Medical Genetics Research Articles

Analysis of public perceptions on the use of artificial intelligence in genomic medicine

Abstract Purpose Next generation sequencing has led to the creation of large pools of genomic data with analysis rather than data generation now the limiting factor. Artificial intelligence (AI) may be required to optimize the benefits of these data, but little is known about how the public feels about the use of AI in genomics. Methods We conducted focus groups with members of the Australian public. Participants were recruited via social media advertisements. We explored potential uses of AI in genomic medicine, the benefits, risks, and the possible social implications of its use. Results Participants (n = 34) largely felt comfortable with AI analysing their own genomic data and generally agreed about its benefits. Concerns were raised over data security, the potential for misdiagnosis, and bias AI may perpetuate. Many participants wanted checking mechanisms for when results were generated using AI. Conclusions The insights gained from these discussions help to understand public concerns around the use of AI in genomic medicine. Our findings can help to inform both policies around genomic AI and how to educate the public on its use. Graphical abstract

Unprecedented Co-occurrence: Identification of a Pathogenic Genetic Variant in the KMT2B Gene in a Wilson Disease Patient with a Pathogenic ATP7B Mutation

The pathophysiology of dystonia in Wilson disease (WD) is complex and poorly understood. Copper accumulation in the basal ganglia, disrupts dopaminergic pathways, contributing to dystonia’s development via neurotransmitter imbalance. Despite advances in diagnosis and management, WD with dystonia remains a challenging condition to treat. We aim to report the unprecedented co-occurrence of pathogenic genetic variants in both the ATP7B and KMT2B genes in a patient with WD. A 13-year-old male presented at 12 with dysarthria and bilateral Kayser-Fleischer rings. Over months, dystonia spread to his left foot, upper limb, and trunk, accompanied by slowed daily activities. Diagnostic tests included MRI for brain structure, abdominal ultrasound for liver function, serum ceruloplasmin and copper levels to assess copper metabolism, and 24-hour urine copper tests for excretion levels. Whole exome sequencing was conducted using genomic DNA from peripheral blood samples. Variant classification followed guidelines from the American College of Medical Genetics and Genomics. The sequencing revealed compound heterozygous pathogenic variants in the ATP7B gene: NM_000053.4:c.2165dupT and NM_000053.4:c.813C>A. A pathogenic variant in the KMT2B gene, NM_014727:c.3052delA, was identified. This case highlights WD co-occurrence with ATP7B and KMT2B mutations, suggesting KMT2B as a potential genetic modifier.

Bibliometric analysis of microphthalmos and anophthalmos over 20 years: from 2004 to 2023

AIM: To conduct a bibliometric analysis of studies on microphthalmos and anophthalmos (M/A), explore research hotspots, and provide information on future research interests in this field to benefit clinicians and researchers. METHODS: Totally 751 publications related to M/A from the year 2004 to 2023 were collected from the Web of Science Core Collection database. These publications consist of both original and review articles, that are composed in English. The contributions of different countries, institutions, journals, and authors were analyzed, and network analysis was conducted by using Microsoft Excel 2021, VOSviewer, and R Studio to visualize research hotspots. RESULTS: Among all publications included, the highest number of publications came from USA (218, 29.03%). China followed with 99 publications (13.18%), and England with 86 publications (11.45%). The publications from the USA had the highest frequency of citations, with 16 699 citations, and the highest H-index of 49. The American Journal of Medical Genetics Part A (43, 5.73%) published the largest number of papers, and the University of London had the most publications (41, 5.46%). The genetic and molecular mechanisms of M/A were still unclear and the clinical intervention for M/A had gained a lot of attention as an emerging area of interest. CONCLUSION: Data have been gathered on the yearly count of published materials and citations, as well as the rise in publication trends, the efficiency of regions or countries, authors, journals, and organizations, along with the high-cited publications in M/A. The recent trend of research has shifted from genetic mechanisms to different clinical phenotypes and corresponding clinical interventions, which can give direction to future research.

Knowledge and perception of medical students on genetics in the genomic era.

The importance of medical genetics in modern healthcare underscores the urgent need for comprehensive genetics education for physicians. Such training should address both fundamental concepts and ethical considerations to bridge existing knowledge gaps and improve early diagnostic capabilities. In Latin America, the level of genetic knowledge among healthcare workers, particularly medical students, remains largely unexplored. This study evaluates the knowledge and attitudes toward genetic testing among final-year medical students at a public university in Monterrey, Mexico. Using a cross-sectional, observational, and anonymous survey design, the International Genetic Literacy and Attitudes Survey version 3 (iGLAS3) was administered from October 1, 2019, to August 16, 2020. This online survey collected demographic information, assessed genetic knowledge, and gauged opinions on genetic topics, focusing on items most relevant to our research objectives. Statistical analyses provided descriptive statistics and measures of central tendency. Of the 323 surveys distributed, 201 participants completed essential sections, revealing a moderate to high level of genetic knowledge, with an average score of 70 ± 11.5. The demographic profile included 58.7% women, 40.3% men, and 0.5% non-binary individuals, with an average participant age of 24years. A majority of participants expressed openness to genetic testing, primarily through private entities; however, significant concerns about the potential misuse of genetic data were noted. These findings underscore the necessity of enhancing genetic education and incorporating practical genetics training into medical curricula to meet the evolving challenges in this field effectively.

The genetic landscape of Lynch syndrome in the Israeli population.

Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49%). Most DCVs (125/157, 80%) were noted in one or two families only. Sixteen DCVs, each detected in ≥ 5 families, and accounted for LS in 378/588 (64%) families. Constitutional mismatch repair deficiency (CMMRD) was diagnosed in 7 families. Twenty-five carriers (2.3%) had an additional DCV or risk alleles in another cancer susceptibility gene. In conclusion, MMR gene variant distribution in Israel is diverse. MSH2 is most commonly mutated due to founder DCVs. Though the 16 prevalent LS-associated DCVs were frequently detected in our cohort, none of them is frequently reported in the general population. These data should facilitate variant interpretation, spouse and cascade testing.

Secondary findings in 443 exome sequencing data.

Exome sequencing (ES) may identify and report secondary findings that are unrelated to the primary disease for which the patient underwent genetic testing, but are of potential value in patient care. In this study, we evaluated 81 American College of Medical Genetics (ACMG) medically actionable genes in 443 patients with various neurological disorders. The variants identified were classified and reported following the 2015 ACMG Standards and Guidelines for the interpretation of sequence variants and the ACMG recommendations for reporting secondary findings (v3.2). We detected a total of 17 variants in 17 patients across 9 different genes as secondary findings. Seven heterozygous variants were found in BRCA1, MSH2, and PALB2 which are part of the cancer phenotype category. Nine heterozygous variants were found in MYH7, TTN, LDLR, DSC2, and DSP which are part of the cardiovascular phenotype category. Finally, one heterozygous variant was found in TTR which is part of the miscellaneous phenotype category. Thirteen of above mentioned variants were classified as known pathogenic and four as expected pathogenic. The information collected in our study may lead to the prevention of severe morbidity and mortality and provides additional insight into the genetic background of the Serbian population.

In Memoriam: Charis Eng MD PhD (1962–2024)

Matthew Ringel On behalf of the entire editorial team of Endocrine-Related Cancer, and personally as trainees and collaborators who at present serve as associate or senior editors of the Journal, it is with profound sadness that we write this memorial to Prof. Charis Eng, M.D., Ph.D who passed away on August 13, 2024. Prof. Eng served as Editor-in-Chief of Endocrine-Related Cancer from 2011-2021 and was dedicated to the Journal before, during, and after she served in that role. She had remarkable impact on Endocrine-Related Cancer moving the journal forward with great vision and energy while maintaining the strongest commitments to publishing the highest quality original research and reviews applying fair, ethical, and rigorous peer-review processes. Charis was a world-recognized leader in cancer genomics and clinical genetics medicine who enabled growth in Endocrine-Related Cancer in these and other areas critical for advancement of research and clinical care of endocrine cancers. She will be remembered by all of us as a superb and consequential researcher, editor, physician, leader, teacher, mentor, colleague, and friend.

Adapting to Adulthood: A Review of Transition Strategies for Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI), known as "brittle bone disease," presents a rare genetic disorder characterized by bone fragility, often accompanied by skeletal deformities and extraskeletal complications. OI is primarily associated with collagen type I defects, responsible for the syndromic nature of the disease affecting a broad range of tissues. As such, its multisystemic complexity necessitates multidisciplinary care approaches in all patient life stages. OI treatment remains largely supportive, commonly including bisphosphonates and orthopedic surgeries, which show promise in children. Although rehabilitation programs for children exist, guidelines for adult care and especially the transition from pediatric to adult care, are lagging behind in OI care and research. The current systematic review summarizes the literature on OI patient pediatric to adult care transition experiences and compares OI transition approaches to other chronic diseases. The review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic searches were conducted across multiple databases. Search terms encompassed synonyms and closely related phrases relevant to "OI" and "Transition to adult care". The initial screening involved the evaluation of article titles, followed by a thorough review of abstracts to assess relevance for the purpose of the current review. Programs aimed at easing the transition from pediatric to adult OI care necessitate a multifaceted approach. Collaborative efforts between different medical disciplines including pediatricians, endocrinologists, orthopedics, cardiology, pulmonology, ophthalmology, otolaryngologists, maxillofacial specialists, psychologists and medical genetics, are crucial for addressing the diverse needs of OI patients during this critical life phase. Comprehensive education, readiness assessments, personalized transition plans, and further follow-up are essential components of a structured transition framework. Further research is warranted to evaluate the feasibility and efficacy of sequential stepwise transition systems tailored to individuals with OI.

Characterizing and Evaluating the Structures of Combined Pediatrics and Medical Genetics and Genomics Residency Programs.

There is limited information on rationale for the current training structure within combined Pediatrics-Medical Genetics and Genomics Residency (MGG) residency programs. This study addresses the benefits and drawbacks of different training structures. Program Directors (PDs) and Associate PDs of combined Pediatrics-MGG residency programs were surveyed to evaluate perceived benefits of different structures and the relative importance of particular pediatric rotations for combined training. Programs varied in terms of how many times a typical resident transitioned between Pediatrics and MGG during training (range 4 to > 9). PDs varied in their opinions of which training structure would be most ideal for training a future Clinical Geneticist within a combined Pediatrics-MGG program. However, the majority of PDs indicated that consecutive training (completing two years of Pediatrics, followed by MGG) would support particular aims of training including continuity of patient care and research productivity. The top six out of twenty pediatric rotations that were ranked as most important in order of importance were neonatal intensive care, development and behavior pediatrics, term newborn, pediatric intensive care, neurology, and inpatient pediatric wards. Particular structures may facilitate distinct aims within training; however, there was not widespread consensus on which program structure would be best. Specific pediatric rotations were highlighted as very important, which could influence future curriculum development.

A comprehensive target panel allows to extend the genetic spectrum of neuroendocrine tumors.

Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NETs development continues to expand. Application of targeted gene panels (TGP) in next-generation sequencing (NGS) is a central strategy for elucidating novel variants associated with NETs development. In this study, we conducted comprehensive molecular-genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n=26), pheochromocytoma and paraganglioma (PPGL) (n=38), parathyroid adenoma (n=18, including three with insulinoma), and NETs of other locations (n=14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mechanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs, facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.

Exon Sequencing of HNF1β in Chinese Patients with Early-Onset Diabetes.

Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ??0 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ?? prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Abstract 4147606: The Risk of Cardiac Events Associated with Psychiatric Drugs in Patients with Long QT Syndrome.

Introduction: Long QT syndrome (LQTS) is a potentially life-threatening genetic heart disease. Patients with LQTS may also have co-existent mental health illnesses that may benefit from psychiatric medications. However, because many of these medications have QT-prolonging potential (www.crediblemeds.org), many of these patients receive suboptimal mental health care. Objective: To evaluate the frequency, management, and incidence of breakthrough cardiac events (BCEs) in patients with LQTS and concomitant mental health issues treated with psychiatric medications. Methods: A retrospective review was conducted on patients cared for in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic between 2000 and 2024 focusing on patients with LQTS and a concomitant psychiatric diagnosis requiring medication with known, possible or conditional risk of torsades de pointes (TdP). Electronic medical records were reviewed for data. BCEs were defined as LQTS-triggered syncope, seizures, appropriate ICD therapy, sudden cardiac arrest (SCA), or sudden cardiac death (SCD). Patients with missing information were excluded. Results: Overall, 195 /1899 LQTS patients [10%, 86 (43%) with LQT1, 83 (42%) with LQT2, and 16 (8%) with LQT3] had a concomitant psychiatric diagnosis requiring medication [150 female (76%), mean age at diagnosis 27 ± 18 years, median follow-up time 6.6 years (IQR 2.9-13)]. The most common psychiatric conditions were depression (71%), anxiety (62%), and ADHD (9%). The mean duration of therapy was 3.36 +/- 3.48 years and the most common medications used were fluoxetine (26%), sertraline (14%), and escitalopram (11%). There was no significant difference in QTc after starting the first psychiatric medication when compared to baseline (473 ± 33 vs 474 ± 35 ms, p=0.6). Prior to their LQTS diagnosis and while therefore untreated, 61/195 (31%) had at least 1 LQTS-associated cardiac event. This occurred in the setting of a psychiatric drug in 7 patients (11%). Following LQTS diagnosis and treatment, 14/195 patients (7%) have experienced a non-lethal BCE of which only 3/14 (21%) while on psychiatric medications. Conclusions: Although avoidance of medications with known QT-prolonging potential is prudent, attention to patient’s overall well-being besides just their LQTS must be given. After correct diagnosis and treatment, LQTS patients with concomitant mental health issues may be safely and effectively treated with medications known to prolong QTc.

Meeting abstracts from the Annual Conference "Clinical Genetics of Cancer 2023".

Meeting abstracts from the Annual Conference "Clinical Genetics of Cancer 2023".

First experiences with the introduction of genetic counselors in human genetic services in the German-speaking countries.

In 2019, the Medical University of Innsbruck introduced the first Genetic and Genomic Counseling master's program in the German-speaking countries. A major challenge of this process was the absence of practicing Genetic Counselors (GC) in these countries, leading to a lack of experience with GCs in medical genetic services and the absence of a legal framework for the profession. Consequently, student placements within the program commenced with neither the students nor their supervising consultants having any previous experience of collaborative teamwork between clinical geneticists and GCs. To share insights from the initial implementation phase, supervising consultants from the seven student placement institutes were invited to participate in semi-structured interviews guided by open-ended questions. From these interviews, three models of interprofessional teamwork between GCs and clinical geneticists emerged: (1) the alternating or tandem model, (2) qualified preliminary and follow-up patient interviews, and (3) the provision of genetic (counseling) services without genetic counseling in the legal sense. In addition, the interviewees provided recommendations for addressing legal concerns and for the effective establishment of appropriate compensation structures for GCs within the German-speaking countries. Clinical geneticists taking part in the study estimated that the integration of GCs could potentially enhance their counseling capacity by as much as 50%. Importantly, they did not foresee any reduction in counseling quality caused by the inclusion of GCs. This study provides evidence that the GC profession can provide additional skills to human genetic services and positively impact both patient support and overall capacity of genetic services also in the German-speaking countries.

SV4GD: a comprehensive structural variation database specially for genetic diseases.

Structural variations (SVs) contribute to a large extent to genomic diversity and are highly relevant for various human genetic diseases. The sensitivity and specificity of SV identification have significantly improved with the development and widespread application of high-throughput sequencing, making clinical diagnosis and treatment more accurate. Therefore, the SV4GD (Structural Variation for Genetic Diseases, https://bio-computing.hrbmu.edu.cn/SV4GD/), a manually curated database, was constructed to provide a comprehensive, standardized and user-friendly data resource for selective batch browsing, searching, downloading and comparing those genetic disease-relevant SVs. This database compiles 10 305 records of germline structural variants from 58 human neoplastic diseases and 232 non-neoplastic genetic diseases, including 2695 disease-related SVs, and other 7610 pending research SVs detected from patients. SV4GD provides a browser and search engine to query for the detailed information of SVs, human genetic diseases and the clinical information of patients, providing an easy-to-use online tool for clinical and molecular genetics research.

Psoriasis is a disease with several clinical presentations

Psoriasis is a common chronic inflammatory skin disease with several clinical subtypes. Recent discoveries in the genetics and immunology of the disease, particularly in plaque psoriasis, have revolutionised the treatment of patients with psoriasis. An understanding of the differences in genetics and immunology between different psoriasis subtypes is emerging. This review finds that the unraveling of the links between clinical presentation, genetics, immunology, treatment response, and comorbidities will allow for more individualised treatment of patients with psoriasis in the future.

Assessment of Phosphorodiamidate Morpholino Oligomer Treatment Patterns for Patients with Duchenne Muscular Dystrophy: A MarketScan Claims Analysis.

Phosphorodiamidate morpholino oligomers (PMOs), weight-based treatments administered weekly by intravenous infusion, are approved in the US for patients with Duchenne muscular dystrophy (DMD) amenable to certain exon skipping. Evidence regarding PMO treatment patterns in real-world settings is limited. This study used longitudinal administrative claims data to characterize PMO treatment patterns among US patients with DMD. MarketScan® commercial and Medicaid data (January 1, 2018-December 31, 2021) were used to identify claims for PMO treatments (eteplirsen, golodirsen, viltolarsen, casimersen). The proportion of days covered (PDC), proportion with continuous PMO claims coverage (no gaps in claims ≥ 30days), and time to subsequent PMO claims after a ≥ 30-day gap in PMO claims were described. One hundred thirty-three patients with ≥ 1 PMO claim were identified. Multiple codes were needed to identify PMO treatment coverage. Mean age was 14.1years; all patients were male. Mean continuous follow-up duration was 669.3days. Median PDC was 83.4%. Seventy-four (55.6%) patients had continuous PMO claims coverage (no ≥ 30-day gaps in claims). Of the 59 patients with ≥ 1 gap in PMO claims of ≥ 30days, 39 had ≥ 1 subsequent PMO claim. Accounting for censoring via Kaplan-Meier analysis, 75.5% had a subsequent PMO claim within 1 year after a ≥ 30-day gap, with a median time of 64days (including the qualifying 30days). Understanding treatment patterns is important for characterizing real-world utilization of precision genetic medicines. This study observed a high PDC for PMO treatments for DMD. Most patients had continuous PMO claims coverage, and most patients with a gap in PMO claims had a subsequent PMO claim. Nonetheless, the observed persistence may have been underestimated given shortcomings of claims data and payer coverage considerations. Caution should be exercised when inferring treatment effectiveness or tolerability based on observed treatment patterns from claims data alone for weight-based, infused PMO treatments.

Analysis of clinical characteristics and genetic variants in two pedigrees affected with Autosomal dominant intellectual developmental disorder 49

To explore the clinical and genetic features of two Chinese pedigrees affected with Autosomal dominant intellectual developmental disorder 49 (MRD49). Two MRD49 pedigrees which were admitted to the Children's Hospital Affiliated to Shandong University respectively on January 28, 2021 and November 10, 2022 were selected as the study subjects. Clinical data of the two pedigrees were collected and analyzed. Genomic DNA was extracted from peripheral blood samples of the probands and their family members. The probands were subjected to mutational analysis by high-throughput sequencing. Candidate variants were validated using real-time fluorescence quantitative PCR (q-PCR) or Sanger sequencing and bioinformatic analysis. This study was approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Shandong University (Ethics No. SDFE-IRB/T-2022002). Proband 1 had presented with language delay, motor retardation and intellectual disability, and his maternal grandmother, mother, aunt and cousin all had various degrees of intellectual disability. Sequencing results showed that proband 1 had deletion of exons 3 ~ 7 of the TRIP12 gene. q-PCR verification showed that his mother, aunt, maternal grandmother and cousin had all harbored the same deletion. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+PM2_Supporting+PP1). Proband 2, who had mainly presented with language delay, motor retardation and intellectual disability, and was found to harbor a heterozygous c.3010C>T (p.Arg1004*) variant of the TRIP12 gene, which was verified to be de novo in origin. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PS2+PM2_Supporting). This study had diagnosed two MRD49 families through high-throughput sequencing. Above findings have enriched the phenotypic and mutational spectrum of MRD49 in China, which has also facilitated genetic counseling for the two pedigrees.

Clinical and genetic analysis of a case of Triadin knockout syndrome due to variant of TRDN gene and a literature review

To explore the genetic etiology and clinical phenotype of a child with Triadin knockout syndrome (TKOS), and to review the relevant literature of TKOS patients due to variants of TRDN gene. A child who was admitted to the Children's Hospital of Xi'an Jiaotong University on March 19, 2023 due to sudden cardiac arrest 3 days earlier was selected as the study subject. Peripheral blood samples (2 to 3 mL) were collected from the child and her parents for the extraction of genomic DNA and whole exome sequencing (WES). Pathogenic variants were searched from databases such as the Genome Aggregation Database (gnomAD) and Online Mendelian Inheritance in Man (OMIM), and were assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was carried out for family validation of the pathogenic variants. Using keywords such as "arrhythmias" "TRDN" and "Triadin" both in Chinese and English, relevant literature on TKOS patients due to variants of the TRDN gene was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the time of literature retrieval was set from January 1, 2012 to December 1, 2023. This study has been approved by the Ethics Committee of the Affiliated Children's Hospital of Xi'an Jiaotong University (No. 20230097), and informed consent was obtained from the parents of the child. The child had experienced syncope and cardiac arrest after exercise. Electrocardiographic examination revealed QTc interval prolongation, T-wave inversion in precordial leads V1-V3, polymorphic ventricular premature beat (VPB), and ventricular tachycardia (VT) along with increased heart rate. WES and Sanger sequencing revealed that the child has harbored a homozygous c.463del(p.E155Kfs*20) variant of the TRDN gene, for which both of the parents were heterozygous. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2+PM3). The child was ultimately diagnosed with TKOS. In total 12 publications on TOKS cases caused by TRDN gene variants were retrieved, which involved 30 patients and 28 carriers of single heterozygous variant of the TRDN gene. Among the 30 TKOS patients, 20 had carried homozygous variants of the TRDN gene, and 10 had carried compound heterozygous variants, and all had exhibited significant clinical phenotype of arrhythmia, with most cases had experienced malignant arrhythmia induced by exercise and/or excitement during infancy or early childhood, leading to recurrent syncope and cardiac arrest. Of note, none of the 28 carriers of single heterozygous variant had abnormal clinical phenotype. The homozygous c.463del(p.E155Kfs20) variant of the TRDN gene probably underlay the pathogenesis of cardiac arrest in this child. Above discovery has enriched the mutational spectrum of the TRDN gene.

Genetic analysis of a pedigree affected with Intellectual disability due to variants of two different genes

To explore the genetic etiology of a pedigree with intellectual disability and explore its pathogenesis. A Chinese pedigree which had presented at the Henan Provincial People's Hospital in March 2023 was selected as the study subject. Clinical data of the pedigree were collected, along with peripheral venous blood samples from its members. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. Amniotic fluid was collected for prenatal diagnosis. This study was approved by the Medical Ethics Committee of the Henan Provincial People's Hospital (Ethics No. 2019-134). Both the proband (a 6-year-old male) and his mother (30 years old) had various degrees of intellectual and motor impairment. WES revealed that the proband has harbored a de novo heterozygous c.2563_2567dup (p.Lys856fs) variant of the UBE3A gene, while his mother, maternal grandmother and fetus had all harbored a novel heterozygous c.409+1G>A variant of the RNF13 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+PS1+PM2_Supporting; PVS1+PM2_Supporting+PP3). Based on the clinical manifestations and the result of genetic testing, the heterozygous c.2563_2567dup (p.Lys856fs) variant of the UBE3A gene probably underlay the intellectual disability and developmental delay in the proband, whilst the heterozygous c.409+1G>A variant of the RNF13 gene may underlie the intellectual disability in the proband's mother and grandmother. Above results have enabled genetic counseling and prenatal diagnosis for this pedigree.