Emerging Topics in Neurogenomics: Summary From Inaugural Child Neurology Society Genetics Summit.

Cardiovascular genetics evaluation in the cardiac ICU (CICU) is essential for patient and family care. However, engaging genetic counseling (GC) consultation by frontline care teams in the CICU is challenging. This quality improvement (QI) project aimed to: 1) increase GC consultations for eligible CICU patients, 2) decrease time from admission to consultation, and 3) assess whether changes aligned with parental preferences. Single-center QI study, from January 2020 to June 2024. Large tertiary care children's hospital in the United States. Two hundred sixty-five patients with congenital heart defect (CHD). None. In 2022, we introduced a standardized admission process for admissions with CHD, including: electronic medical record (EMR) notifications, accurate diagnostics, improved referral workflow and collaboration with fetal cardiology clinic, and parent surveys. A before-vs.-after analysis showed an associated increase in GC consultation from 76% to 94%; the mean time from admission to consultation decreased from 6 to 3 days. Post-introduction, there was reduced variability and less delay compared with pre-implementation. A needs assessment survey via a parent-support group had 151 responses, which indicated that 83% of families wanted genetic testing. Sixty-nine percent of families wanted to discuss genetic testing through in-person consultation during their child's initial inpatient admission. Thirty-two percent of families preferred contact as soon as possible and 47% preferred contact before cardiac surgery. Last, 75% of parents with a fetal diagnosis of CHD expressed interest in discussing testing while pregnant. In our pre- vs. post-introduction of a QI intervention, we found that eligible CICU patients are more reliably and promptly identified for GC consultation by leveraging the EMR and partnering with CICU staff and fetal cardiology. Parents supported genetic testing, typically delivered through integrated GC consultations in both the fetal and inpatient settings.

Aymé-Gripp syndrome is an ultra-rare autosomal dominant multisystem disorder caused by pathogenic variants in the MAF gene, typically affecting the N-terminal transactivation domain. It is characterized by craniofacial dysmorphism, early-onset cataracts, sensorineural hearing loss, developmental delay or intellectual disability, and variable neurological or skeletal anomalies. Here, we report two unrelated Turkish patients harboring heterozygous MAF variants within the glycogen synthase kinase 3 recognition motif, evaluated using clinical, neuroimaging, and molecular approaches. Targeted next-generation sequencing (NGS) and parental segregation analyses by NGS and Sanger sequencing were performed, and a literature review of cases published between January 2015 and April 2026 was conducted. Both patients presented with craniofacial and neurodevelopmental features. However, one patient showed no clinically detectable ocular abnormalities or hearing impairment at the time of evaluation. The detected variant in this patient was inherited from his asymptomatic father with low-level mosaicism (16% variant allele frequency in blood and 22% in buccal mucosa), representing the first reported case suggestive of paternal germline mosaicism in Aymé-Gripp syndrome. Literature review (n = 38) revealed consistent findings of sensorineural hearing loss (94.5%), cataracts (78.3%), developmental delay/intellectual disability (100%), epilepsy (68.5%), skeletal anomalies (72.7%), and cardiac involvement (55.1%). Additional features, including non-cataract ocular abnormalities, renal involvement, dermatologic findings, and hematological manifestations, have also been reported. All variants clustered within residues 54-69 of the transactivation domain. These findings provide clinically and molecularly relevant insights into Aymé-Gripp syndrome and highlight the importance of molecular diagnosis and the detection of parental mosaicism for accurate recurrence risk assessment and genetic counseling.

A recent international case involving a sperm donor who unknowingly transmitted a pathogenic TP53 variant to numerous offspring has renewed attention to germline mosaicism and its clinical implications. This column traces the evolution of mosaicism from early clinical observations of segmental and asymmetric phenotypes to its current recognition as a common biological phenomenon. Advances in genetic technologies, including ultra-deep next-generation sequencing, have transformed the detection of mosaicism and helped clarify its biological and clinical significance. These insights have prompted important shifts in clinical thinking, as mosaicism challenges traditional assumptions about genotype-phenotype relationships, contributes to variable expressivity across disorders, and complicates genetic testing and counseling. This column also provides a foundation for a companion article in this issue, which presents clinically focused case studies illustrating different forms of mosaicism and offering practical guidance for nurse practitioners in applying these principles to patient care.

The DES gene encodes the IF (intermediate filament) protein desmin, which connects different multiprotein complexes, such as the cardiac desmosomes, and is highly important for the structural integrity of cardiomyocytes. Pathogenic DES mutations cause filament assembly defects leading to cardiomyopathies. However, most DES variants listed in genetic disease databases are currently classified as variants of unknown significance. Here, we characterized 21 different DES variants of unknown significance and 18 additional proline variants, localized in a highly conserved stretch at the C terminus of the desmin coil-2 subdomain. We inserted desmin variants via site-directed mutagenesis and investigated the filament assembly in transfected cell lines and cardiomyocytes derived from induced pluripotent stem cells by confocal microscopy. In addition, we purified recombinant wild-type and mutant desmin and analyzed the filament formation by atomic force microscopy. Coexpression with wild-type desmin delivered by adeno-associated virus was used to model the heterozygous status of cardiomyopathy patients. Twelve DES variants of unknown significance formed cytoplasmic aggregates, which were likewise verified by atomic force microscopy. Of note, these 12 variants disturb the filament assembly even when coexpressed with wild-type desmin. Using a proline screen, we showed that proline residues localized at nearly each of the positions in this stretch cause filament assembly defects. By modeling the tetrameric structure of desmin, we demonstrated that specific heptad positions, as well as positions of intramolecular and intermolecular ion bridge sites, are particularly susceptible to mutations that promote desmin aggregation. In summary, our study demonstrated that the highly conserved stretch at the C terminus of the coil-2 subdomain is a hotspot region, where several pathogenic DES mutations cause an aberrant desmin aggregation. Based on our molecular data, we suggest reclassifying the aggregate-forming variants as likely pathogenic mutations rather than variants of unknown significance. Our study may have relevance for the genetic counseling of cardiomyopathy patients with similar DES variants.

Pathogenic variants in MED13L, including copy-number changes and sequence variants, cause MED13L syndrome. This rare neurodevelopmental disorder is characterized by global developmental delay, intellectual disability (ID), distinctive facial dysmorphism, hypotonia, and variable congenital heart defects. The phenotypic heterogeneity of MED13L syndrome underscores the significance of genotype-phenotype correlation analysis for improving clinical diagnosis and precise phenotypic characterization of affected individuals. Venous blood samples anticoagulated with EDTA were collected from the patient and family members, followed by whole-exome sequencing analysis and subsequent validation using fluorescent quantitative PCR. Concurrently, a systematic search of the PubMed database was performed to summarize previously reported cases harboring MED13L copy number Variations (CNVs). Whole-exome sequencing revealed a de novo heterozygous single-copy duplication of a ~19-kb region within the MED13L gene (exons 8-16) in the proband. The patient presents phenotypic features consistent with MED13L syndrome and represents the first reported case exhibiting cleft lip. A literature review indicates that vision impairment, developmental delay, and congenital heart disease are widely observed phenotypes, while other less frequent manifestations vary between patients with duplications and deletions. This study, integrating a case report and a literature review, provides important reference evidence for the clinical genetic counseling of MED13L syndrome.

To determine if the developed Know Your Risk (KYR) intervention is similar to conventional genetic counseling; we evaluated participants' knowledge of cancer genetics, breast cancer risk perception, attitudes about genetic counseling and testing, and satisfaction with genetic counseling. Women (n = 866) who screened at elevated risk for breast cancer were randomized to the KYR intervention or conventional genetic counseling (2022-2024). The KYR intervention included a series of online pre-test educational videos, direct access to genetic testing, and patient preference for receiving post-test genetic counseling. Participants completed surveys at baseline and after genetic counseling and testing. Non-inferiority hypothesis testing compared the two participant groups. The mean knowledge score (range 0-12) increased in both study groups from a baseline mean of 6.87 (standard deviation (SD) = 2.46) to 8.66 (SD = 2.16) for the KYR intervention and 8.56 (SD = 2.14) for conventional counseling. Additionally, statistical analyses suggest the non-inferiority of the KYR intervention for participants' accuracy of their breast cancer risk, attitudes about genetic counseling and genetic testing, and satisfaction with genetic counseling compared to participants randomized to conventional genetic counseling. Findings support that the components included in the KYR intervention are non-inferior for cancer genetic knowledge, risk perception, genetic counseling and testing attitudes, and genetic counseling satisfaction among women who screen at elevated risk for breast cancer. By using the combination of components included in the KYR intervention, genetic counseling and genetic testing are more accessible, convenient, and patient-driven. ClinicalTrials.gov Identifier: NCT05325151.

Changing Referral Patterns in Paediatric Neurology: A Tertiary Outpatient Study within Brazil's Unified Health System, 2014-2024.

Mitochondrial diseases, often stemming from recessive nuclear gene mutations, represent a heterogeneous group of disorders with significant morbidity and mortality. Carrier screening for these conditions is population-specific, yet data on the pathogenic variant burden in the Iranian population remain limited. This study aimed to analyze whole-exome sequencing (WES) data from 9989 Iranian individuals to identify the spectrum and frequency of recessive mitochondrial disease variants and to develop a population-specific carrier screening panel. We analyzed WES data from 9989 unrelated Iranian individuals. Variants in 1,564 nuclear genes associated with mitochondrial function were filtered for rarity (minor allele frequency < 0.01 in public databases), predicted pathogenicity, and recessive inheritance patterns (homozygous or compound heterozygous). Clinically relevant variants were manually curated, and carrier frequencies for significant recessive mitochondrial conditions were calculated. Our analysis identified variants across 15 groups of mitochondrial-related nuclear genes in 345 individuals recognized as carriers. Of these, 123 variants (35.6%) were classified as Pathogenic, and 154 variants (44.6%) were classified as Likely Pathogenic according to ACMG guidelines. This study provides the first large-scale WES-derived assessment of recessive mitochondrial disease carrier burden in the Iranian population. The high estimated carrier rate supports implementing population-specific preconception screening. The results of this study can be used for design of targeted panels of nuclear mitochondrial genes to identify at-risk couples, facilitating genetic counseling and reproductive decision-making in Iran.

PRRT2 is associated with autosomal dominant paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE) and other diseases. To explore the phenotypic spectrum associated with PRRT2 mutations, we analyzed a patient carrying a 16p11.2 deletion including PRRT2. A retrospective analysis was conducted on the clinical and genetic characteristics of a patient with a 16p11.2 deletion containing PRRT2. A literature search was performed in CNKI, Wanfang, and PubMed from the establishment of the databases to December 2025, using the keywords "acute encephalopathy", "PRRT2", "paroxysmal non-kinesigenic dyskinesia", "ataxia", "copy number variation of chromosome 16", and "16p11.2 deletion", to identify case reports similar to the present case. This patient presented with infection-induced acute encephalopathy, acute-onset non-motor-induced movement disorders and ataxia phenotype. Genetic testing indicated a 16p11.2 deletion involving PRRT2, de novo. After immunotherapy and rehabilitation treatment, the patient achieved a favorable prognosis. Literature review identified only two complete international case reports similar to this case (specifically regarding ataxia), and genetic analysis showed that they were respectively a 16p11.2 deletion containing PRRT2 and a PRRT2 gene variation. The 16p11.2 deletion containing PRRT2 has been reported for the first time to present as an acute encephalopathy phenotype. Rare cases of paroxysmal non-motor-induced movement disorder (PNKD) and ataxia have also been reported. These findings underscore the importance of timely genetic testing and appropriate genetic counseling for patients presenting with unexplained acute encephalopathy and/or acute episodic non-motor-induced movement disorders, as well as those with ataxia symptoms.

Fabry disease(FD) is a rare X-linked lysosomal storage disorder associated with progressive multiorgan damage. Because perceptual differences between patients and clinicians regarding diagnosis and treatment can contribute to suboptimal management. We aimed to compare the perceptions of patients with FD and nephrologists in South Korea regarding the diagnostic process, treatment decisions, and genetic counseling. We conducted a cross-sectional survey enrolling 25 patients with FD, 33 patients with chronic kidney disease (without a known genetic etiology), and 27 nephrologists. The surveys assessed diagnostic testing considerations, treatment preferences, attitudes toward angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), and genetic counseling priorities. All three groups prioritized diagnostic accuracy, while both patient groups emphasized procedural concerns (e.g., pain from blood draw and blood loss risk) significantly more than clinicians. A perception gap existed regarding ACEi/ARB therapy: 92.3% of clinicians believed in its renoprotective effect, whereas only 26.1% of patients agreed to treatment without strong evidence. Both groups agreed on the importance of genetic counseling for family screening.Regarding treatment, 96% of patients and 81.5% of clinicians preferred oral over injectable enzyme replacement therapy. These significant perception gaps highlight the need for improved patient education and shared decision-making to enhance treatment adherence and clinical outcomes in FD management.

X-linked Intellectual Disability (XLID) is one of the heterogenous neurodevelopmental disorders caused by a gene defect on the X chromosome. Clinical symptoms of ID are comprised of the disability of adapting to social environments and cognitive dysfunction which is often defined by having an IQ of less than 70. Whole exome sequencing revealed a hemizygous variant c.2680G > A (p.Asp894Asn) in IQSEC2 in the proband, further validated by Sanger sequencing. Subsequently, the three-dimensional structures of the wild and mutated type (Asp894Asn) IQSEC2 were deduced by structural bioinformatics approaches in order to compare the structural changes in both the structures. Molecular dynamics simulations revealed that the D894N mutation significantly destabilizes the protein structure, as reflected by increased backbone RMSD, elevated residue-level fluctuations (RMSF), and altered intramolecular interactions, collectively leading to enhanced conformational variability in the mutant protein compared with the wild type. The results obtained from this study will pave the way for early diagnosis, genetic counseling, and better therapeutic interventions.

The scope of preimplantation genetic testing for monogenic disorders (PGT-M) in Japan, initially limited to severe childhood-onset diseases, appears to be expanding following the 2022 revision of the Japan Society of Obstetrics and Gynecology's definition of "severity." This study examines the impact of this definitional change on the acceptability of PGT-M by comparing attitudes of Japanese genetic professionals before and after the revision, focusing on three childhood-onset cancer predisposition syndromes: Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and neurofibromatosis type 1 (NF1). A two-phase survey was conducted in 2019-2020 and 2024 among clinical genetic specialists supervisors and certified genetic counselors. The survey explored views on PGT-M acceptability, the concept of "selection of life," awareness of the revised severity definition, and background factors influencing opinions. Among 382 respondents, LFS was most frequently judged acceptable for PGT-M, followed by FAP and NF1. Between the two phases, "unacceptable" responses declined, while "neither" increased. Those viewing PGT-M as "selection of life" were more likely to oppose it (r=-.293, p<.01). Genetic professionals in the pediatric field were more likely to consider PGT-M unacceptable (r=-.22, p<.01). These findings suggest that clinical experience, ethical perceptions, and institutional guidelines shape professional attitudes toward PGT-M. These findings have implications for genetic counseling practice and policy discussions surrounding the evolving scope of PGT-M. Ongoing dialogue and education are essential as eligibility criteria and societal values continue to evolve.

Workers in the textile dyeing industry are occupationally exposed to high concentrations of particulates and volatile organic compounds (VOCs). This work aimed to study the environment-gene interaction as a risk factor for rheumatoid arthritis in textile dyeing workers. This cross-sectional comparative study included 140 exposed male workers and 130 matched control workers. Air monitoring of chemical air pollutants in the workplace was conducted for 12 months. Estimation of anti-CCP, CRP, RF, ANA antibodies, and the CYP2E1 and GST genes polymorphisms was studied in both groups. High air concentrations of PM10, SO2, H2S, and VOCs were detected in the preparatory and dyeing sections compared to the printing section. Anti-CCP, CRP, RF, and ANA were statistically higher in exposed workers compared to the control group. Anti-CCP and RF in preparatory workers were significantly higher compared to printing workers. Multivariate analysis revealed interaction in CYP2E1, GST polymorphism and different environmental exposures on RF. The environment-gene interaction of the elevation of PM10 and VOCs concentrations in the dyeing section, with the CYP2E1 (C2/C2 mutant genotype) and the GST (M1 polymorphism), could be a risk factor for RF elevation in the workers from the dyeing section compared to the other two sections. The key recommendations include improving environmental control in the workplace, ensuring the proper use of personal protective equipment (PPE), conducting pre-employment screening for genetic susceptibility through genetic counseling for CYP2E1 and GST polymorphisms, and providing regular medical follow-up for workers carrying the CYP2E1 (C2/C2) genotype and the GST (M1) allele.

Increasing Familial Retinoblastoma in High-Income Countries Despite Stable Overall Incidence, 2017-2024.

Screening for pathogenic variants associated with hereditary cancer syndromes has a positive impact on public health by identifying patients at risk of developing the associated cancers. This survey assesses the current practice of screening for hereditary cancer syndromes and the acceptability of chatbot utilization among primary care providers and residents in rural Southwest Virginia. A two part survey was conducted among primary care providers and residents in rural Southwest Virginia to assess demographics, health practices, genetic screening practices, and interest in chatbot technology in a geographically underserved population. The response rate for the provider and resident surveys were 8.9% and 19.9% respectively. A total of 66 providers responded to the survey. One third (32.3%) of providers in our study never screen for hereditary cancer syndromes and almost two thirds (63.1%) screen their patients for cancer syndromes less than half the time. About (77%) of providers felt chat bots would be useful in identifying patients who need testing and directing what testing to order. Surveys of 476 residential responders showed (81.9%) of residents felt that chatbot technology sounds somewhat to very useful for genetic screening and counseling. Over (57%) of residents noted they would feel comfortable with utilizing chatbot technology to discuss results of genetic screening. Residents and their providers in geographically underserved populations are interested in using chatbots to improve access to genetic testing. Implementation of technology, such as chatbots, in these under resourced settings has the potential to amplify access to genetic counseling and testing.

Telemedicine has broadened access to genetic counseling while maintaining high levels of patient satisfaction. However, emerging evidence suggests lower completion rates of genetic testing following virtual visits compared with in-person encounters. This study evaluated genetic testing completion rates among patients who underwent cancer risk assessment via telemedicine and assessed the effect of a structured follow-up telephone reminder on genetic testing completion. We conducted a retrospective review of a quality improvement initiative - Genetic Engagement via Navigation and Encouragement (GENE CALL) - designed to address incomplete genetic testing following telemedicine counseling. The study included all patients who underwent virtual cancer risk assessment between September 2023 and July 2024 at a single urban academic cancer genetics program. Patients who expressed interest in genetic testing but had not scheduled specimen collection were contacted by telephone as a reminder. During the call, patients were asked about ongoing interest in testing and barriers to scheduling; they were also offered assistance completing specimen collection. Among 647 patients evaluated via telemedicine, 469 (72.5%) expressed interest in genetic testing. Of these, 290 (61.8%) had scheduled or completed testing, while 179 (38.2%) had not. Among those who had not scheduled testing, 120 (67.0%) were successfully reached by telephone, and 98 (81.7%) confirmed ongoing interest in completing testing. At 3-month follow-up, 48 (40.0%) of the 120 contacted patients had completed testing, compared with 13 (22.0%) of 59 patients who were not reached (p = 0.017). Telephone follow-up is an effective strategy to improve genetic testing completion after virtual counseling.

This study aimed to identify disease-related genetic variants in 41 patients with retinitis pigmentosa (RP) and to evaluate their phenotypic effects on the retina and choroid. Patients diagnosed with RP underwent targeted next-generation sequencing of RP-related genes and mitochondrial DNA analysis, with genetic counseling. Variants were classified according to ACMG guidelines. Central macular thickness (CMT), retinal nerve fiber layer thickness (RNFLT), subfoveal choroidal thickness (SfCT), foveal avascular zone area (FAZa), ellipsoid zone (EZ) integrity, and vascular density (VD) in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) were assessed using OCT and OCTA. Patients were classified into three groups: Group 1 (USH2A; n = 11), Group 2 (other single-gene variants; n = 21), and Group 3 (multiple-gene variants; n = 9). There were no significant differences in age, sex, consanguinity, symptom onset, disease duration, best-corrected visual acuity, intraocular pressure, RNFLT, or EZ integrity. Pairwise comparisons showed a higher preserved EZ rate in Group 2 (66.7%) than in Group 3 (4.8%, p = 0.020). Mean SfCT was lower in Group 3 (147.9 ± 107.7μm) than in Group 2 (243.9 ± 26.3μm, p = 0.046). SCP and DCP FAZa and VD did not differ significantly; inferior-quadrant CC VD was lower in Group 3 than in Groups 1 and 2 (p ≤ 0.01). RP patients harboring more than one variant showed reduced preserved EZ, SfCT, and inferior-quadrant CC VD compared to patients with a single variant. These findings require further investigation in larger cohorts, together with functional studies, to clarify their clinical and biological significance.

This study aims to screen for genetic variants associated with premature ovarian insufficiency (POI) in a Chinese Miao pedigree. The proband underwent whole exome sequencing (WES), and the extracted data were subjected to bioinformatics analysis using the Rare Disease Data Center (RDDC) splicing tool to identify potential genetic causes in the lineage. Sanger sequencing was employed to confirm the variants in the family, and minigene assays were used to analyze how the FIGLA variant affects pre-mRNA splicing. A novel heterozygous intronic and POI-associated variant in the FIGLA gene (c.385-9G>A) was identified. Splice prediction analysis showed that this variant may disrupt splicing patterns. This result was supported by the outcome of minigene assays, which revealed that the variant led to aberrant splicing of FIGLA introns. As a result, retention of a 7-bp intronic sequence from intron 2 was found in the mature mRNA. The FIGLA variant (c.385-9G>A) disrupts mRNA splicing in cells and may contribute to POI in this pedigree. Therefore, our results expand the variant spectrum of the FIGLA gene, provide valuable insights into the pathogenesis of POI for genetic counseling, and may assist clinicians in the early diagnosis of women with infertility.

Protein S deficiency (PSD) markedly increases cerebral venous sinus thrombosis (CVST) risk; although global PROS1 variant data are extensive, Chinese reports remain limited. To characterize the genetic and clinical phenotypes of a family with hereditary PSD presenting as CVST, and to preliminarily explore underlying molecular pathogenesis. Clinical and coagulation data were collected from the proband and family members. CVST was confirmed by magnetic resonance venography (MRV). The coding region of PROS1 gene was sequenced, and the pathogenicity, evolutionary conservation, and functional impact of identified variant was evaluated using bioinformatics tools and Pymol software. The thrombin generation assay (TGA) was used to preliminarily assess the proband's thrombin generation capacity. The proband exhibited reduced PS activity (PS: A, 59%), along with decreased total and free PS antigen levels. Similar reductions were observed in her father, two sisters, and two nephews. MRV revealed extensive CVST. Genetic sequencing identified a heterozygous missense variant c.886A > C (p.Lys296Gln) in exon 9 of the PROS1 gene in all affected individuals. The variant was classified as variant of uncertain significance. It resides in highly conserved region, altering local hydrophilicity and hydrogen bond interactions and likely impairing PS function. The TGA results indicated that the proband's thrombin generation capacity was significantly increased. This study reports a PROS1-related CVST case in which inherited variant acted synergistically with modifiable prothrombotic risk factors. The findings underscore the importance of comprehensive etiological screening in unexplained thrombosis and support familial genetic counseling and surveillance for early prevention.