, and facilitated genetic counseling for the family.

OBJECTIVE: To explore the genetic basis for a girl with primary microcephaly and growth retardation. METHODS: A girl who was admitted to Guangdong Maternal and Child Health Care Hospital in was selected as the study subject. Peripheral blood samples were collected from the child and her parents. Trio whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing and bioinformatic analysis. This study was approved by the Medical Ethnics Committee of Guangdong Maternal and Child Health Care Hospital (Ethics No. 202201278). RESULTS: DNA sequencing revealed that the child has harbored compound heterozygous variants of the WDR62 gene, including a frameshifting c.2963delC (p.Pro988Argfs*80) variant in exon 24 which was inherited from the unaffected father, and a nonsense c.3163G>T (p.Glu1055*) variant in exon 26, which was inherited from her unaffected mother. Both variants were predicted to affect the reading frame of the WDR62 gene. CONCLUSION Based on the clinical manifestations, results of genetic testing and pedigree analysis, the compound heterozygous variants were predicted to underlay the pathogenesis of microcephaly and growth retardation in this child. Above discovery has expanded the mutational spectrum for WDR62-associated Primary microcephaly type 2, and facilitated genetic counseling for the family.
Female ; Humans ; Cell Cycle Proteins ; Heterozygote ; Microcephaly/genetics* ; Mutation ; Nerve Tissue Proteins/genetics* ; Pedigree

Objective:To explore the genetic etiology of congenital solitary functioning kidney (CSFK).Methods:This retrospective study included 422 fetuses diagnosed with CSFK by prenatal ultrasound who underwent invasive prenatal genetic testing at Guangdong Women and Children Hospital between January 2015 and February 2023. These CSFK fetuses were classified into different subtypes (unilateral renal agenesis and unilateral multicystic dysplastic kidney) and divided into the isolated group ( n=312) and the non-isolated group ( n=110) based on whether there were other associated abnormalities. The results of G-banding karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES) among fetuses with different subtypes or from different groups were analyzed. Statistical analysis was performed using the Chi-square (or Fisher's exact) test and rank-sum test. Results:(1) The median maternal age at the time of invasive prenatal diagnosis was 29 years (range: 18-43 years), and the median gestational age was 25 weeks (range: 17-34 weeks). Among the 422 cases, 234 underwent karyotyping and CMA, 63 underwent CMA and WES, and seven underwent all three tests. Therefore, karyotyping, CMA, and WES were completed in 257, 406, and 70 cases, respectively. (2) The detection rate of chromosomal abnormality by G-banding karyotyping was 1.6% (4/257). Among these four cases, CMA detected no abnormalities in one case with chromosomal mosaicism, while the CMA results were consistent with G-banding karyotyping in three cases with chromosomal structural rearrangements. (3) CMA results: The CNV detection was 8.9% (36/406), with 22 cases being classified as pathogenic/likely pathogenic CNVs. Common CNV loci included 17q12 (five cases), 22q11.21 (five cases), and 16p11.2 (two cases). Fifteen cases (68.2%) were associated with microdeletion syndromes. Nineteen mothers opted for pregnancy termination, two continued the pregnancies, and one was lost to follow-up. (4) Among the 241 cases that underwent both G-banding karyotyping and CMA (including seven cases with all three tests), the positive rates for G-banding karyotyping and CMA were 1.7% (4/241) and 5.8% (14/241), respectively. Compared to G-banding karyotyping, CMA provided an additional diagnostic yield of 4.1% (10/241). (5) Among the 70 cases that underwent family-based WES, 26 (37.1%) showed abnormal results, including 12 pathogenic/likely pathogenic variants and 14 variants of uncertain significance. The positive rateby WES was 17.1% (12/70). Six gene variants (mainly PKD1 and HNF1B variants) were associated with the CSFK phenotype, including five autosomal dominant and one autosomal recessive inheritance. Among the 12 WES-positive cases, six had heterozygous variants and six had compound heterozygous variants. Eight mothers chose to continue the pregnancy, two opted for termination, and two were lost to follow-up. (6) Among the 422 CSFK fetuses, 35 (8.3%) had genetic abnormalities. The highest genetic abnormality rate was observed in CSFK fetuses with isolated urinary system abnormalities (15.1%, 8/53), followed by those with additional non-urinary system abnormalities (12.3%, 7/57), and isolated CSFK fetuses (6.4%, 20/312). The differences among the three groups were statistically significant ( χ2=5.95, P=0.048), but no significant differences were found in pairwise comparisons. Conclusion:The primary genetic etiologies of CSFK fetuses include 17q12 microdeletion syndrome, 22q11.2 microdeletion syndrome, and variants in the PKD1 and HNF1B genes.

Objective:To explore the genetic basis for a girl with primary microcephaly and growth retardation.Methods:A girl who was admitted to Guangdong Maternal and Child Health Care Hospital in was selected as the study subject. Peripheral blood samples were collected from the child and her parents. Trio whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing and bioinformatic analysis. This study was approved by the Medical Ethnics Committee of Guangdong Maternal and Child Health Care Hospital (Ethics No. 202201278).Results:DNA sequencing revealed that the child has harbored compound heterozygous variants of the WDR62 gene, including a frameshifting c. 2963delC (p.Pro988Argfs*80) variant in exon 24 which was inherited from the unaffected father, and a nonsense c.3163G>T (p.Glu1055*) variant in exon 26, which was inherited from her unaffected mother. Both variants were predicted to affect the reading frame of the WDR62 gene. Conclusion:Based on the clinical manifestations, results of genetic testing and pedigree analysis, the compound heterozygous variants were predicted to underlay the pathogenesis of microcephaly and growth retardation in this child. Above discovery has expanded the mutational spectrum for WDR62-associated Primary microcephaly type 2, and facilitated genetic counseling for the family.

Objective:To explore the genetic etiology of congenital solitary functioning kidney (CSFK).Methods:This retrospective study included 422 fetuses diagnosed with CSFK by prenatal ultrasound who underwent invasive prenatal genetic testing at Guangdong Women and Children Hospital between January 2015 and February 2023. These CSFK fetuses were classified into different subtypes (unilateral renal agenesis and unilateral multicystic dysplastic kidney) and divided into the isolated group ( n=312) and the non-isolated group ( n=110) based on whether there were other associated abnormalities. The results of G-banding karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES) among fetuses with different subtypes or from different groups were analyzed. Statistical analysis was performed using the Chi-square (or Fisher's exact) test and rank-sum test. Results:(1) The median maternal age at the time of invasive prenatal diagnosis was 29 years (range: 18-43 years), and the median gestational age was 25 weeks (range: 17-34 weeks). Among the 422 cases, 234 underwent karyotyping and CMA, 63 underwent CMA and WES, and seven underwent all three tests. Therefore, karyotyping, CMA, and WES were completed in 257, 406, and 70 cases, respectively. (2) The detection rate of chromosomal abnormality by G-banding karyotyping was 1.6% (4/257). Among these four cases, CMA detected no abnormalities in one case with chromosomal mosaicism, while the CMA results were consistent with G-banding karyotyping in three cases with chromosomal structural rearrangements. (3) CMA results: The CNV detection was 8.9% (36/406), with 22 cases being classified as pathogenic/likely pathogenic CNVs. Common CNV loci included 17q12 (five cases), 22q11.21 (five cases), and 16p11.2 (two cases). Fifteen cases (68.2%) were associated with microdeletion syndromes. Nineteen mothers opted for pregnancy termination, two continued the pregnancies, and one was lost to follow-up. (4) Among the 241 cases that underwent both G-banding karyotyping and CMA (including seven cases with all three tests), the positive rates for G-banding karyotyping and CMA were 1.7% (4/241) and 5.8% (14/241), respectively. Compared to G-banding karyotyping, CMA provided an additional diagnostic yield of 4.1% (10/241). (5) Among the 70 cases that underwent family-based WES, 26 (37.1%) showed abnormal results, including 12 pathogenic/likely pathogenic variants and 14 variants of uncertain significance. The positive rateby WES was 17.1% (12/70). Six gene variants (mainly PKD1 and HNF1B variants) were associated with the CSFK phenotype, including five autosomal dominant and one autosomal recessive inheritance. Among the 12 WES-positive cases, six had heterozygous variants and six had compound heterozygous variants. Eight mothers chose to continue the pregnancy, two opted for termination, and two were lost to follow-up. (6) Among the 422 CSFK fetuses, 35 (8.3%) had genetic abnormalities. The highest genetic abnormality rate was observed in CSFK fetuses with isolated urinary system abnormalities (15.1%, 8/53), followed by those with additional non-urinary system abnormalities (12.3%, 7/57), and isolated CSFK fetuses (6.4%, 20/312). The differences among the three groups were statistically significant ( χ2=5.95, P=0.048), but no significant differences were found in pairwise comparisons. Conclusion:The primary genetic etiologies of CSFK fetuses include 17q12 microdeletion syndrome, 22q11.2 microdeletion syndrome, and variants in the PKD1 and HNF1B genes.

Objective:To investigate whether stress hyperglycemia (SH) is an independent risk factor for the occurrence and mortality of sepsis-associated encephalopathy (SAE).Methods:From August 2016 to October 2021, sepsis patients admitted to the ICU of Guangdong Provincial People's Hospital were selected as the study subjects. According to whether they developed to SH (RBG>11.1 mmol/L) within 7 days of enrollment, the pat ients were divided into the SH group and the non-SH group for analysis. Logistic regression was used to analyze whether SH was an independent risk factor for SAE occurrence, and ROC curve was used to analyze the predictive value of SH to SAE. Kaplan-Meier curve was used to compare the 90-day survival of SAE patients with or without SH. Cox regression analysis was used to analyze the risk factors of 28-day and 90-day death in SAE patients.Results:A total of 183 sepsis patients were included, including 62 patients in the SH group and 121 in the non-SH group. Logistic regression analysis demonstrated that SH was an independent risk factor for SAE ( OR=4.452, 95% CI: 2.021-9.808, P <0.001). ROC curve demonstrated that SH could accurately predict SAE (AUC=0.831; Sensitivity=78.4%; Specificity=76.8%; and Yoden index=0.553). Kaplan-Meier curve demonstrated that the 90-day survival of SAE patients with SH significantly declined (log-rank test: P<0.01). Cox regression analysis suggested that SH was a risk factor for death at day 28 and day 90 in SAE patients (28 d, HR=2.272, 95% CI: 1.212-4.260, P=0.010; 90 d, HR=2.456, 95% CI: 1.400-4.306, P<0.01). Conclusions:SH is an independent risk factor for SAE and can predict SAE occurrence. SH significantly reduces 90-day survival and increase mortality at 28 and 90 days in SAE patients.

Objective:To investigate the diagnostic and early-warning value of laboratory test indicators for sepsis-induced myocardial injury (SIMD).Methods:The clinical data of 183 patients with sepsis admitted to the Department of Emergency and Critical Care Medicine of Guangdong Provincial People's Hospital from August 2016 to October 2020 were collected. The patient's age, gender, past medical history, vital signs and pathogen culture results were extracted. Cardiac function, blood routine, liver function, renal function, inflammatory factors, coagulation function, APACHE Ⅱ and SOFA scores were recorded at enrollment and 72 h after admission. SIMD was defined as cTnT ≥300 pg/mL and NT-proBNP ≥1243 pg/mL twice in 72 h intervals between enrolled cases, and the early-warning factors of patients with SIMD were analyzed. The differences in various indicators between the two groups were compared, and Logistic regression analysis was used to explore the diagnostic efficacy of cTnT and NT-proBNP combined for SIMD, and the correlation between PCT/PLT ratio and the occurrence of SIMD.Results:Among 250 patients, 67 patients were excluded for lack of the main indicators, and 183 patients (including 62 patients with history of cardiac disease) were enrolled finally. Among 183 patients with sepsis, 105 patients (57.38%) with cTNT ≥300 pg/mL and NT-proBNP ≥1 243 pg/mL, were diagnosed as myocardial injury; after excluding 62 patients with history of cardiac disease, 59 patients (48.76%) with cTNT ≥300 pg/mL and NT-proBNP ≥1 243 pg/mL were diagnosed as myocardial injury. Logistic regression analysis showed that increased PCT/PLT ratio ( OR=1.585, 95% CI: 1.124-2.237, P=0.009) was an independent risk factor for early-warning of SIMD. The PCT/PLT ratio ( OR= 1.850, 95% CI: 1.103-3.102, P=0.020) could stably predict the occurrence of SIMD in patients without previous history of heart disease. ROC curve analysis showed that PCT/PLT ratio could effectively predict the occurrence of SIMD (AUC=0.693, 95% CI: 0.617-0.769, P<0.001), the optimal cut-off value was 0.177 (sensitivity: 65.7%, specificity: 66.7%). The PCT/PLT ratio was still effective in predicting the occurrence of SIMD after excluding patients with previous history of heart disease (AUC=0.733, 95% CI: 0.643-0.823, P<0.001), and the optimal cut-off value was 0.429 (sensitivity: 55.9%, specificity: 83.9%). Conclusions:The combination of cTnT and NT-proBNP has certain diagnostic value for SIMD, and the PCT/PLT ratio could warn the occurrence of SIMD.

Objective:To evaluate the predictive effect of sepsis-induced coagulopathy (SIC) score level on the prognosis of septic patients under sepsis 3.0 criteria.Methods:A retrospective single-center observational study was conducted on the septic patients admitted to the department of critical care medicine and the department of emergency in Guangdong Provincial People's Hospital from August 2016 to July 2021. The baseline data, laboratory indexes and SIC scores of the patients were collected on the first and fourth (4th) day after hospitalization. Whether the patients were survival within 30 days after enrollment was recorded. Univariate and multivariate Logistic regression were used to analyze the independent risk factors for 30-day mortality in septic patients. The receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of SIC score on the 30-day prognosis of septic patients.Results:A total of 173 patients met the inclusion criteria including 111 (64%) survivors and 62 (36%) non-survivors. There were significant differences in lymphocyte count (LYM), sequential organ failure assessment (SOFA), oxygenation index (PaO 2/FiO 2) and cardiovascular SOFA score between the survival group and the non-survival group. And there were no significant differences in other indexes. On the first day of admission, there were statistically significant differences in PaO 2/FiO 2, cardiovascular SOFA score, LYM, SIC score between the non-survival group and the survival group. There were significant differences in international normalized ratio (INR), prothrombin activity (PTA), prothrombin time (PT), PaO 2/FiO 2, cardiovascular SOFA score, LYM, C-reactive protein (CRP) and procalcitonin (PCT) between the two groups on the 4th day after admission. The mortality of septic patients increased with the increase of SIC score. Binary Logistic regression analysis showed that SIC score and LYM on the 4th day after admission were independent risk factors for 30-day mortality in septic patients (both P < 0.05). The ROC curve showed that SIC score had a certain predictive value for the 30-day prognosis of septic patients [area under the ROC curve (AUC) = 0.712, 95% confidence interval (95% CI) was 0.629-0.794, P < 0.001]. The predictive value of SIC score combined with LYM was better than that of the two alone (AUC = 0.748, 95% CI was 0.688-0.828, P < 0.001). Conclusions:The SIC score has a certain predictive value for the 30-day prognosis of septic patients. The predictive value of SIC score combined with LYM is better than that of the two alone, which is expected to be a potential indicator for early assessment of the condition and prognosis of septic patients.

OBJECTIVE: To analyze the clinical and genetic characteristics of a patient featuring autosomal dominant Olmsted syndrome. METHODS: Clinical features of the patient was reviewed. High-throughput sequencing was carried out to detect potential genetic variants. RESULTS: The proband, a 12-year-old girl, featured excessive keratinization on hands and feet, contracture of finger joints, and abnormal position and residual contraction of the fifth toes. Skin biopsy showed significant hyperkeratosis, epidermal hyperplasia, and mild interepidermal cell edema. A de novo heterozygous missense variant c.2016G>T(p.Met672Ile) was identified in the TRPV3 gene by high-throughout sequencing. The result was verified by Sanger sequencing. CONCLUSION The destructive palmoplantar keratosis in the child may be attributed to the c.2016G>T(p.Met672Ile) variant of the TRPV3 gene. Aboving finding has provided new evidence for the correlation of genetic variants with clinical phenotypes of Olmsted syndrome.
Child ; Female ; Heterozygote ; Humans ; Keratoderma, Palmoplantar/genetics* ; Skin ; Syndrome ; TRPV Cation Channels/genetics*

Objective:To explore the change of blood-brain barrier (BBB) permeability in septic rats.Methods:A rat model of sepsis was established by cecal ligation and puncture. Rats were randomly (random number) grouped according to the intervention time: sham-operated group, sepsis 1-day group, sepsis 4-day group, and sepsis 7-day group. Fluorescein sodium was used to test the permeability of the BBB. Western blot and immunofluorescence methods were applied to detect the expression of tight junction proteins including Claudin-5, Occludin and ZO-1.Results:Compared with the sham-operated group, rats in the sepsis group presented quick breath, slow response, decreased intake of food and water, obvious abdominal distension and loose stools. After abdominal anatomy of sepsis rats, we found mesenteric adhesions, dilatation of proximal intestinal, black cecum ligation site with purulent exudate, enlarged liver and diffused bloody exudate. Compared with the sham-operated group, body weight of sepsis rats was reduced remarkably ( P < 0.05). The body weight of rats of sepsis 7-day group was the lowest, which was significantly lower than that of rats of sepsis 4-day group ( P< 0.05) and 1-day group ( P< 0.05). Compared with the sham-operated group, the content of fluorescein sodium in sepsis 1-day rats was increased remarkably ( P< 0.05). The content of fluorescein sodium in rats of sepsis 7-day group was the highest, which was significantly higher than that in rats of sepsis 4-day group ( P< 0.05) and 1-day group ( P< 0.05). Compared with the sham-operated rats, the expression of Claudin-5, Occludin and ZO-1 in sepsis rats were decreased remarkably (all P < 0.05). The expression of Claudin-5, Occludin and ZO-1 were the lowest in rats of the sepsis 7-day group, which were significantly decreased than those of rats in the sepsis 4-day group (all P< 0.05) and rats in sepsis 1-day group (all P < 0.05). Conclusions:Sepsis rats showed increased permeability of the BBB, and the permeability of BBB increased continuously along with the duration of sepsis.