Diagnostic utility of rapid sequencing in critically ill infants: a systematic review and meta-analysis

Genetic disorders are a major cause of death in critically ill infants. Several studies have assessed the diagnostic yield of rapid genomic sequencing in critically ill infants. This meta-analysis aimed to summarize the diagnostic utility of rapid genomic sequencing in critically ill infants. PubMed, Scopus, Web of Science, and Cochrane Library, were searched before 1 July 2022. Studies reported diagnostic rate of rapid genomic sequencing in critically ill infants were selected. Two authors screened and extracted data regarding the method of genetic test, total number of patients, and number of diagnosed patients. Twenty-three studies, comprising 1567 critically ill infants were included in the meta-analysis. In the overall analysis, the pooled diagnostic utility of rapid genomic sequencing was 0.42 (95% CI: 0.37–0.49, I2 = 79%, P 2 = 74%; P 2 = 77%; P This meta-analysis proved that rapid genomic sequencing has a good diagnostic utility for critically ill infants.</p

Additional file 1 of Safety and efficacy of therapeutic hypothermia in neonates with mild hypoxic-ischemic encephalopathy

Additional file 1. Logistic regression analysis of the influencing factors of hypothermia in infants with mild HIE

Additional file 1: of Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates

Table S1 Reported PAH/PPHN related genes. (DOCX 18 kb

Additional file 2: of Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates

Table S2 Clinical phenotypes of 9 genetic positive PPHN patients. (DOCX 17 kb

Additional file 3: of Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates

Table S3 Gene-level analysis for rare variants. (DOCX 15 kb

Additional file 1 of Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis

Additional file 1: Additional method. The inclusion criteria of the China Neonatal Genomes Project (CNGP). Table S1. Uniparental disomy (UPD) types and disease associated with growth failure. Table S2. The matching results of cases and controls for gestational age, sex, and whether the pregnant mother had gestational hypertension by matching (PSM). Table S3. Characteristics of SGA newborns with different genetic diagnosis. Table S4. The OMIM diseases and detailed developmental phenotypes for SGA-related genes. Table S5. The OMIM diseases and the relevance of disease to underdevelopmental abnormalities for non SGA-related genes. Table S6. The OMIM diseases and multiple organs or systems involved for syndromic genes. Table S7. Monogenetic variants result. Table S8. Characteristics of SGA newborns with different monogenic variants results. Table S9. Chromosomal abnormalities result. Table S10. The risk genes identified based on the gene burden test. Table S11. The baseline information of the SGA-model generation dataset and the SGA-validation dataset

Data_Sheet_1_Galloway–Mowat Syndrome Type 3 Caused by OSGEP Gene Variants: A Case Report and Literature Review.PDF

BackgroundGalloway–Mowat syndrome type 3 (GAMOS3) is an extremely rare and severe autosomal-recessive disease characterized by early-onset nephrotic syndrome (NS), microcephaly and neurological impairment. Reported GAMOS cases have gradually increased since pathogenic OSGEP variants were identified as the aetiology in 2017.MethodsUsing whole-exome sequencing and a data analysis process established by Children's Hospital of Fudan University, the clinical and molecular features of 3 infants with OSGEP mutations were summarized. Literature regarding the clinical features of GAMOS3 caused by OSGEP variants was reviewed.ResultsThirty-seven individuals (3 from this study) from 34 families were included. Twenty-two different OSGEP variants were identified. The c.740G>A (p.Arg247Gln) variant in OSGEP was detected in 15 families (44%), all from Asia. Most affected individuals (including patients I and II in this study) showed a typical phenotype, including microcephaly (92%) with brain anomalies (97%), developmental delay (81%), congenital NS (54%), and craniofacial (94%) and skeletal dysmorphism (84%). Renal manifestations varied from proteinuria (94%, median onset = 1.5 months) to NS (83%) and end-stage renal disease (48%, 11 months) during follow-up. Patients with congenital NS had a lower survival probability (median survival time = 3 months) than those without congenital NS (78 months) (P ConclusionGAMOS3 is a progressive renal-neurological syndrome with a poor prognosis, especially with congenital NS. Microcephaly with dysmorphic features are vital clues to further evaluate renal impairment and brain anomalies. Timely molecular diagnosis is crucial for clinical decision-making, appropriate treatment and genetic counselling.</p

Table7_Primary carnitine deficiency: Estimation of prevalence in Chinese population and insights into newborn screening.XLSX

Primary carnitine deficiency (PCD) caused by pathogenic variants in the solute carrier family 22 member 5 (SLC22A5) gene is a rare autosomal recessive disease that results in defective fatty acid oxidation. PCD can be detected through tandem mass spectrometry (MS/MS), but transplacental transport of free carnitine from mothers may cause false negatives or positives during newborn screening (NBS). This study aimed to analyze the genetic characteristics of SLC22A5 and estimate the prevalence of PCD in the Chinese population, providing useful information for NBS and genetic counseling. We manually curated SLC22A5 pathogenic or likely pathogenic (P/LP) variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines and identified 128 P/LP variants. Based on the China Neonatal Genomes Project (CNGP), the estimated PCD prevalence was 1:17,456, which was higher than that in other populations. The genotype–phenotype association analysis showed that patients carrying homozygous c.760C>T and c.844C>T were more likely to present cardiomyopathy, whereas those carrying homozygous c.1400C>G were more likely to be asymptomatic (all p-values < 0.05). We found that there was no significant difference in initial C0 concentrations between patients and carriers, but there was a significant difference in the second-tier screening of C0 concentration between them (p-value < 0.05). We established a cost-effective variant panel containing 10 high-frequency sites and developed a screening algorithm incorporating gene panels with MS/MS, which could rescue one more patient who was undetected from MS/MS. In conclusion, the prevalence of PCD in the Chinese population is relatively high. The combination of conventional NBS with genetic sequencing is suggested for early diagnosis of PCD.</p

Table4_Primary carnitine deficiency: Estimation of prevalence in Chinese population and insights into newborn screening.XLSX

Primary carnitine deficiency (PCD) caused by pathogenic variants in the solute carrier family 22 member 5 (SLC22A5) gene is a rare autosomal recessive disease that results in defective fatty acid oxidation. PCD can be detected through tandem mass spectrometry (MS/MS), but transplacental transport of free carnitine from mothers may cause false negatives or positives during newborn screening (NBS). This study aimed to analyze the genetic characteristics of SLC22A5 and estimate the prevalence of PCD in the Chinese population, providing useful information for NBS and genetic counseling. We manually curated SLC22A5 pathogenic or likely pathogenic (P/LP) variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines and identified 128 P/LP variants. Based on the China Neonatal Genomes Project (CNGP), the estimated PCD prevalence was 1:17,456, which was higher than that in other populations. The genotype–phenotype association analysis showed that patients carrying homozygous c.760C>T and c.844C>T were more likely to present cardiomyopathy, whereas those carrying homozygous c.1400C>G were more likely to be asymptomatic (all p-values < 0.05). We found that there was no significant difference in initial C0 concentrations between patients and carriers, but there was a significant difference in the second-tier screening of C0 concentration between them (p-value < 0.05). We established a cost-effective variant panel containing 10 high-frequency sites and developed a screening algorithm incorporating gene panels with MS/MS, which could rescue one more patient who was undetected from MS/MS. In conclusion, the prevalence of PCD in the Chinese population is relatively high. The combination of conventional NBS with genetic sequencing is suggested for early diagnosis of PCD.</p

Table6_Primary carnitine deficiency: Estimation of prevalence in Chinese population and insights into newborn screening.XLSX

Primary carnitine deficiency (PCD) caused by pathogenic variants in the solute carrier family 22 member 5 (SLC22A5) gene is a rare autosomal recessive disease that results in defective fatty acid oxidation. PCD can be detected through tandem mass spectrometry (MS/MS), but transplacental transport of free carnitine from mothers may cause false negatives or positives during newborn screening (NBS). This study aimed to analyze the genetic characteristics of SLC22A5 and estimate the prevalence of PCD in the Chinese population, providing useful information for NBS and genetic counseling. We manually curated SLC22A5 pathogenic or likely pathogenic (P/LP) variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines and identified 128 P/LP variants. Based on the China Neonatal Genomes Project (CNGP), the estimated PCD prevalence was 1:17,456, which was higher than that in other populations. The genotype–phenotype association analysis showed that patients carrying homozygous c.760C>T and c.844C>T were more likely to present cardiomyopathy, whereas those carrying homozygous c.1400C>G were more likely to be asymptomatic (all p-values < 0.05). We found that there was no significant difference in initial C0 concentrations between patients and carriers, but there was a significant difference in the second-tier screening of C0 concentration between them (p-value < 0.05). We established a cost-effective variant panel containing 10 high-frequency sites and developed a screening algorithm incorporating gene panels with MS/MS, which could rescue one more patient who was undetected from MS/MS. In conclusion, the prevalence of PCD in the Chinese population is relatively high. The combination of conventional NBS with genetic sequencing is suggested for early diagnosis of PCD.</p