Pheochromocytoma/Paraganglioma Syndrome Type 1 Presenting with Atypical Symptoms and a Novel Pathogenic Variant in the SDHD Gene: A Case Report.

This case report presents a 10-year-old patient diagnosed with pheochromocytoma/paraganglioma syndrome type 1 (PPGL1), underlined by a novel heterozygous pathogenic variant (c.154_161del, p.ser52Profster14) in the SDHD gene. Initially, the patient manifested symptoms unusual for pheochromocytoma, including polyuria and polydipsia; however, further diagnostic investigations revealed a pheochromocytoma (PCC) tumor in the adrenal gland. Subsequently, whole exome sequencing (WES) test identified a pathogenic frameshift variant in the SDHD gene, strongly suggestive of PPGL1. This study highlights the importance of considering atypical symptoms in diagnosing rare pediatric pheochromocytoma/paraganglioma tumors and underscores the value of genetic testing in identifying underlying genetic causes, thereby facilitating personalized management of the condition.

A sensorineural hearing loss harboring novel compound heterozygous variant in the TRIOBP gene: A case report.

Background: Autosomal recessive non-syndromic deafness-28 (DFNB28; OMIM #609823) specifically refers to prelingual sensorineural hearing loss (SNHL) resulting from homozygous or compound heterozygous mutations in the TRIO- and F-actin-binding protein, TRIOBP gene. In this report, we present a pediatric patient exhibiting novel compound heterozygous deleterious variants in the TRIOBP gene. Methods: The auditory brainstem response result revealed both left- and right-sided deafness with a threshold of 20 dB normal hearing level in the proband. A comprehensive trio whole exome sequencing (WES) using the Celemics G-Mendeliome Whole Exome Sequencing Panel was employed. Results: The WES analysis revealed compound heterozygous TRIOBP variants in the proband, namely c.1192_1195delCAACinsT/p.Gln398* classified as pathogenic and c.3661C > T/p.Arg1221Trp categorized as a variant of uncertain significance according to American College of Medical Genetics and Genomics guidelines. These variants are considered the most probable cause of the proband's SNHL. Conclusion: TRIOBP isoforms are predominantly expressed in the inner ear, contributing to the formation of stereocilia rootlets. Further investigations are required to fully understand the phenotypic variability and establish the pathogenicity of the identified variant in relation to the TRIOBP gene and SNHL.

Somatic and germline mutations in endometrial cancer.

Endometrial cancer is a complex disease influenced by both somatic and germline mutations. While individual mutations in genes such as PTEN, PIK3CA, and members of the DNA mismatch repair (MMR) system have been extensively studied, comprehensive analyses comparing somatic and germline mutations within the same cohort are limited. This study compares these mutations using whole exome sequencing (WES) data from tumor and blood samples in patients with endometrial cancer. Thirteen female patients with histologically confirmed endometrial cancer were selected. Tumor tissues and matched blood samples were collected and subjected to WES at the CeGaT laboratory, followed by bioinformatics analysis and annotation using the Geneyx platform. WES revealed significant somatic and germline DNA mutations, with key pathogenic variants identified in genes such as PTEN, PIK3CA, TP53, MLH1, and MSH2. Comparative analysis showed distinct and overlapping mutation profiles, highlighting the importance of integrating somatic and germline data in endometrial cancer research.

Severe Invasive Infections Linked to Novel IRAK2 Immune Variants.

In subjects with peculiar susceptibility to severe infections by common pyogenic bacteria, mutations of interleukin-1 receptor-associated kinase proteins (IRAK)1 and IRAK4 had been identified. The IRAK kinases function as downstream signal transductors following activation of pathogen recognition receptors. In 2 patients with sequential or repeated invasive infections: herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and Streptococcus pneumoniae bacteremia with candidemia respectively, novel mutations of IRAK2 were identified. These mutations compromised the capacity to ubiquinate (or functionally modify) the signal adaptor tumor necrosis factor receptor-associated factor 6 (TRAF6). The result is impairment of the cytokine TNF-alpha production. This susceptibility to a varied range of pathogens underlines a potential central role played by IRAK2 in mediating host defense in infectious diseases.

Wiskott-Aldrich Syndrome: A Report of a Rare X-Linked Disorder.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disorder marked by eczema, thrombocytopenia, and immunodeficiency. The associated immune dysregulation increases the risk of autoimmune disorders and lymphoid malignancies. WAS results from mutations in the WAS protein gene on the short arm of the X chromosome. Here, we present the case of a seven-month-old male, born to non-consanguineous parents with no significant birth or family history. The child had height, weight, and head circumference below the third percentile for age and presented with recurrent mild upper respiratory infections, mild eczema, and thrombocytopenia. Despite symptomatic treatment and clinical improvement, platelet counts continued to decline. A provisional diagnosis of immune thrombocytopenia was made, and intravenous immunoglobulin was administered, which halted the downward trend but did not improve platelet counts. Autoimmune testing revealed strong positivity for antinuclear antibodies (ANA). Given the early-onset thrombocytopenia, anemia, and failure to thrive, autoimmune lymphoproliferative syndrome was suspected. However, T cell subset analysis was normal. A bone marrow biopsy suggested myelodysplastic syndrome or myeloproliferative neoplasm, but molecular studies were negative. Due to the early-onset autoimmunity and strongly positive ANA, genetic testing via whole exome sequencing confirmed the diagnosis of WAS.

Clinical sequencing reveals diagnostic, therapeutic, and prognostic biomarkers for adult-type diffuse gliomas.

Diffuse gliomas in adults are highly infiltrative and largely incurable. Whole exome sequencing (WES) has been demonstrated very useful in genetic analysis. Here WES was performed to characterize genomic landscape of adult-type diffuse gliomas to discover the diagnostic, therapeutic and prognostic biomarkers. Somatic and germline variants of 66 patients with adult-type diffuse gliomas were detected by WES based on the next-generation sequencing. TCGA and CGGA datasets were included to analyze the integrated diagnosis and prognosis. Among 66 patients, the diagnosis of 9 cases was changed, in which 8 cases of astrocytoma were corrected into IDH-wildtype glioblastoma (GBM), and 1 oligodendroglioma without 1p/19q co-deletion into astrocytoma. The distribution of mutations including ATRX/TP53 differed in three cohorts. The genetic mutations in GBM mainly concentrated on the cell cycle, PI3K and RTK pathways. The mutational landscape of astrocytoma was more similar to that of GBM, with the highest frequency in germline variants. Patients with IDH-mutant astrocytoma harboring SNVs of PIK3CA and PIK3R1 showed a significantly worse overall survival (OS) than wild-type patients. AEBP1 amplification was associated with shorter OS in GBM. Our study suggests that clinical sequencing can recapitulate previous findings, which may provide a powerful approach to discover diagnostic, therapeutic and prognostic markers for precision medicine in adult-type diffuse gliomas.

Case report: Whole exome sequencing reveals a novel splicing variant of ANKRD17 gene in a Chinese male juvenile with developmental delay and transient tic disorder.

Background: The Ankyrin Repeat Domain Containing Protein 17 (ANKRD17, OMIM:615929) gene is a protein-coding gene associated with diseases such as Chopra-Amiel-Gordon Syndrome and Non-Specific Syndromic Intellectual Disability. The protein encoded by ANKRD17 gene belongs to the ankyrin repeat-containing protein family, which is one of the most widely existing protein domains that exclusively mediate protein-protein interactions. To date, the research and reports on the ANKRD17 gene are limited. Case presentation: Trio whole exome sequencing (Trio-WES) was conducted on the proband and his unaffected parents to elucidate the genetic etiology in the proband, who was clinically diagnosed with developmental delay and other phenotypes. Subsequently, Sanger sequencing was employed for validation of the identified candidate variant. Furthermore, RNA analysis was utilized to ascertain the impact of the variant on splicing. The WES revealed a novel heterozygous ANKRD17 splicing variant (c.7248 + 1G>A) in the proband, but not detected in his unaffected parents. And the presence of the splicing variant of the ANKRD17 gene was valided by the Sanger sequencing subsequently. And the RNA analysis confirmed that the novel variant was predicted to result in loss of donor splice site, and the analysis at mRNA level confirmed that it leads to exon 32 skipping (r.7100_7278del179) and causes premature termination of translation to the protein (p.D2357fs), therefore is classified as pathogenic. Conclusion: Our study reported a novel splicing variant in ANKRD17 gene, which may be associated with partial eating, frequent urination, and tic syndrome. This finding expands both the phenotypic and genotypic spectrum of ANKRD17 gene. Although there is currently no curative therapy available for ANKRD17 gene variants, a definitive diagnosis of its genetic etiology is significant for genetic counseling and family planning purposes. Furthermore, this is the first reported case of the ANKRD17 gene in China.

HAPLN3 p.T34A contributes to incomplete penetrance of moyamoya disease in Chinese carrying RNF213 p.R4810K.

BACKGROUND AND PURPOSE: The penetrance of the RNF213 p.R4810K, a founder mutation of moyamoya disease (MMD), is estimated to be only 1/150-1/300. However, the factors affecting its penetrance remain unclear. Therefore, our study aims to identify modifier genes associated with the incomplete penetrance of this founder mutation. METHODS: Whole-exome sequencing (WES) was performed on 36 participants, including 22 MMD patients and 14 non-MMD controls with RNF213 p.R4810K mutation. Fisher's exact test was used to assess the presence of genetic variants that differed significantly between MMD patients and non-MMD controls. In order to exclude false-positive results, another 55 carriers were included to perform Fisher's exact test for the selected sites in the WES discovery stage. Subsequently, human brain microvascular endothelial cells were transfected with wild-type and mutant HAPLN3 for tube formation assays and western blotting to explore the impact of candidate genes on angiogenesis. RESULTS: Analysis of variants from WES data revealed a total of 12 non-synonymous variants. Through bioinformatics analysis, the focus was on the HAPLN3 p.T34A variant with a significant p value of 0.00731 in Fisher's exact test. Validation through Sanger sequencing confirmed the presence of this variant in the WES data. In vitro experiments revealed that silencing HAPLN3 and transfecting HAPLN3 p.T34A significantly enhanced tube formation and increased the relative protein expression of vascular endothelial growth factor in endothelial cells. CONCLUSIONS: These results suggest that HAPLN3 may function as a modifier gene of RNF213 p.R4810K, promoting the development of MMD and contributing to the incomplete penetrance of MMD founder mutations.

Comprehensive genetic analysis for identification of monogenic disorders and selection of appropriate treatments in pediatric patients with persistent thrombocytopenia.

Persistent thrombocytopenia is caused by various diseases, including immune thrombocytopenia, inherited thrombocytopenia, and inherited bone marrow failure syndromes. Considering the large number of genes responsible for inherited disorders, comprehensive genetic analysis is required to diagnose monogenic disorders. In this study, we enrolled 53 pediatric patients with persistent thrombocytopenia exhibiting visually small or normal-sized platelets. We performed whole-exome sequencing, including 56 genes responsible for inherited thrombocytopenia, and evaluated clinical parameters according to disease type. Among 53 patients, 12 patients (22.6%) were diagnosed with monogenic disorders. Nine patients had a family history of thrombocytopenia. Pathogenic or novel variants of genes responsible for inherited thrombocytopenia were identified in three and six patients, respectively. The variants in genes for inherited thrombocytopenia with large or giant platelets were unexpectedly identified in six patients. Pathogenic variants in genes for inherited bone marrow failure syndromes with systemic features were identified in three patients with atypical symptoms. Since the definitive diagnostic methods for immune thrombocytopenia are limited, and a substantial number of patients with inherited thrombocytopenia are at a high risk of developing malignancies, comprehensive genetic analysis is indispensable for selecting appropriate therapies, avoidance of unnecessary treatments for immune thrombocytopenia, and long-term follow-up of patients with inherited thrombocytopenia.

Utility of exome sequencing in primary spermatogenic disorders: From research to diagnostics.

BACKGROUND: Primary spermatogenic disorders represent a severe form of male infertility whereby sperm production is impaired due to testicular dysfunction, leading to reduced quality or quantity of spermatozoa. Gene-centered research has certainly demonstrated the importance of the genetic factor in the etiology of both poor sperm morphology or motility and reduced sperm count. In the last decade, next-generation sequencing has expanded the research to whole exome which has transformed our understanding of male infertility genetics, but uncertainty persists in its diagnostic yield, especially in large unrelated populations. OBJECTIVE: To evaluate the utility of exome sequencing in detecting genetic factors contributing to various traits of primary spermatogenic disorders, which is a crucial step before interpreting the diagnostic yield of the platform. MATERIALS AND METHODS: We manually curated 415 manuscripts and included 19 research studies that predominantly performed whole exome sequencing in cohorts of unrelated cases with primary spermatogenic defects. RESULTS: The detection rate, defined as the fraction of cases with an identifiable genetic cause, typically remained below 25% for quantitative defects of spermatozoa, whereas improved rates were observed for traits of abnormal sperm morphology/motility and in populations enriched with consanguineous families. Unlike the quantitative defects, the genetic architecture of the qualitative issues of spermatozoa featured a small number of recurrent genes describing a large fraction of studied cases. These observations were also in line with the lower biological complexity of the pathways affected by the reported genes. DISCUSSION AND CONCLUSIONS: This review demonstrates the variability in detection rates of exome sequencing across semen phenotypes, which may have an impact on the expectations of the diagnostic yield in the clinical setting.

A novel PAX9 variant in a Chinese family with non-syndromic oligodontia and genotype-phenotype analysis of PAX9variants.

OBJECTIVES: This study aimed to identifyPAX9variants in non-syndromic tooth agenesis families of China, as well as to analyze the genotype⁃phenotype of non-syndromic tooth agenesis caused by PAX9variants, which can provide a basis for the genetic diagnosis of tooth agenesis. METHODS: We collected the data of 44 patients with non-syndromic oligodontia who underwent treatment at Stomatological Hospital of Hebei Medical University between 2018 and 2023. Whole-exome sequencing was performed on the peripheral blood of the proband and its core family members, and the variants were verified by Sanger sequencing. Pathogenicity analysis and function prediction of the variants were performed using bioinformatics tools. The correlation between the genotype of PAX9 variant and its corresponding phenotype was examined by reviewing 55 publications retrieved from PubMed. The studies involved 232 tooth agenesis patients with PAX9 variants. RESULTS: A novel PAX9 c.447delG (p.Pro150Argfs*62) and a reported PAX9 c.406C>T (p.Gln136*) were identified in two Chinese families. Through bioinformatics analysis and three-dimensional structural modeling, we postulated that the frameshift variant was pathogenic. The outcome was the premature cessation of PAX9 protein, which caused severe structural and functional deficiencies. Summarizing the PAX9 genotype-phenotype relationship revealed that patients carrying the PAX9 variant commonly led to loss of the second molars. CONCLUSIONS: We identified the novel PAX9 c.447delG (p.Pro150Argfs*62) in a Chinese family of non-syndromic oligodontia, expanding the known variant spectrum of PAX9. The most susceptible tooth position for PAX9 variants of tooth agenesis was the second molars and the deciduous molars during the deciduous dentition.

Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects.

Pediatric intestinal pseudo-obstruction (PIPO) is a rare congenital disorder of the enteric nervous system with distal colon aganglionosis potentially leading to intestinal obstruction. Recently, biallelic variants in KIF26A, encoding a crucial motor protein for the migration and differentiation of enteric neural crest cells, have been associated with a neurodevelopmental condition featuring cortical defects and PIPO-like features, though in absence of aganglionosis. So far, only 10 patients have been reported. In this study, we investigated three subjects with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction megacolon syndrome. Brain MRI revealed malformations within cortical dysplasia spectrum, including polymicrogyria and heterotopia. Pathology study of the intestine revealed aganglionosis and elevated acetylcholinesterase activity in parasympathetic nerve fibers. Through trio-exome sequencing (ES), we detected four novel biallelic KIF26A variants, including two missense changes (#1) and two distinct homozygous truncating variants in (#2 and #3). All variants are rare and predicted to be deleterious according to in silico tools. To characterize the impact of the missense variants, we performed 3D protein modeling using Alphafold3 and YASARA. Mutants exhibited increased energy scores compared to wild-type protein, supporting a significant structural destabilization of the protein. Our study expands the genotype and phenotype spectrum of the emerging KIF26A-related disorder.

SF3B2 Haploinsufficiency Associated With Hirschprung Disease and Complex Cardiac Defect Without Craniofacial Microsomia.

Haploinsufficiency of SF3B2 is associated with craniofacial microsomia, characterized by mandibular hypoplasia and microtia, often with preauricular tags or pits, epibulbar dermoids, and cleft palate. In addition, extracraniofacial anomalies may be present, such as skeletal, cardiac renal, and abnormalities of the central nervous system. Variants have been either de novo or inherited, and both inter- and intrafamilial variability has been observed. Here we describe a patient referred for exome sequencing for a complex congenital heart defect and Hirschsprung disease found by exome sequencing to be heterozygous for a loss of function variant, c.945dup (p.Val316SerfsTer5), in SF3B2. This variant was inherited from a parent with an isolated cardiac defect. Interestingly, neither have the defining craniofacial features or other dysmorphisms. This report further illustrates the degree of phenotypic variability seen in SF3B2-related disease and expands the spectrum to include Hirschsprung disease.

Comprehensive Analysis of Juvenile Nasopharyngeal Angiofibromas via Whole-Exome Sequencing.

INTRODUCTION: The molecular basis and mechanisms of juvenile nasopharyngeal angiofibromas (JNA) pathogenesis are still unknown. Despite being a rare and benign neoplasm, JNA is a locally aggressive and potentially destructive head and neck neoplasm, typically found in young males. The advancement of genome technologies and analytical tools has provided an unparalleled opportunity to explore the intricacy of JNA. The present study provides the first evidence of the involvement of Y-chromosome genes in JNA. METHODS: A total of 13 JNA patients at an advanced disease stage and five age-matched male controls were registered for this study. Whole-exome sequencing (WES) analysis was conducted followed by functional analysis to understand the molecular mechanism of the JNA. RESULTS: WES analysis revealed a high prevalence of mutations in 14 genes within the protein-coding, male-specific region of the Y-chromosome of young males (mean age: 13.8 ± 2.4) with JNA. These mutations, occurring at 28 distinct positions, were characterized as moderate to high impact and were prevalent in nine JNA patients but not in the control group. The most frequently mutated genes were USP9Y and UTY, followed by KDM5D, DDX3Y, and TSPY4. The expression of USP9Y, UTY, and DDX3Y was found to be co-modulated, implying their coordinated regulation as a complex. Furthermore, somatic mutations were detected in genes previously linked to JNA. CONCLUSION: The wide array of genetic mutations in the Y-chromosome male-specific region, along with the somatic alterations identified in JNA, provides novel insights into JNA pathophysiology.

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN SIZE DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS SETTING METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTERESTS: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Whole exome sequencing in relapsed or refractory childhood cancer: case series.

Background: The prognosis for relapsed or refractory childhood cancer is approximately 20%. Genetic alterations are one of the significant contributing factors to the prognosis of patients. Objective: To investigate the molecular profile of relapsed or refractory childhood cancers in Thai cases. Methods: The study design is a descriptive study of patients <18 years old, suspected or diagnosed of relapsed or refractory childhood cancer who underwent whole exome sequencing (WES). Results: WES was successfully performed in both the tumor and the blood or saliva samples obtained from 4 unrelated patients. Six different variants were identified in the NCOR2, COL6A3, TP53, and SMAD4 genes. These alterations were found to be associated with tumor aggressiveness. Conclusion: This study is the first one to demonstrate genetic alterations by using WES in relapsed or refractory childhood cancer in Thai cases.

Identification of a novel FERMT1 variant causing kindler syndrome and a review of the clinical and molecular genetic features in Chinese patients.

Background: Kindler Syndrome (KS, OMIM #173650), a rare autosomal recessive genetic disorder, is characterized by a spectrum of symptoms such as cutaneous fragility, blistering, photosensitivity, and mucosal involvement. These symptoms result from variations in the FERMT1 gene (Fermitin family member 1, OMIM: 607900), encoding kindlin-1, an essential component of focal adhesions. Objective: This study aims to ascertain the potential pathogenicity of a FERMT1 variant identified in a Chinese patient and to explore the phenotypic and molecular genetic characteristics of all reported cases of Kindler Syndrome in the Chinese population. Methods: Whole-exome sequencing (WES) was performed on the patient to identify candidate variants associated with KS, and Sanger sequencing was utilized to authenticate their presence and origin. To further assess the potential impact of these genetic variants, we employed a variety of in silico prediction tools. Concurrently, a review of various databases was undertaken to ascertain and consolidate information regarding cases of KS in Chinese families. Results: We identified a novel likely pathogenic frameshift variant in the FERMT1 gene, specifically c.567_579delTATATATGACCCC (p.Ile190Serfs*10). The clinical presentation of this patient aligns with the diagnostic criteria for KS. The literature review reveals that the core clinical features of KS reported in the Chinese population include skin abnormalities (100%), as well as hyperkeratosis of the palms and soles (91.70%). Other clinical phenotypes encompass nail abnormalities (77.78%), abnormalities of the fingers/toes (75.00%), oral damage (70.00%), eye abnormalities (57.14%), and constipation (50.00%). Conclusion: Our study enriches the genetic landscape of KS in the Chinese population and augments the understanding of phenotypic variability resulting from FERMT1 gene variants. The findings hold considerable significance for refining variant-based screening, genetic diagnosis, and comprehending the molecular pathogenesis underlying FERMT1-related disorders.

Ketogenic diet effectiveness is superior for drug resistant epilepsy with causative genetic mutation than those without genetic etiology.

AIM: Epilepsy with genetic etiology is high prevalence of DRE, which is reported responsive to ketogenic diet therapy (KDT). Our retrospective cohort study attempted to investigate the KD responsiveness between DRE with genetic and non-genetic etiology. METHOD: Non-fasting gradual KD initiation protocol (GRAD-KD) and five-day diet program was implemented. Participants were categorized into genetic epilepsy or non-genetic epilepsy groups based on genetic tests. Monthly seizure frequencies and seizure reduction rate after KDT 3 months and 6 months were compared between two groups. RESULTS: Forty-six patients with genetic epilepsy and ninety-four patients with non-genetic epilepsy were recruited. Among 46 patients with genetic epilepsy, 12 patients withdrew from diet before 3 months of KDT, and 7 patients withdrew from diet before 6 months of KDT, thus, 27 patients retained the diet. Among 94 patients with non-genetic epilepsy, 20 patients withdrew from diet before 3 months of KDT, and 21 patients withdrew from diet before 6 months of KDT, 53 patients retained the diet. For the 46 patients with genetic epilepsy, 12 patients had pathogenic variants related to developmental and epileptic encephalopathy (DEE), whereas other 34 patients had disease-causing variants other than DEE. The mean monthly seizure frequencies showed significantly decreased both in patient with genetic-and non-genetic epilepsy after 6 months of KDT, however, the seizure reduction rate was significantly higher in patients with genetic epilepsy than patients with non-genetic epilepsy after 6 months of KDT. In addition, our data demonstrated that KDT could significantly reduce seizure burden in patients with non-DEE than patients with DEE. In addition, the patients with non-DEE significantly achieved greater seizure reduction rate than patients with DEE after 6 months of KDT. INTERPRETATION: Our data highlighted that KD effectiveness is more outstanding in decreasing seizure burdens for epileptic patients with genetic etiology than those without causative gene mutation. Additionally, KDT is also significantly effective for decreasing more seizure burdens for non-DEE patients than for DEE patients. We suggested epileptic patients caused by genetic mutation should implement KDT as early as possible.

Molecular diagnostic yield of exome sequencing in a Chinese cohort of 512 fetuses with anomalies.

BACKGROUND: Currently, whole exome sequencing has been performed as a helpful complement in the prenatal setting in case of fetal anomalies. However, data on its clinical utility remain limited in practice. Herein, we reported our data of fetal exome sequencing in a cohort of 512 trios to evaluate its diagnostic yield. METHODS: In this retrospective cohort study, the couples performing prenatal exome sequencing were enrolled. Fetal phenotype was classified according to ultrasound and magnetic resonance imaging findings. Genetic variants were analyzed based on a phenotype-driven followed by genotype-driven approach in all trios. RESULTS: A total of 97 diagnostic variants in 65 genes were identified in 69 fetuses, with an average detection rate of 13.48%. Skeletal and renal system were the most frequently affected organs referred for whole exome sequencing, with the highest diagnostic rates. Among them, short femur and kidney cyst were the most common phenotype. Fetal growth restriction was the most frequently observed phenotype with a low detection rate (4.3%). Exome sequencing had limited value in isolated increased nuchal translucency and chest anomalies. CONCLUSIONS: This study provides our data on the detection rate of whole exome sequencing in fetal anomalies in a large cohort. It contributes to the expanding of phenotypic and genotypic spectrum.

Clinical Characteristics, Genetic Analysis, and Literature Review of Cornelia de Lange Syndrome Type 4 Associated With a RAD21 Variant.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is an uncommon congenital developmental disorder distinguished by intellectual disorder and distinctive facial characteristics, with a minority of cases attributed to RAD21 variants. METHODS: A patient was admitted to the endocrinology department at Peking Union Medical College Hospital, where 2 mL of peripheral venous blood was collected from the patient and his parents. DNA was extracted for whole-exome sequencing (WES) analysis, and the genetic variation of the parents was confirmed through Sanger sequencing. RESULTS: A 13.3-year-old male patient with a height of 136.5 cm (-3.5 SDS) and a weight of 28.4 kg (-3.1 SDS) was found to have typical craniofacial features. WES revealed a pathogenic variant c.1143G>A (p.Trp381*) in the RAD21 gene. He was diagnosed with CdLS type 4 (OMIM #614701). We reviewed 36 patients with CdLS related to RAD21 gene variants reported worldwide from May 2012 to March 2024. Patient's variant status, clinical characteristics, and rhGH treatment response were summarized. Frameshift variants constituted the predominant variant type, representing 36% (13/36) of cases. Clinical features included verbal developmental delay and intellectual disorder observed in 94% of patients. CONCLUSION: This study reported the third case of CdLS type 4 in China caused by a RAD21 gene variant, enriching the genetic mutational spectrum.