Refining the genetic diagnostic puzzle: A case report on a Chinese ARPKD patient with a reciprocal balanced translocation and c.2507 T > C (p.V836A) in PKHD1.

INTRODUCTION: Autosomal recessive polycystic kidney disease (ARPKD) ranks among the most severe chronic kidney diseases (CKD). Its primary cause is variants in the Polycystic Kidney and Hepatic Disease 1 gene (PKHD1). The clinical spectrum of ARPKD varies widely, ranging from mild late-onset symptoms to severe perinatal mortality. However, achieving an early genetic diagnosis in ARPKD patients before clinical symptoms appear proves challenging. CASE PRESENTATION: This case is a 4-year-old boy who experienced a convulsion characterized by a generalized tonic attack lasting approximately 3-5 minutes and later sought treatment to our hospital. However, routine abdominal ultrasound examination accidentally detected that he had diffuse liver lesions, splenomegaly, and bilateral renal enlargement with renal pelvis dilation. Given the uncertainty regarding the underlying cause of the patient's structural abnormalities and convulsions, karyotyping, whole exome sequencing (WES), structural variant analysis (SV analysis) of whole genome sequencing (WGS) were recommended. The result of SV analysis revealed that he has an RBT impacting PKHD1 and the precise location of breakpoints was confirmed through Long-Range Polymerase Chain Reaction (LR-PCR). However, WES did not screen out pathogenic variants initially, the WES data was reviewed subsequently based on SV analysis results. CONCLUSION: We identified an infrequent variant combination, c.2507T>C (p.V836A) in PKHD1 and an RBT with broken PKHD1, which extends the genetic spectrum of ARPKD, and provide a basis for further genetic counselling to the family.

CTSG polymorphisms in Chinese children with type 1 diabetes mellitus.

Cathepsin G (CTSG) plays an important role in the regulation of immune processes. Accumulated studies show that CTSG is involved in the onset and development of type 1 diabetes mellitus (T1DM). As the genetic background of T1DM varies widely among populations, we aimed to study the relationship between genetic polymorphisms in CTSG and T1DM susceptibility in Chinese populations. A total of 141 patients with T1DM and 200 healthy controls were enrolled in the study. Serum CTSG expression was detected using enzyme-linked immunosorbent assay (ELISA). Genotyping of two selected single nucleotide polymorphisms (SNPs) (rs2236742 and rs2070697) of CTSG was performed using PCR and Sanger sequencing. CTSG expression in patients with T1DM was significantly higher than in the control group. Alleles C and T of CTSG SNP rs2236742 were increased in T1DM. No significant associations were found for the SNP rs2070697. Our results indicate that the CTSG rs2236742 allele (C/T) is associated with T1DM in Chinese children and may serve as a new biomarker for predicting T1DM susceptibility.

Identification of the synonymous variant c.3141G > A in TNRC6B gene that altered RNA splicing by minigene assay.

BACKGROUND: Global developmental delay with speech and behavioral abnormalities (OMIM: 619243) is an autosomal dominant disease caused by variants in TNRC6B gene. METHOD: We reviewed and summarized clinical manifestations and genotypes in patients previously reported with TNRC6B gene variants. We used several prediction tools to predict pathogenicity and performed minigene assays to verify the function of the synonymous variant affecting RNA splicing. RESULT: The patient presented with convulsive seizures and developmental delay. WES combined with functional studies diagnosed a child with a synonymous variant in TNRC6B gene. Through minigene assay and Sanger sequencing, we demonstrated that c.3141G > A variant induced exon 7 skipping and the synonymous variant was pathogenic. CONCLUSION: Synonymous variants do not change the amino acids encoded by the codon, so we usually consider synonymous variants to be benign and ignore their pathogenicity. Minigene assay is a valuable tool to identify the effect of variation on RNA splicing and identify synonymous variants' benign or pathogenic. We showed that the synonymous variant was pathogenic by minigene assay. WES combined with minigene assay establishes a robust basis for genetic counseling and diagnosing diseases.

Circulation patterns and molecular characteristics of respiratory syncytial virus among hospitalized children in Tianjin, China, before and during the COVID-19 pandemic (2017-2022).

Respiratory syncytial virus (RSV) is the main pathogen that causes hospitalization for acute lower respiratory tract infections (ALRIs) in children. With the reopening of communities and schools, the resurgence of RSV in the COVID-19 post-pandemic era has become a major concern. To understand the circulation patterns and genotype variability of RSV in Tianjin before and during the COVID-19 pandemic, a total of 19,531 nasopharyngeal aspirate samples from hospitalized children in Tianjin from July 2017 to June 2022 were evaluated. Direct immunofluorescence and polymerase chain reaction (PCR) were used for screening RSV-positive samples and subtyping, respectively. Further analysis of mutations in the second hypervariable region (HVR2) of the G gene was performed through Sanger sequencing. Our results showed that 16.46% (3215/19,531) samples were RSV positive and a delayed increase in the RSV infection rates occurred in the winter season from December 2020 to February 2021, with the average RSV-positive rate of 35.77% (519/1451). The ON1, with H258Q and H266L substitutions, and the BA9, with T290I and T312I substitutions, are dominant strains that alternately circulate every 1-2 years in Tianjin, China, from July 2017 to June 2022. In addition, novel substitutions, such as N296Y, K221T, N230K, V251A in the BA9 genotype, and L226I in the ON1 genotype, emerged during the COVID-19 pandemic. Analysis of clinical characteristics indicated no significant differences between RSV-A and RSV-B groups. This study provides a theoretical basis for clinical prevention and treatment. However, further studies are needed to explore the regulatory mechanism of host immune responses to different lineages of ON1 and BA9 in the future.

Epilepsy due to potential loss of ATP6V1B2 function with mechanistic insight by a Drosophila Vha55 model.

ATP6V1B2 encodes the subunit of the vacuolar H+-ATPase, which is an enzyme responsible for the acidification of intracellular organelles and essential for cell signaling and neurotransmitter release. The aim of the study is to identify the correlation between ATP6V1B2 and epilepsy. Trio-exome sequencing was performed. Reverse Transcription-PCR and Quantitative real-time PCR analyses were carried out to determine whether this variant leads to nonsense-mediated mRNA decay (NMD). Drosophila models with knocked-down homologous genes of ATP6V1B2 were generated to study the causal relationship between the ATP6V1B2 and the phenotype of epilepsy. We described a 5-year-old male with a novel variant c.1163delT(p.Tyr389IlefsTer13) in ATP6V1B2, who presented with epilepsy. The expression level of the premature termination codon (PTC) transcript was normal in the patient, which indicated that NMD evasion existed in the PTC transcript. We generated an animal model using Drosophila to study the knock down effects of Vha55, which is the ATP6V1B2 ortholog in fly. The Vha55 knockdown flies show seizure-like behaviors and climbing defects. This study expands the variation spectrum of the ATP6V1B2 gene. Cross-species animal model demonstrates the causal relationship between ATP6V1B2 defect and epilepsy, and shed new insights into the disease mechanism caused by ATP6V1B2 LOF variants.

Correlation of tuberculosis-related anemia severity with tuberculosis-induced inflammation in children: a six-year retrospective study.

BACKGROUND: Anemia is a common complication of tuberculosis (TB), and there is evidence that its prevalence is higher in patients with TB. Although TB is very important in epidemiology, careful investigation of TB-related anemia in children has not been carried out systematically. This study aimed to describe the details of anemia in children with TB and its association with clinical characteristics and the severity of inflammation. METHODS: In this retrospective study, we explored Hb levels in 103 children with pulmonary TB (PTB) and they were divided into anemic or non-anemic groups. Logistics regression analysis was used to study the associations between anemia and demographic characteristics. Spearman correlations analysis was performed to analyse the associations between the biochemical parameters and hemoglobin levels in blood. RESULTS: The prevalence of anemia in children with TB was 37.9% (48.7% showed microcytic hypochromic anemia, and 5.1% showed normal cell anemia). Compared with the anemia (n = 39) group, the non-anemic group (n = 64) had longer fever duration and increased respiratory rate (P < 0.05). In logistic regression analysis, anemia was associated with lower levels of Alb and higher levels of WBC, CRP, LDH, and ESR (P < 0.05). Spearman correlations analysis showed a significant negative correlation between hemoglobin (Hb) levels and inflammatory markers. After one month of antitubercular therapy (ATT), the Hb levels of 76.9% children returned to normal. CONCLUSIONS: Anemia is common among children with TB at diagnosis. The majority of children with TB-related anemia are mild to moderate microcytic hypochromic anemia. There is a strong correlation between the severity of anemia and the inflammation induced by TB. This suggests that anemia is a biomarker of the severity of TB in clinical practice among children.

Novel Genetic Variants Distinguishing Myelin Oligodendrocyte Glycoprotein-IgG-Positive From Myelin Oligodendrocyte Glycoprotein-IgG-Negative Pediatric Acute Disseminated Encephalomyelitis in Northern China.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a common phenotype in children with myelin oligodendrocyte glycoprotein IgG (MOG-IgG)-associated disease. We aimed to identify novel genetic variants that distinguish children with MOG-IgG-positive ADEM (MOG-IgG+ ADEM) from children with MOG-IgG-negative ADEM (MOG-IgG- ADEM) using whole exome sequencing (WES) analysis. METHODS: We conducted a two-stage study design. First, we performed WES on five patients with MOG-IgG+ ADEM and five patients with MOG-IgG- ADEM. Following bioinformatics analysis, the candidate variant list was constructed. Second, 29 children with MOG-IgG+ ADEM and 27 children with MOG-IgG- ADEM, together with discovery cohort, were genotyped to identify the novel variants. RESULTS: WES resulted in 33,999 variants, and 5388 nonsynonymous variants were selected for downstream analysis. In total, 118 protein-affecting variants that were significantly different between the two groups were identified. Together with the five variants extracted from the literature, 49 variants were selected as the candidate variant list for genotyping in the replication cohort. Finally, we identified three variants: rs11171951 in NACα, rs231775 in CTLA4, and rs11171951 in GOLGA5, which were significantly different between MOG-IgG+ ADEM and MOG-IgG- ADEM. Only rs12440118 in NACα remained significant after Bonferroni correction for multiple testing (Padj < 0.001). CONCLUSIONS: We identified strong associations between NACα, CTLA4, and GOLGA5 variants and MOG-IgG+ ADEM in a Han Chinese population of Northern China, which may present novel genetic risk factor distinguishing patients with MOG-IgG+ ADEM from those with MOG-IgG- ADEM.

A rare ACAN non-canonical splicing-site intron variant results in familial short stature.

OBJECTIVE: ACAN gene variants, prevalent monogenic defects linked to short stature, are characterized by impaired cartilage generation in growth plates. We aimed to unravel the genetic basis of short stature in a specific pedigree by investigating the role of a novel non-canonical splicing-site variant, c.630-13G > A, within the ACAN gene. METHOD: Sanger sequencing was used for pedigree verification, and the effects of this variant on mRNA splicing were analyzed through minigene assay. RESULTS: The study revealed that this variant led to the creation of a previously unreported splice site in the fourth intron, resulting in the incorporation of an 11 bp sequence from the intron into the final transcript. This alteration led to a frameshift and formation of a premature termination codon, impacting the structure of the aggrecan protein. CONCLUSIONS: We document the pathogenicity of an ACAN non-canonical splicing-site variant, emphasizing the significance of considering intronic variants during genetic testing.

Whole-exome sequencing as the first-tier test for patients in neonatal intensive care unit: a Chinese single-center study.

BACKGROUND: Genetic disorders significantly affect patients in neonatal intensive care units, where establishing a diagnosis can be challenging through routine tests and supplementary examinations. Whole-exome sequencing offers a molecular-based approach for diagnosing genetic disorders. This study aimed to assess the importance of whole-exome sequencing for neonates in intensive care through a retrospective observational study within a Chinese cohort. METHODS: We gathered data from neonatal patients at Tianjin Children's Hospital between January 2018 and April 2021. These patients presented with acute illnesses and were suspected of having genetic disorders, which were investigated using whole-exome sequencing. Our retrospective analysis covered clinical data, genetic findings, and the correlation between phenotypes and genetic variations. RESULTS: The study included 121 neonates. Disorders affected multiple organs or systems, predominantly the metabolic, neurological, and endocrine systems. The detection rate for whole-exome sequencing was 52.9% (64 out of 121 patients), identifying 84 pathogenic or likely pathogenic genetic variants in 64 neonates. These included 13 copy number variations and 71 single-nucleotide variants. The most frequent inheritance pattern was autosomal recessive (57.8%, 37 out of 64), followed by autosomal dominant (29.7%, 19 out of 64). In total, 40 diseases were identified through whole-exome sequencing. CONCLUSION: This study underscores the value and clinical utility of whole-exome sequencing as a primary diagnostic tool for neonates in intensive care units with suspected genetic disorders. Whole-exome sequencing not only aids in diagnosis but also offers significant benefits to patients and their families by providing clarity in uncertain diagnostic situations.

DEPDC5 plays a vital role in epilepsy: Genotypic and phenotypic features in cohort and literature.

OBJECTIVE: DEPDC5 emerges to play a vital role in focal epilepsy. However, genotype-phenotype correlation in DEPDC5-related focal epilepsies is challenging and controversial. In this study, we aim to investigate the genotypic and phenotypic features in DEPDC5-affected patients. METHODS: Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies. RESULTS: Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335). SIGNIFICANCE: The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.

Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa.

BACKGROUND: Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and saggy in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic. METHODS: In this study, we reported a case of a Han-Chinese male newborn with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the novel variant, and their parents were verified by Sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function. RESULTS: The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the newborn carried a non-canonical splicing-site variant c.117 + 5G > T, p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of the ATP6V0A2 gene. CONCLUSIONS: In this study, it was identified that ATP6V0A2 gene c. 117 + 5G > T may be the cause of the disease. The non-canonical splicing variants of ATP6V0A2 gene were rarely reported in the past, and this variant expanded the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the level of evidence for the pathogenicity of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.

Case Report: A developmental and epileptic encephalopathy 45 due to de novo variant of GABRB1.

Background: The gamma-aminobutyric acid (GABA) variant causes developmental and epileptic encephalopathy 45 (DEE45), an autosomal dominant disorder that results in oculocortical visual impairment, reduced muscle tone, psychomotor retardation, and epilepsy. Analysis of the clinical features and genetics of DEE45 may be helpful in complementing genotype-phenotype studies. Case presentation: We collected peripheral blood samples from the affected children and parents and extracted genomic DNA. Whole exome sequencing (WES) was utilized to identify the underlying disease-causing variant. WES showed that the prior carried a heterozygous variant c.686C > T p.(Ala229Val) in exon 7 of the GABRB1 (NM_000812.4), and no variant was detected in either parental sample. The child has DEE45. Conclusion: The variant c.686C > T of the GABRB1 is a possible cause of DEE45. Gene variant analysis of the relevant family lines using WES provides effective genetic counseling for developing and regressing such patients in the clinic. However, further studies are needed to verify the pathogenic mechanism.

Phosphoserine aminotransferase deficiency diagnosed by whole-exome sequencing and LC-MS/MS reanalysis: A case report and review of literature.

BACKGROUND: Phosphoserine aminotransferase deficiency (PSATD) is an autosomal recessive disorder associated with hypertonia, psychomotor retardation, and acquired microcephaly. Patients with PSATD have low concentrations of serine in plasma and cerebrospinal fluid. METHODS: We reported a 2-year-old female child with developmental delay, dyskinesia, and microcephaly. LC-MS/MS was used to detect amino acid concentration in the blood and whole-exome sequencing (WES) was used to identify the variants. PolyPhen-2 web server and PyMol were used to predict the pathogenicity and changes in the 3D model molecular structure of protein caused by variants. RESULTS: WES demonstrated compound heterozygous variants in PSAT1, which is associated with PSATD, with a paternal likely pathogenic variant (c.235G>A, Gly79Arg) and a maternal likely pathogenic variant (c.43G>C, Ala15Pro). Reduced serine concentration in LC-MS/MS further confirmed the diagnosis of PSATD in this patient. CONCLUSIONS: Our findings demonstrate the importance of WES combined with LC-MS/MS reanalysis in the diagnosis of genetic diseases and expand the PSAT1 variant spectrum in PSATD. Moreover, we summarize all the cases caused by PSAT1 variants in the literature. This case provides a vital reference for the diagnosis of future cases.

A novel MMUT splicing variant causing mild methylmalonic acidemia phenotype.

Objectives: Methylmalonic acidemia (MMA) is a rare inborn genetic disorder that is characterized by increased levels of methylmalonic acid in blood plasma and urine. Isolated methylmalonic acidemia is one of the most common types of MMA and is caused by mutations in the gene encoding methyl-malonyl coenzyme A mutase (MMUT). In this study, we investigated the possible mechanisms underlying the symptoms of isolated MMA in a patient by molecular analysis. Methods: PCR amplification and Sanger sequencing analysis was performed to identify variants in the MMUT gene in the proband and his family. Furthermore, minigene constructs were generated to validate the splicing defects in the MMUT gene variant identified in the proband. Results: The 3-year-old patient was admitted to the hospital with symptoms of MMA, including fever, convulsions, and vomiting. He showed metabolic acidosis, high levels of methylmalonic acid in blood and urine, and normal blood homocysteine levels. Genetic analysis demonstrated that the patient was a compound heterozygous carrier of two variants in the MMUT gene: a missense c.278G > A variant that has already been reported in a patient with the severe mut° phenotype; and a novel splice site variant c.2125-2A > G. RT-PCR analysis showed that, while the novel variant clearly alters splicing, a minor amount of a full-length transcript is generated, suggesting that a wild-type protein may be produced although at a lower quantitative level. The patient's condition improved after treatment with vitamin B12. Serious complications were not reported during follow-up at age 5. Conclusions: We identified a novel splice site variant that partially disrupts normal splicing of the MMUT pre-mRNA. Production of a reduced amount of full-length transcript is responsible for the mild clinical phenotype observed in this patient. Functional studies have proven useful in exploring the genotype-phenotype association and in providing guidance for the genetic diagnosis of MMA.

Genetic Association of Lipids and Lipid-Lowering Drug Target Genes With Attention Deficit Hyperactivity Disorder.

BACKGROUND: Lipid metabolism plays an essential role in nervous system development. Cholesterol deficiency leads to a variety of neurodevelopmental disorders, such as autism spectrum disorder and fragile X syndrome. There have been a lot of efforts to search for biological markers associated with and causal to ADHD, among which lipid is one possible etiological factor that is quite widely studied. We aimed to evaluate the causal relationship between lipids traits, lipid-lowering drugs, and attention deficit hyperactivity disorder (ADHD) outcomes using Mendelian randomization (MR) studies. METHODS: We used summary data from genome-wide association studies to explore the causal relationships between circulating lipid-related traits and ADHD. Then, quantitative trait loci for the expression of lipid-lowering drug target genes and genetic variants associated with lipid traits were extracted. Summary-data-based MR and inverse-variance-weighted MR (IVW-MR) were used to investigate the correlation between the expression of these drug-target genes and ADHD. RESULTS: After rigorous screening, 939 instrumental variables were finally included for univariable mendelian randomization analysis. However, there is no correlation between lipid profile and ADHD risk. Drug target analysis by IVW-MR method observed that APOB-mediated low-density lipoprotein cholesterol was associated with lower ADHD risk (odds ratio [OR] = 0.90, 95% confidence interval [CI] [0.84, 0.97]; p = .007), whereas LPL-mediated triglycerides levels were associated with a higher risk of ADHD (OR = 1.13, 95% CI [1.06, 1.21]; p < .001). CONCLUSION: Our results suggest that APOB gene and LPL gene may be candidate drug target genes for the treatment of ADHD.

Whole exome sequencing approach for identification of the molecular etiology in pediatric patients with hematuria.

BACKGROUND: Hematuria is a common condition in clinical practice of pediatric patients. It is related to a wide spectrum of disorders and has high heterogeneity both clinically and genetically, which contributes to challenges of diagnosis and lead many pediatric patients with hematuria not to receive accurate diagnosis and early management. METHODS: In this single center study, 42 children with hematuria were included in Tianjin Children's Hospital between 2019 and 2020. We analyzed the clinical information and performed WES (Whole exome sequencing) for all cases. Then the classification of identified variants was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines for interpreting sequence variants. For the fragment deletion, qPCR was performed to validate and confirm the inherited pattern. RESULTS: For the 42 patients, 16 cases had gross hematuria and 26 had microscopic hematuria. Molecular genetic causes were uncovered in 9 (21.4%) children, including 7 with Alport syndrome (AS), one with polycystic nephropathy and one with lipoprotein glomerulopathy. The genetic causes for other patients were not related with hematuria. CONCLUSIONS: WES is a rapid and effective way to evaluate patients with hematuria. The analysis of genotype-phenotype correlations of patients with AS indicated that severe variants were associated with early kidney failure. Secondary findings were not rare in Chinese children, thus the clinician should pay more attention to the clinical interpretation of sequencing results and properly interaction with patients and their family.

A Pair of Compound Heterozygous IARS2 Variants Manifesting West Syndrome and Electrolyte Disorders in a Chinese Patient.

Background Aminoacyl-tRNA synthetases (ARSs) are evolutionarily conserved enzymes that ensure the accuracy of the translation process. Isoleucyl-tRNA synthetase 2 ( IARS2 ) gene is a type of ARS that encodes mitochondrial isoleucine-tRNA synthetase. Pathogenic variants in the IARS2 gene are associated with mitochondrial disease which involves several patients presenting broad clinical phenotypes. These clinical phenotypes include West syndrome, Leigh syndrome, and Cataract, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia syndrome. Only 29 cases have been reported worldwide. The patient manifested recurrent convulsions, and specific clinical manifestations included electrolyte disorders and recurrent infections. Methods Whole-exome sequencing was performed on the child with West syndrome. Three-dimensional structure reconstruction and thermodynamic stability prediction were performed to further analyze the relationship between variation and phenotype. Conclusion This study further expands the clinical spectrum of IARS2 pathogenic variants. The case summaries help raise clinical awareness of IARS2 -associated disease and reduce misdiagnosis. Result In this report, a 13-month-old girl was diagnosed with West syndrome and Leigh syndrome for 7 months. Compound heterozygous variants in the IARS2 gene (NM_018060.4), c.2450G>A (Arg817His) and copy number variation (NC_000001. 11: g. (220267549_220284289) del), were detected by WES. This study further expands the clinical spectrum of IARS2 pathogenic variants. The case summaries help raise clinical awareness of IARS2-associated disease and reduce misdiagnosis.

Identification of Two Variants c.2697A > C and c.3305A > C in USP7 by Analysis of Whole-Exome Sequencing in Chinese Patients with Hao-Fountain Syndrome.

Background Variants of ubiquitin-specific protease 7 ( USP7 ) gene in humans are associated with a neurodevelopmental disorder-Hao-Fountain syndrome, its core symptoms including developmental delay, intellectual disability, and speech delay. Other variable symptoms can affect multiple systems. In present study, we report two patients with core features from two unrelated consanguineous families originating from the Tianjin Children's Hospital. Methods and Results Genomic DNA was extracted from the peripheral blood samples collected from the probands with their family members and whole-exome sequencing (WES) was used to detect the pathogenic genes in the probands. Suspected variants were subsequently validated by Sanger sequencing. In family 1, WES revealed that the proband carried the de novo variant c.2697A > C (p.Leu899Phe) in USP7 (NM_003470.3). In family 2, WES identified the variant c.3305A > C (p.Asn1102Thr) in USP7 (NM_003470.3) from the proband. Conclusion We reported two cases of Hao-Fountain syndrome caused by novel USP7 variants. In addition, we report the first case of mosaicism with a USP7 variant in Chinese family. Our findings demonstrate the importance of WES in diagnosis of genetic diseases and expands the USP7 variants spectrum in Hao-Fountain syndrome. Moreover, we summarize the cases caused by USP7 variants in the literature. Our study can provide a vital reference for the diagnosis of future cases.

Novel Variants of CEP152 in a Case of Compound-Heterozygous Inheritance of Epilepsy.

Introduction CEP152 encodes protein Cep152, which associates with centrosome function. The lack of Cep152 can cause centrosome duplication to fail. CEP152 mutates, causing several diseases such as Seckel syndrome-5 and primary microencephaly-9. Methods In this study, we reported a patient diagnosed with epilepsy in Tianjin Children's Hospital. We performed clinical examination and laboratory test, and whole-exome sequencing was performed for the proband's and his parents' peripheral blood. The suspected compound-heterozygous variant in the CEP152 gene was verified by Sanger sequencing and quantitative real-time polymerase chain reaction technology. Results We discovered three variants-two of them from CEP152 and one from HPD . The result showed the variants in CEP152 only. The patient presented with seizures frequently. Sanger sequencing showed two novel variants in CEP152 are in exon26 (NM_014985.3 c.3968C > A p.Ser1323*) and in exon16 (NM_014985.3 c.2034_2036del p.Tyr678*). Conclusions We reported a novel compound-heterozygous variant in the CEP152 gene in this study. Most of the phenotypes are Seckel syndrome and primary microencephaly, and the novel variant may cause an atypical phenotype that is epilepsy.

Network-based analysis on the genes and their interactions reveals link between schizophrenia and Alzheimer's disease.

Schizophrenia (SCZ) is a heterogeneous psychiatric disorder marked by impaired thinking, emotions, and behaviors. Studies have suggested a strong connection between SCZ and Alzheimer's disease (AD), however, controversies exist and the underlying mechanisms linking these two disorders remain largely unknown. Therefore, systematic studies of SCZ- and AD-related genes will provide valuable insights into the molecular features of these two diseases and their comorbidities. In this study, we obtained 331 SCZ-related genes, 650 AD-related genes, 65 shared genes between SCZ and AD. Enrichment analysis shown that these 65 shared genes were mainly involved in cognition, neural development, synaptic transmission, drug reactions, metabolic processes and immune related processes, suggesting a complex mechanism for the co-existence of SCZ and AD. In addition, we performed pathway enrichment analysis and found a total of 57 common pathways between SCZ and AD, which could be largely grouped into three modules: immune module, neurodevelopment module and cancer module. We eventually identified the potential disease-related genes whose interactions provide clues to the overlapping symptoms between SCZ and AD.