Genotypic and phenotypic characteristics of sodium channel-associated epilepsy in Chinese population.

Variants in voltage-gated sodium channel (VGSC) genes are implicated in seizures, epilepsy, and neurodevelopmental disorders, constituting a significant aspect of hereditary epilepsy in the Chinese population. Through retrospective analysis utilizing next-generation sequencing (NGS), we examined the genotypes and phenotypes of VGSC-related epilepsy cases from a cohort of 691 epilepsy subjects. Our findings revealed that 5.1% of subjects harbored VGSC variants, specifically 22 with SCN1A, 9 with SCN2A, 1 with SCN8A, and 3 with SCN1B variants; no SCN3A variants were detected. Among these, 14 variants were previously reported, while 21 were newly identified. SCN1A variant carriers predominantly presented with Dravet Syndrome (DS) and Genetic Epilepsy with Febrile Seizures Plus (GEFS + ), featuring a heightened sensitivity to fever-induced seizures. Statistically significant disparities emerged between the SCN1A-DS and SCN1A-GEFS+ groups concerning seizure onset and genetic diagnosis age, incidence of status epilepticus, mental retardation, anti-seizure medication (ASM) responsiveness, and familial history. Notably, subjects with SCN1A variants affecting the protein's pore region experienced more frequent cluster seizures. All SCN2A variants were of de novo origin, and 88.9% of individuals with SCN2A variations exhibited cluster seizures. This research reveals a significant association between variations in VGSC-related genes and the clinical phenotype diversity of epilepsy subjects in China, emphasizing the pivotal role of NGS screening in establishing accurate disease diagnoses and guiding the selection of ASM.

Gut microbiota-metabolite interactions meditate the effect of dietary patterns on precocious puberty.

Precocious puberty, a pediatric endocrine disorder classified as central precocious puberty (CPP) or peripheral precocious puberty (PPP), is influenced by diet, gut microbiota, and metabolites, but the specific mechanisms remain unclear. Our study found that increased alpha-diversity and abundance of short-chain fatty acid-producing bacteria led to elevated levels of luteinizing hormone and follicle-stimulating hormone, contributing to precocious puberty. The integration of specific microbiota and metabolites has potential diagnostic value for precocious puberty. The Prevotella genus-controlled interaction factor, influenced by complex carbohydrate consumption, mediated a reduction in estradiol levels. Interactions between obesity-related bacteria and metabolites mediated the beneficial effect of seafood in reducing luteinizing hormone levels, reducing the risk of obesity-induced precocious puberty, and preventing progression from PPP to CPP. This study provides valuable insights into the complex interplay between diet, gut microbiota and metabolites in the onset, development and clinical classification of precocious puberty and warrants further investigation.

Establishment of human induced pluripotent stem cell line SDQLCHi029-A from one Type 1 familial glucocorticoid deficiency patient carrying compound heterozygote mutations in MC2R gene.

Type 1 familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder due to variation of the melanocortin-2-receptor (MC2R) gene. Induced pluripotent stem cell (iPSC) line SDQLCHi029-A was successfully generated from peripheral blood mononuclear cells obtained from a 5-day-old girl with MC2R mutations (c.428C > T and c.409C > T). The iPSC line showed genetically stable and matched the donor's PBMCs. displayed a normal karyotype, expressed high pluripotent markers, and exhibited differentiation potential of three germ layers in vitro. The iPSC line could be a good model to study the pathogenesis of FGD type 1 and screen new drugs for the disease.

Establishment of a non-integrated iPSC (SDQLCHi066-A) line derived from Segawa syndrome patients harboring heterozygous mutations in the TH gene (p.G247S and p.D491H).

Segawa syndrome, an autosomal recessive genetic disorder, arises from homozygous or compound heterozygous mutations in the TH gene. We established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells (PBMCs) of an 4-month-old girl with Segawa syndrome, who carried compound heterozygous mutations of c.739G > A/chr11:2188714 and c.1471G > C/chr11:2185579 in TH. The iPSCs displayed a normal karyotype, expressed pluripotency markers, were devoid of genomically integrated episomal plasmids, and demonstrated trilineage differentiation potential in vitro.

Establishment of a human induced pluripotent stem cell line（SDQLCHi059-A）from a patient with congenital disorder of glycosylation carrying heterozygous mutation in MPI gene.

Congenital disorder of glycosylation (CDG) is inherited metabolicdiseasecaused by defects in the genes important for the process of protein and lipidglycosylation. We established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a 6-month-old boy with congenital disorder of glycosylation carrying heterozygous mutations c.1193 T > C (p.I398T) and c.376_384dup CCGCAGCAC (p.P126_H128 dupPQH) in MPI gene. This iPSC line was free of exogenous gene, expressed pluripotency markers, has normal karyotype, exhibited differentiation potential and harbored the same mutations found in the patient. This cell line will provide a reliable cell model for further studies on the potential therapeutic targets of CDG.

Generation and characterization of an induced pluripotent stem cell (iPSC) line SDQLCHi063-A from peripheral blood mononuclear cells of a patient with Maturity-onset diabetes of the young type 2 carrying GCK exon 1 deletion.

Maturity-onset diabetes of the young type 2 (MODY2) is an autosomal dominant disorder caused by mutations in the GCK gene. It is characterized by a non-progressive slight increase in glycosylated hemoglobin (HbA1c), and mildly raised fasting glucose. Here, we generated an induced pluripotent stem cell line SDQLCHi063-A from a five-year-old boy with MODY2 carrying exon 1 deletion of the GCK gene (OMIM*138079). The iPSC line carries original gene mutation, expresses pluripotency markers, has normal karyotype and differentiated spontaneously in the three germ layers.

Establishment of a non-integrated iPSC (SDQLCHi068-A) line derived from a patient with autosomal dominant immunodeficiency-14A carrying a heterozygous mutation (c.3061G>A) in PIK3CD gene.

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD) gene (OMIM#602839) encodes the p110δ catalytic subunit, mainly expressed in immune cells, and is associated with autosomal dominant immunodeficiency-14A with lymphoproliferation (IMD14A, #615513). We generated a human iPS cell line from a 50-month-old boy with IMD14A carrying a heterozygous mutation (c.3061G>A, p.E1021K) in PIK3CD gene. This cell line retains the original mutation site and shows differentiation potential towards three germ layers in vitro, which can be used as a disease model for research.

Human induced pluripotent stem cell line (SDQLCHi064-A) derived from a patient with Canavan disease carrying c.556_559dup GTTC and c.919delA mutations in the ASPA gene.

Canavan disease (CD, OMIM# 271900) is an autosomal recessive neurodegenerative disorder caused by homozygous or compound heterozygous mutations in ASPA gene, which result in catalytic deficiency of the aspartoacylase enzyme and the accumulation of N-acetylaspartic acid (NAA). Clinical presentation varies according to the age of disease onset. Here, we generated a human induced pluripotent stem cell line (hiPSCs) SDQLCHi064-A from a 5-month old boy with CD carrying two novel frame shift mutations c.556_559dupGTTC (p.L187Rfs*5) and c.919delA (p.S307Vfs*24) of the ASPA gene, in order for us to better understanding the disease.

Generation and characterization of PBMCs-derived human induced pluripotent stem cell (iPSC) line SDQLCHi055-A from a patient with NEDSDV carrying a heterozygote mutation in the CTNNB1 gene.

Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, #615075), a rare autosomal dominant genetic disorder caused by heterozygous mutation in the CTNNB1 gene, is characterized by global developmental delay, impaired intellectual development, axial hypotonia, and dysmorphic craniofacial features with microcephaly. Here, we established an iPSC line (SDQLCHi055-A) from a patient with NEDSDV carrying a heterozygote mutation (c.854 T > A, p.L285*) in the CTNNB1 gene. The iPSC line has typical iPSCs characteristics, including pluripotency and trilineage differentiation hallmarks.

An integration-free iPSC line SDQLCHi065-A from a patient with down syndrome, possessing a 47, XY,+21, inv(9)(p12q21),16qh + karyotype.

Down syndrome, a chromosomal aneuploidy genetic disorder, is primarily caused by trisomy 21 in all cells of a patient's body. In fewer cases, it can be attributed to a trisomy 21 chimera or trisomy 21 in specific cells within the body. We established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of an 8-day-old boy with Down syndrome possessing a 47, XY,+21, inv(9)(p12q21),16qh + karyotype. The iPSCs exhibited consistent karyotype, expressed markers indicative of pluripotency, lacked genomic integration of episomal plasmids, and demonstrated in vitro differentiation potential across three germ layers.

Establishment of iPS cell line (SDQLCHi061-A) from a patient with carbamoylphosphate synthetase I deficiency due to CPS1 mutation.

The induced pluripotent stem cells (iPSCs) line was generated using peripheral blood mononuclear cells (PBMCs) from a patient with compound heterozygous mutation of c.2374A > G/p.M792V and c.3949C > T/p.R1317W in the CPS1 gene by non-integrating vectors. The expression of pluripotency markers, potential for in vitro trilineage differentiation and exhibiting normal karyotype were demonstrated in the SDQLCHi061-A cell line. This cell line could provide a useful CPS1D model in vitro for further study.

Establishment of a non-integrated iPSC line (SDQLCHi043-A) from a male infant with propionic acidemia carrying compound heterozygote mutations in PCCB gene.

In this study, peripheral blood mononuclear cells were contributed from a male infant with propionic acidemia (PA) verified by clinical and genetic diagnosis, who inherited compound heterozygous mutations in the propionyl-CoA carboxylase subunit beta (PCCB) gene. Here, this iPS was generated by non-integrated episomal vectors with SOX2, BCL-XL, OCT4, C-MYC and OCT4. Also, this iPSC line exhibited the morphology of pluripotent stem cells, upward mRNA and protein expression of pluripotency markers, conspicuous in vitro differentiation potency and regular karyotype, and carried PCCB gene mutations, which provided an excellent model for the research and drug screening of PA.

Generation of a human induced pluripotent stem cell line (SDQLCHi057-A) from an Isovaleric aciduria patient carrying novel compound heterozygous mutations in the IVD gene.

Isovaleric acidemia (IVA; OMIM ID#243500) is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD). In this study, we generated a human induced pluripotent stem cell line (hiPSCs) SDQLCHi057-A from a 2-year-7-month old boy with IVA carrying two heterozygous missense mutations c.215A > G (p.N72S) and c.883A > G (p.M295V) of the IVD gene. Patient-specific hiPSCs provide a proper model for further understanding this rare disease.

Generation of an induced pluripotent stem cell line (SDQLCHi067-A) from a patient with subcortical band heterotopia harboring a heterozygous mutation in DCX gene.

Subcortical band heterotopia (SHB) is a rare severe brain developmental malformation caused by deficient neuronal migration during the development of cerebral cortex. Here, a human induced pluripotent stem cell (iPSCs) line was established from a 4-year-1-month-old girl with SHB carrying a heterozygous mutation (c.568A > G, p.K190E) in DCX. The generated iPSC line showed the ability to differentiate into three lineages in vitro and was confirmed by pluripotency markers and the original gene mutation.

[Clinical and genetic analysis of a child with Canavan disease due to compound heterozygous variants of ASPA gene].

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics for a child with Canavan disease. METHODS: A child who was admitted to the Children's Hospital Affiliated to Shandong University on April 9, 2021 for inability to uphold his head for 2 months and increased muscle tone for one week was subjected to whole exome sequencing, and candidate variants were verified by Sanger sequencing. RESULTS: Genetic testing revealed that the child has harbored compound heterozygous variants of the ASPA gene, including a paternally derived c.556_559dupGTTC (p. L187Rfs*5) and a maternally derived c.919delA (p. S307Vfs*24). Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2_Supporting+PM3). CONCLUSION: The c.556_559dupGTTC (p.L187Rfs*5) and c.919delA (p.S307Vfs*24) compound heterozygous variants of the ASPA gene probably underlay the pathogenesis of Canavan disease in this child.

Generation of an iPSC line (SDQLCHi030-A) derived from PBMCs of a patient with Lesch-Nyhan syndrome caused by HPRT1 mutation.

Lesch-Nyhan syndrome (LNS, MIM300322) is a rare inherited disorder caused by mutations in HPRT1 gene. Here we describe the generation of induced pluripotent stem cells (iPSCs) from an infected child carrying the HPRT1 mutation c.508C > T(p.R170X) by reprogramming peripheral blood mononuclear cells (PBMCs) with episomal vectors. The obtained hiPSCs exhibited normal karyotype, expressed pluripotency markers, and possessed trilineage differentiation capacity.

DCX variants in two unrelated Chinese families with subcortical band heterotopia: Two case reports and review of literature.

Introduction: Subcortical band heterotopia (SBH) is a rare brain developmental malformation caused by deficient neuronal migration during embryogenesis. Published literature on pediatric SBH cases caused by DCX mutations is limited. Methods: The detailed clinical and genetic features of two pediatric SBH with DCX mutations were analyzed. The available literature on DCX mutations was reviewed. Results: Both patients were girls with varying degrees of developmental delay. Patient 1 was short in stature with peculiar facial features. Patient 2 had an early seizure onset and developed drug-resistant epilepsy. Whole-exome sequencing (WES) revealed two de novo heterozygous variants of DCX (NM_178153.3), including a novel missense variant of c.568A > G (p.K190E) in P1 and a reported nonsense variant of c.814C > T (p.R272*) in P2. We reviewed all the available literature regarding DCX mutations. A total of 153 different mutations have been reported, with the majority of 99 (64.7 %) being missense mutations. Conclusion: Our study expanded the mutational spectrum of DCX, which has important implications for the study of genotype-phenotype correlations. Furthermore, it provided insights to better understand SBH and genetic counseling.

Establishment of human induced pluripotent stem cell line (SDQLCHi060-A) from a patient with AUTS2 syndrome carrying a heterozygous mutation in AUTS2 gene.

AUTS2 syndrome is a neurodevelopmental disorder caused by pathogenic variants and deletions of the AUTS2 gene, resulting in intellectual disability, microcephaly, and other phenotypes. Here, we generated a human induced pluripotent stem cell (iPSC) line from a 21-month-old boy with AUTS2 syndrome caused by a heterozygous mutation (c.1486C > T, p.Q496X) in the AUTS2 gene. The iPSCs had normal morphology and karyotype, expressed pluripotency markers, showed differentiation potential in vitro, and carried the AUTS2 gene mutation.