Large-scale genomic medicine implementation efforts are presenting relevant and authentic opportunities for the health workforce to learn genomics in the workplace, particularly from genomic expert colleagues or 'champions'. This paper presents novel insights on genomic experts' role and influence on learning genomics from the perspective of physicians not trained in genetics. As part of a study on workplace learning of genomics, longitudinal qualitative datasets were collected in 2021-2023 from ten non-genetics physicians working in hospitals in Victoria, Australia. Reflexive thematic analysis was used to characterise participants' perceptions of, and workplace interactions with, genomic experts. Deductive content analysis was then applied to sort and synthesise participants' relationships with genomics experts. Designated the 'Genomics Friend', these individuals are trained in genetics or recognised as same-specialty genomic champions and perceived as trusted and accessible sources of genomic expertise. Participants who had a Genomics Friend leveraged their established relationship on an ad hoc basis to address identified knowledge gaps. Sorting participants into the Genomics Friend Relationship Matrix demonstrated how having a Genomics Friend enhanced genomic workplace learning and practice for physicians across different career stages and specialties. These findings offer insights into how intra- and inter-disciplinary interactions and collegial relationships provide professional development opportunities through workplace learning. Moreover, we consider how genomic expert 'friends' could support implementation efforts by facilitating the health workforce to learn, adopt and practise genomics.

The influence of genetic factors on the prognosis of amyotrophic lateral sclerosis (ALS) has attracted considerable attention, with numerous studies exploring this relationship in clinically diagnosed patients. The present study attempted to clarify the precise impact of genetic factors on prognosis in patients with pathologically confirmed sporadic ALS. We conducted exome analysis on 137 consecutively autopsied patients with sporadic ALS exhibiting TDP-43 pathology, screening for non-synonymous or splice-site rare variants (RVs) in ALS-related genes. The impact of these variants on ALS prognosis was subsequently assessed. The exome analysis identified 31 RVs in 27 of the 137 patients, including TAF15 exon 15 insertion/deletion mutations (TAF15-15 indels) in 9 patients. Patients harboring RVs had significantly shorter survival times (median 18.0 months) than those without RVs (28.5 months), as determined by log-rank test (p = 0.02). Notably, the 9 cases with TAF15-15 indels demonstrated a significantly poorer outcome (15.0 months, p = 3e-06). Lattice Simulation of Sticker-Spacer Interactions (LASSI) simulations revealed stronger negative sticker-sticker interactions, and a tendency toward lower saturation concentration and higher dense-phase concentration in TAF15-15 indel proteins, suggesting enhanced condensation. The present analysis of pathologically diagnosed ALS patients has yielded genetic factors that could potentially aid more accurate diagnosis and prognostication. The frequent identification of TAF15-15 indels among ALS cases, and their association with significantly poorer outcome, suggests that this type of mutation could be prognostically significant in ALS. Furthermore, the mechanism by which TAF15-15 indels influence the course of ALS could be a promising target for future treatments.

Expanded carrier screening (ECS) is increasingly used in China, but implementation remains heterogeneous across regions, laboratories, and reproductive-care settings. This focused narrative review synthesizes Chinese evidence on population variation, panel design, analytical methods, variant interpretation, couple-level reproductive risk, and health-system delivery. The review was informed by a reproducible PubMed search through 29 July 2026, supplemented by targeted identification of Chinese empirical studies and professional guidance. Chinese studies demonstrate substantial variation in carrier frequencies and screening yield across populations, while reported carrier and at-risk couple (ARC) rates are strongly influenced by panel composition, analytical methods, and variant-reporting criteria, particularly the inclusion of low-penetrance variants. Technical limitations at structurally complex loci and uneven access to genetic counseling and laboratory resources further affect implementation. On this basis, we propose a review-derived conceptual framework centered on universal minimum access, core screening principles, population-informed content adaptation, separation of variant-level classification from couple-level reproductive-risk assessment, and health-system support. Regional epidemiology and founder variants may inform panel content but should not determine screening eligibility. The framework also emphasizes partner testing, counseling and referral pathways, quality assurance, reimbursement, and measurable implementation outcomes. It is intended to organize current evidence and support future consensus development rather than function as a validated clinical guideline. Prospective multicenter evaluation, stakeholder consensus, and China-specific health-economic analyses are needed before national practice recommendations can be established.

The 100,000 Genomes Project (100KGP) undertook genome sequencing of patients with rare diseases and cancer to study the role that genes play in disease, and to integrate genomics into UK healthcare. To contribute to 100KGP, the Wales Genomic Medicine Centre (a partnership between the NHS All Wales Medical Genomics Service (AWMGS), Cardiff University and Genomics England) recruited 438 individuals from 154 families that had been subject to pre-genomic genetic testing without reaching a diagnosis. The majority of probands (64%, 98/154) had neurological or neurodevelopmental phenotypes. Genome sequencing, variant calling, gene-based filtering and variant prioritisation were performed by Genomics England. AWMGS undertook clinical interpretation, validation and reporting of variants. Initial diagnostic yield was 20.8% (32/154) with variants of uncertain significance (VUS) reported for 11 more families. Most of the initial findings (83.7%, 36/43) could have been detected by clinical exome sequencing which was standard of care in Wales at the time. Reanalysis of the 100KGP Wales data using updated variant prioritisation tools, expanded gene lists, re-phenotyping and segregation studies, has increased diagnostic yield to 42.2% (65/154) (an improvement of 103%). RNA analysis was used to clarify the clinical significance of VUS in COQ4, ENPP1, GATAD2B, NCAPD2, and THOC2. These findings demonstrate the clinical utility of genome sequencing, RNA analysis, and periodic reanalysis of genomic data.

Comprehensive knowledge of cancer predisposition syndromes (CPS) is essential for the implementation of surveillance programs with proven clinical benefit. An interdisciplinary expert panel was established at our center to facilitate early identification of children with suspected CPS. This retrospective cohort study assessed the diagnostic yield and clinical impact of this consultation model. A total of 144 pediatric patients were evaluated. Clinical characteristics, family histories, and molecular diagnostic results were systematically retrieved from medical records. Of the 144 individuals, 99 presented with clinical features suggestive of CPS, of whom 53 had cancer. Clinically asymptomatic children (45/144) were referred due to positive family history. Prior to consultation, 34 of 99 symptomatic patients had been diagnosed with CPS. Among those symptomatic and undiagnosed undergoing molecular genetic testing, a disease-causing variant was identified in CPS genes in 46% (23/50). Predictive testing in asymptomatic children revealed the familial pathogenic variant in 43.8% (14/32). Nearly all patients with confirmed CPS 93,4% (71/76) received surveillance recommendations. The interdisciplinary CPS consultation model contributes to identifying hereditary cancer predisposition in pediatric patients and families. This expert-led approach emphasizes the importance of personalized surveillance strategies for rare CPS entities and provides a scalable foundation for systematic CPS assessment and development of standardized, evidence-based surveillance protocols in pediatric oncology.

Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with an HTX/laterality defect spectrum, presenting with complex CHD without extracardiac organ malposition and no evidence of PCD. Whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1 G > A, chr2:227,903,110 G > A (GRCh38)) and a paternally inherited missense variant (c.341 G > A; p.Arg114Gln, chr2: 227,893,818 G > A (GRCh38)), both classified as variants of uncertain significance under ACMG/AMP guidelines. Using Xenopus tropicalis, we show that Daw1 depletion disrupts left-right patterning, cardiac looping, and mucociliary flow, all of which are rescued by wild-type human DAW1. Functional testing of patient alleles showed notable tissue specificity: p.Arg114Gln rescued mucociliary flow but did not restore left-right patterning, while the splice-site variant resulted in a complete loss of function in both contexts. These findings closely match the proband's clinical phenotype and provide strong functional evidence to support reclassifying c.648+1 G > A as likely pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele. This study establishes functional criteria for interpreting DAW1 variants, shows how developmental context clarifies genotype-phenotype relationships, and highlights how in vivo models can support ACMG reclassification of unresolved HTX-related variants.

Decreasing DNA sequencing costs has paved the way to the use of next generation sequencing (NGS) to expand the number of conditions tested in routine newborn screening (NBS) programs. Expanding NBS programs by NGS, however, raises technical, ethical and economic concerns that are important for low-middle income countries or countries that are hesitant to use sequencing in a public health setting. qPCR-based DNA analyses have already been implemented in routine NBS programs; however, qPCR cannot be highly multiplexed. digitalMLPA (dMLPA) is a highly multiplexed probe-based DNA technique. Here, we describe the new dMLPA EZtec-MS technique that was specifically developed for use on dried blot spots (DBS) and can target up to 1200 DNA sequences representing different variant types, allowing high-throughput testing of crude DNA extracts prepared from a single DBS punch. The assay was validated using positive DNA samples and crude DNA extracts from DBS of 2069 negatively screened Philippine newborns. The EZtec-MS assay used in this study successfully detected copy number variants, (including complex genomic regions (SMN1/2, HBA1/2)), inversions (F8), methylation (imprinting diseases, Fragile X), single nucleotide variants (including ATP7B, CTNS, MT-RNR1), and low copy number sequences (TRECs for SCID, cytomegalovirus) in a single reaction in both positive DNA and crude DNA extracts from DBS. The results also demonstrated that dMLPA EZtec-MS is a high-throughput method, suitable for DBS, and has a relatively short turn-around time of 36-40 h. Our findings indicate that the dMLPA EZtec-MS technique is a promising versatile tool for DNA-based NBS programs.

PURA heterozygous microdeletions and pathogenic variants have been previously associated with neurodevelopmental disorders (NDDs), grouped into PURA-NDDs, characterized by severe neonatal hypotonia, feeding difficulties, developmental delay, intellectual disability, epilepsy, and distinctive facial features. Here we report four individuals carrying overlapping 5q31 duplications encompassing PURA, in addition to five cases from the DECIPHER database and one previously described in the literature. All patients share common features including developmental delay and mild to moderate intellectual disability. The minimal region of overlap spans 215 kb and contains only the PURA gene, suggesting PURA as the candidate gene underlying the observed phenotype. Using transcriptomic and biochemical analyses on cultured lymphocytes from one patient, we found that 5q31 duplication causes a significant upregulation of PURA mRNA and PURA protein, respectively. RNA Sequencing also revealed dysregulated expression of various genes involved in human pathology, especially in neurodevelopmental disorders characterized by intellectual disability. Using primary hippocampal neuronal cultures from mouse embryos, we demonstrated that PURA overexpression impairs neuronal morphology in vitro, inducing a reduction in dendritic arborization and in dendritic spine density. Our findings support that 5q31 duplications encompassing PURA represent a novel genomic disorder presenting with a milder phenotype than the reciprocal deletion syndrome and implicate PURA dosage dysregulation as a key contributor to the associated clinical features.

Primordial dwarfism (PD) is a genetic disorder characterized by severe intrauterine and postnatal growth failure. While some subtypes involve impaired DNA damage responses, the molecular basis of PD remains incompletely defined. We describe two siblings of non-consanguineous Indian-Jewish ancestry with a likely autosomal recessive syndrome featuring borderline intrauterine growth restriction, severe postnatal growth restriction, hypotonia, consistent dysmorphic features (elongated face, low-set ears, hypotelorism, prominent nose), hypothyroidism, late-onset insulin-dependent diabetes, borderline immune dysregulation, and recurrent pneumonia with interstitial lung disease, leading to death in adolescence. Karyotype and microarrays were normal, but cytogenetic analysis of PHA-stimulated lymphocytes revealed spontaneous chromosomal breakage and polyploidy, without hypersensitivity to cross-linking agents. Linkage analysis, whole genome sequencing, and Manta structural variant calling identified a homozygous tandem duplication within NSMCE2, NC_000008.11(NM_173685.4:c.265-11431_418+8879dup), validated by PCR and Sanger sequencing. RT-PCR of lymphoblastoid cells confirmed an aberrant transcript, predicted to cause a frameshift, premature stop codon, and loss of the SUMO domain. NSMCE2 encodes a core component of the SMC5/6 complex, essential for chromosome structure and repair. Only one prior report has linked NSMCE2 mutations to PD. Our findings determine the clinical and molecular spectrum of this severe chromosome breakage syndrome with PD, lung fibrosis, immune-endocrine abnormalities, and early lethality.

Retinoblastoma (Rb) is a rare childhood eye cancer. Almost half of cases are heritable, associated with germline RB1 pathogenic variants that pre-dispose to Rb and extraocular cancers. This study aimed to investigate the prevalence and penetrance of RB1-heritable Rb in two adult population cohorts. We screened participants with whole genome sequencing in the UK Biobank (UKB) (n = 490,413) and All of Us (AoU) (n = 317,964) cohorts for predicted loss-of-function (pLoF) and/or ClinVar pathogenic/likely pathogenic RB1 variants. Electronic health records and questionnaires were used to screen participants for Rb-associated features. In the UKB we generated a stringent and permissive phenotype category, ranging from Rb to Rb-associated extraocular cancers; in AoU we included participants with Rb or ocular cancer. A total of 21 pathogenic pLoF RB1 variants were detected in the UKB (n = 12) and AoU (n = 13) participants. In the UKB, only 25.0% (3/12) of variant carriers reported developing Rb by the age of 60, increasing to 50.0% when including ocular/extraocular cancers. Similarly, 30.8% (4/13) AoU participants developed Rb and/or ocular cancer by the age of 60. Overall, this results in a combined penetrance estimate of 28.0% (7/25). We found 21 and 28 individuals with Rb in the UKB and AoU, respectively, which is consistent with published prevalence estimates, suggesting these cohorts are not depleted of Rb cases. Notably, the penetrance of pathogenic RB1 variants in >800,000 clinically unselected adults was substantially lower than the near complete penetrance reported in clinical cohorts. This has important implications for counselling families following a positive newborn screening result.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are essential for neuronal development, synaptic organization and signaling. Defects in GPI-anchor biosynthesis or remodeling cause rare neurodevelopmental disorders, including post-GPI attachment to proteins 1 (PGAP1) deficiency. PGAP1 encodes an inositol deacylase required for GPI-anchor remodeling and appropriate trafficking and membrane localization of GPI-APs. Loss of PGAP1 function disrupts GPI-AP processing, but the clinical spectrum remains incompletely defined because reported cohorts are small. We report 15 individuals with biallelic PGAP1 variants from 11 unrelated families identified through international collaboration. Clinical information was collected using a standardized phenotyping questionnaire and review of available clinical records. The most frequently recorded features were developmental delay or intellectual disability, motor developmental delay, speech impairment, facial dysmorphism, hypotonia and seizures. Independent walking was clearly recorded in a minority of individuals, while feeding, ophthalmological, musculoskeletal and neuroimaging findings were recorded in subsets of the cohort. Clinical investigations were performed as part of routine care and were not uniform across sites. Accordingly, source-dependent assessments including MRI, EEG, EMG/NCS, formal ophthalmology, hearing assessment, systemic imaging, IQ/DQ testing, MRC scoring and anthropometric Z-scores are reported descriptively or using available-data denominators. Spasticity, hypertonia or possible peripheral nerve involvement was recorded in some clinical summaries; however, electrophysiological confirmation was not uniformly available, and confirmed peripheral neuropathy was not analyzed as a cohort-level prevalence outcome. Functional studies in selected patient-derived cells or model systems demonstrated PI-PLC resistance of GPI-APs, supporting impaired GPI-anchor remodeling. These findings expand the genotypic and recorded phenotypic spectrum of PGAP1 deficiency.