The aetiology of childhood motor speech disorders of dysarthria and apraxia has been poorly understood. Recent evidence suggests a moderate genetic contribution for these rare and severe speech disorders. To date, however, no studies have examined genetic diagnostic yield for childhood apraxia of speech (CAS) and dysarthria in a clinical setting. Here, we used a clinically accredited genomics pipeline to investigate genetic diagnostic yield and variables predictive of a genetic diagnosis in a tertiary hospital speech clinic. A cohort of 153 children (range 2;7-16;5 years, 42 female) ascertained for motor speech disorder were assessed by a clinical geneticist and speech pathologist and underwent chromosomal microarray, Fragile X and exome sequencing. Odds ratios identified predictors of genetic diagnosis. 44/153 (29%, 15 female) had pathogenic variants (30 de novo), encompassing monogenic conditions (n = 35) and copy number variants (n = 9) across 38 distinct disorders. Delayed walking, fine and gross motor disorder, receptive language impairment and/or cognitive impairment, and dysmorphism were associated with a genetic diagnosis. The presence of CAS and dysarthria was more commonly associated with a genetic diagnosis than CAS alone. Autism spectrum disorder was less commonly associated with a genetic diagnosis. No child had a Fragile X diagnosis. The clinical genetic diagnostic yield for motor speech disorders is comparable to epilepsy and cerebral palsy, conditions where genetic testing is routine in most centres, unlike for motor speech disorders. Children with motor speech disorder with co-occurring motor, language and/or learning deficits, should be prioritised for genomic testing.

Background and ObjectivesThe highest incidence of epilepsy in childhood occurs in the first year of life. Infantile epilepsies are associated with substantial morbidity and mortality. Although most are presumed to have genetic etiologies, many infants with nonacquired epilepsy remain genetically unsolved after clinical genome sequencing. The yield of reanalysis after nondiagnostic genome sequencing in this population is unknown. We aimed to determine the diagnostic yield of comprehensive reanalysis after nondiagnostic genome sequencing in infants with unexplained epilepsy.MethodsThis cohort study included infants with unexplained epilepsy or complex febrile seizures who were recruited from 4 pediatric referral centers from September 2021 to March 2024 and had nondiagnostic clinical rapid genome sequencing. We performed comprehensive reanalysis of genome sequencing data from infants and available biological parents using multiple bioinformatics pipelines through July 2025 and clinically confirmed reanalysis findings. The primary outcome was diagnostic yield of genome sequencing reanalysis, defined as the percentage of infants who received genetic diagnoses from reanalysis. The secondary outcome was clinical utility of reanalysis findings.ResultsFrom an initial cohort of 312 infants with unexplained epilepsy who underwent clinical rapid genome sequencing, we performed comprehensive genome reanalysis in 176 infants with initially nondiagnostic results at a median age of 642 days, including 63 female patients (36%) and 30 (17%) with neonatal-onset seizures. The diagnostic yield of reanalysis was 5.1% (9/176, 95% CI 2.4%-9.5%), increasing the overall yield from 43.6% (136/312, 95% CI 38.0%-49.3%) to 46.5% (145/312, 95% CI 40.8%-52.2%). Of the new diagnoses, 6 involved variants not reported by clinical laboratories (2 single nucleotide variants, 2 structural variants, 1 tandem repeat expansion, 1 mosaic variant) and 3 involved previously reported variants of uncertain significance with new evidence. All diagnoses had clinical utility.DiscussionComprehensive reanalysis after nondiagnostic rapid genome sequencing has utility for infants with unexplained epilepsy. Our findings support implementation of reanalysis within 1-2 years after nondiagnostic genomic sequencing into routine clinical care of children with unexplained epilepsy and the expansion of clinically accredited genomic sequencing to include complex and noncoding variant detection.

Education and consent processes for genomic newborn screening (gNBS) must be informed by evidence about parental decision-making. BabyScreen+ piloted gNBS for 1000 newborns in Victoria, Australia. Prospective parents consented online with genetic counselling available on request. We aimed to explore how BabyScreen+ participants (n = 1139) made decisions about gNBS using a convergent parallel mixed methods design. Demographic (n = 1080), survey (n = 1010), and interview (n = 24) data were analysed using descriptive statistics, logistic regression, and deductive content analysis mapped to the Health Belief Model (domains indicated in italics). Most participants perceived low susceptibility of having a child with a genetic condition and found it difficult to conceptualise severity. Participants were motivated to consider gNBS due to benefits such as information about their child’s health, reassurance, and research contributions. Some perceived barriers included inequitable access to gNBS information, difficulty navigating high chance results, and potential data misuse. Most participants (987/1139, 87%) proceeded with gNBS because they believed barriers were outweighed by benefits or were manageable due to high self-efficacy. Remaining participants (152/1139, 13%) did not proceed with gNBS because benefits were unclear, or due to low self-efficacy. Experiences were modified by sociodemographic factors and the BabyScreen+ model of care. This research provides timely evidence about parental gNBS decision-making. It supports acceptability and feasibility of the BabyScreen+ model of care. Moving forward, education and consent processes must be equitable, tailored to individual context, and designed to foster self-efficacy. Such considerations will support decision-making and reduce psychological impacts for parents considering gNBS in the future.

Introduction: Genomic testing has substantial diagnostic and clinical value in nephrology, yet integrating testing into routine care requires service-level changes to ensure timely and equitable access. Methods: We conducted an observational cohort study at four tertiary centres, with a pragmatic, quasi-experimental design to evaluate evidence-informed, service-level interventions to make genomic testing more accessible and routinely embedded within nephrology practice. We implemented a ‘hub and spoke’ model which provided nephrologists with training, practical resources, and regular case-based discussions, to support test ordering and interpretation within their own clinics. Laboratory audits (June 2021-July 2024) evaluated how public reimbursement and implementation interventions influenced testing patterns. Three periods were compared: pre-funding, post-funding and post-intervention. Results: Across the study period, 1,028 genomic tests were ordered (63% adults, 37% children; median age 32 years). Results were available for 1,014 tests, with an overall diagnostic yield of 34%, which remained stable across all timepoints. The diagnostic yield was similar regardless of whether testing occurred at tertiary genomics services (249 out of 772, 32%) or via local nephrologists (92 out of 242, 38%). The number of unique providers ordering tests were higher (T1:37, T2:69, T3:87). The proportion of testing in mainstream nephrology settings rose from 23% to 74%, while absolute testing numbers in multidisciplinary clinics remained consistent over the study period. Conclusion: Mainstreaming genomic testing in nephrology was feasible, scalable and clinically effective. This model was associated with better access without compromising diagnostic yield and provides a practical framework for integrating genomic medicine into routine kidney care.

INTRODUCTION:Genomic testing has substantial diagnostic and clinical value in nephrology, yet integrating testing into routine care requires service-level changes to ensure timely and equitable access. METHODS:We conducted an observational cohort study at four tertiary centres, with a pragmatic, quasi-experimental design to evaluate evidence-informed, service-level interventions to make genomic testing more accessible and routinely embedded within nephrology practice. We implemented a 'hub and spoke' model which provided nephrologists with training, practical resources, and regular case-based discussions, to support test ordering and interpretation within their own clinics. Laboratory audits (June 2021-July 2024) evaluated how public reimbursement and implementation interventions influenced testing patterns. Three periods were compared: pre-funding, post-funding and post-intervention. RESULTS:Across the study period, 1,028 genomic tests were ordered (63% adults, 37% children; median age 32 years). Results were available for 1,014 tests, with an overall diagnostic yield of 34%, which remained stable across all timepoints. The diagnostic yield was similar regardless of whether testing occurred at tertiary genomics services (249 out of 772, 32%) or via local nephrologists (92 out of 242, 38%). The number of unique providers ordering tests were higher (T1:37, T2:69, T3:87). The proportion of testing in mainstream nephrology settings rose from 23% to 74%, while absolute testing numbers in multidisciplinary clinics remained consistent over the study period. CONCLUSION:Mainstreaming genomic testing in nephrology was feasible, scalable and clinically effective. This model was associated with better access without compromising diagnostic yield and provides a practical framework for integrating genomic medicine into routine kidney care.

Reanalysis of genomic data in rare disease is highly effective in increasing diagnostic yields but remains limited by manual approaches. Automation and optimization for high specificity will be necessary to ensure scalability, adoption and sustainability of iterative reanalysis. We developed Talos, an open-source tool that automates variant prioritization by integrating dynamically updated gene-disease and variant-level evidence with inheritance-aware filtering and validated its performance using data from 1,089 individuals with rare disease. Trio-based analysis identified 90% of known diagnoses, returning 1.3 variants per case on average. Variant burden reduced to one variant per 200 cases on iterative monthly reanalysis. Application to an unselected cohort of 4,735 undiagnosed individuals identified 241 diagnoses (5.1% yield): 78 (32%) due to new gene-disease relationships, 54 (22%) due to new variant-level evidence and 109 (45%) due to improved analysis strategies. Our automated, iterative reanalysis model demonstrates the feasibility of delivering frequent, systematic reanalysis at scale.

XRN1 encodes a highly conserved cytoplasmic 5’-3’ exoribonuclease involved in mRNA decay and quality control. It localizes to transient ribonucleoprotein aggregates, P-bodies and stress granules, where it interacts with other mRNA decay proteins and is involved in various cellular responses, including an emerging role in viral infection responses. Complete knockout of XRN1 in multicellular organisms is lethal, most likely due to its central role in mRNA homeostasis, with no prior human disease association reported. Here, we characterize seven individuals from six unrelated families with a lethal infantile form of mitochondrial cardiomyopathy caused by heterozygous de novo frameshift truncation variants clustering in the C-terminal region of XRN1 , each predicted to evade nonsense-mediated mRNA decay. Each variant results in a near-identical XRN1 C-terminal sequence predicted to alter a characterized binding domain that interacts with the mRNA decapping enhancer EDC4. Biochemical investigations of striated muscle revealed combined oxidative phosphorylation deficiencies, demonstrated by decreased respiratory chain enzyme activities, decreased proteomics abundances, and abnormal histochemical reactivities. Despite having no established mitochondrial function in mammals, clinical and molecular findings across the cohort were consistent with mitochondrial disease. The precise mechanism by which the altered XRN1 proteins cause disease remains to be elucidated.

Monoallelic variants in catalytic immunoproteasome subunits have recently been linked to proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID), yet their molecular mechanisms and clinical spectra are not fully defined. In this study, seven individuals from five unrelated families carrying five distinct monoallelic PSMB8 variants were identified. Individuals presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Additional findings included leukocyte vacuolization in blood and bone marrow. Pathogenic variants in immunoproteasome subunits were analyzed to identify structural features associated with dominant-negative behavior. Immunoproteasome assembly and activity were investigated using complexome profiling, immunoblotting, and in-gel activity assays in proband-derived fibroblasts and transfected HEK293T cells, with downstream effects assessed by proteomic and RT-qPCR analyses. Mutant PSMB8 subunits were inefficiently incorporated into immunoproteasome complexes, leading to impaired assembly, including reduced fully assembled complexes and accumulation of assembly intermediates. This defect was accompanied by activation of the integrated stress response alongside impaired immune signaling. Monoallelic pathogenic variants in PSMB8, PSMB9, and PSMB10 associated with PRAAS-ID affected residues that are highly conserved and biophysically similar between the three immunoproteasome catalytic subunits. These shared structural features may help identify additional variants with similar disruptive effects on immunoproteasome assembly. Together, our data show that monoallelic PSMB8 variants disrupt immunoproteasome assembly, resulting in clinically variable disease with immunodeficiency and systemic inflammation. Our findings support immunoproteasome assembly disruption as a unifying dominant-negative mechanism underlying PRAAS-ID.

Abstract Objective To determine whether prompt genetic diagnosis in children with KCNQ2 neonatal epilepsy enabling targeted therapy is associated with improved outcomes, and identify early predictors of developmental outcomes. Methods Thirty‐seven children with KCNQ2 neonatal epilepsy were recruited from five pediatric centers. We reviewed demographic, clinical, EEG, and genetic data. We determined differences in outcomes between individuals with prompt (greater than 30 days from seizure onset) and later genetic diagnosis, and we identified neonatal factors associated with developmental outcome. Results Baseline characteristics were similar between children with prompt (n = 6, median age at genetic diagnosis 15 days) and later (n = 31, median age 309 days, p < .05) diagnosis. All with prompt diagnosis received sodium channel blocking (SCB) anti‐seizure medication (ASM) in the neonatal period compared with 15/31 (48%) in the later diagnosis group. Children with prompt diagnosis had higher rates of seizure freedom at age 12 months than those with later diagnosis (6/6 [100%] vs. 17/31 [54%]; p .049], and lower number of emergency department representations (median 0 vs. 2), and hospital readmissions (median 0 vs. 1). Factors in the neonatal period associated with abnormal developmental outcome included neurological abnormalities (e.g., abnormal tone) and markedly abnormal neonatal EEG background (11/11 [100%] with markedly abnormal EEG vs. 11/24 [46%] with normal to moderately abnormal EEG). Significance Prompt genetic diagnosis was associated with targeted therapy, resulting in improved seizure control and reduced hospital representation. Clinical features present in the neonate assist in predicting outcome severity, which is critically important in counselling families receiving a KCNQ2 diagnosis soon after seizure onset. Plain Language Summary In KCNQ2 neonatal epilepsy, sodium channel blocking antiseizure medicines are recommended, but the benefits of starting treatment early have been uncertain. Our findings show that prompt genetic diagnosis enabled early targeted treatment, with potential to improve outcomes. Specifically, prompt genetic diagnosis was associated with improved seizure control and reduced hospital visits compared with delayed diagnosis. However, a prospective, long‐term study is needed to determine whether early treatment also improves developmental outcomes. Predicting outcome severity in newborns remains challenging, although abnormal neurological examination and markedly abnormal EEG in the newborn period were linked to abnormal developmental outcomes.

Glomerular diseases are complex conditions, many of which have a genetic basis. However, although some genetic variants can affect glomerular and thereby kidney function, not all identified variants are pathogenic. The process of evaluating genetic and experimental evidence to determine the validity of gene-disease relationships is known as gene curation, and it is critical for the identification of genes that should be examined in diagnostic tests and used to guide clinical management. Gene curation is a key role of the Clinical Genome Resource (ClinGen) and aims to ensure that the evidence underlying asserted gene-disease relationships across a range of diseases is sufficiently robust through comprehensive review of evidence and standardized evaluation by genetic and disease area-specific experts. The ClinGen Glomerulopathy Gene Curation Expert Panel has evaluated 57 gene-disease relationships from 56 genes that have been putatively linked to glomerular phenotypes. This evaluation identified 34 genes that reached a definitive level of evidence for gene-disease clinical validity. Ten genes had moderate supporting evidence and 11 had limited supporting evidence. A further two genes had insufficient evidence for any clinically valid relationship to disease. This curation establishes a comprehensive framework for the ongoing assessment of gene-disease relationships and provides a valuable reference for diagnostic genetic testing panels that target glomerular disease.

Genomic newborn screening (gNBS) provides the potential to offer significant health benefits. However, more evidence, including psychosocial impacts on parents, is needed before gNBS is ready for population-level implementation. The aim of this qualitative study was to explore parental experiences of receiving gNBS results from a prospective study, BabyScreen+. BabyScreen+ screened 1000 newborns for >600 genetic conditions that were early-onset, severe, and had management options available (prevention, surveillance or treatment). We interviewed parents three months after receiving their result. Interviews were analysed using reflexive thematic analysis, guided by Interpretive Description. Twenty-seven parents were interviewed, including nine who received a ‘high chance’ result for their newborn. Waiting for gNBS results was not unduly anxiety provoking. Low chance results provided psychosocial benefits including peace-of-mind and empowerment. Receiving a high chance result was unexpected and shocking, especially if the result was for a condition with significant treatment recommendations (e.g., transplantation). Psychosocial adaption to the subsequent diagnosis was an evolving process; access to genetic counselling, high-quality information and prompt referrals to specialists increased confidence in managing the condition and facilitated adaptation. All parents valued the high chance gNBS result given its clinical utility. The study provides support for gNBS by highlighting that it can provide valuable health information with minimal harms. Findings can be used to inform the implementation of population-scale gNBS.

Digital tools for pre-test education provision and decision support could assist the scalability of opportunistic genomic screening. We evaluated the utility of a digital platform, the Genetics Adviser (GA), for supporting parental decisions about screening for additional findings in the paediatric acute care context. Parents of children who had completed ultrarapid diagnostic genomic testing in the acute setting were offered opportunistic screening following hospital discharge. Interested participants were provided with optional access to GA and offered pre-test genetic counselling (GC). GC sessions were audio-recorded, transcribed verbatim, and participant/counsellor interactions qualitatively analysed to examine the impact of GA use on counselling sessions. Surveys were administered: prior to and after pre-test GC; 1 month after return of results. One hundred and sixty-seven families were offered genomic screening and given access to GA. Family engagement with GA was 52% (87/167) overall, with three-quarters (81/119) of those who attended genetic counselling having engaged with GA. GA use impacted genetic counselling: in consultations where not all parents used GA, more concerns were raised and more questions asked about topics included in GA; GCs also spent more time clarifying values or understanding. GA users correctly answered more knowledge questions at every survey time point. Eighty-three per cent of post-result survey respondents believed GA contained enough information for them to make decisions about opportunistic screening without additional genetic counselling. These findings demonstrate the utility of GA in supporting the scalability of opportunistic genomic screening.

Digital platforms hold promise to scale implementation of population screening. We tailored the Genetics Adviser platform to provide education, decision support, consent, and result return in a genomic newborn screening (gNBS) study, BabyScreen + . Participants were surveyed and interviewed on the usability and value of Genetics Adviser. Genetics Adviser was used by 1048 participants and 1007 (96%) provided feedback. The majority (96%, n = 963) found the platform easy to navigate, with 85% (n = 851) spending <20 min online. Participants demonstrated excellent understanding, over 80% answering at least 6/8 knowledge questions correctly. Only 7% (12/173) of participant-initiated contacts with the study team were for genetic counselling. Interview participants valued the online process. We demonstrate the successful use of a digital platform for a genomic screening program. This model is streamlined, providing consistent, user-friendly education to support decision-making with minimal input from healthcare practitioners. Further evaluation in diverse populations will be essential for future use.

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male-protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open avenues toward understanding the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

Interest in the potential of population-based genomic sequencing is growing. However, integrating a large-scale screening program into an already complex healthcare system is challenging. The implementation of gNBS needs a thorough understanding of the process. The purpose of this study is to investigate how gNBS can be integrated into the Australian health system and delivered at scale. Embedded within the BabyScreen+ study, we utilised a research design informed by process mapping and phenomenology. Fifty-one semi-structured interviews with parents (n = 33), healthcare providers (n = 15), and BabyScreen+ study team members (n = 8) were conducted. Additionally, we analysed the operational team meeting minutes. A baseline process map, developed in consultation with team members, consisted of six stages: 1. Raising awareness of the screening program; 2. Offer; 3. Participant enrolment and consent; 4. Sample collection; 5. Testing; and 6. Result disclosure and management. We recorded changes made over the study period to inform the post-implementation process map. Most changes occurred at stages: 1. Raising awareness, 4. Sample collection and 5. Testing. Lastly, a process map to inform the scale up of screening, was developed. Four key aspects of the gNBS process needing modification are: (1) growing awareness of screening amongst the public and HCPs; (2) building flexibility and accessibility into the consent process; (3) developing automation capabilities and infrastructure for large-scale sequencing and analysis, and (4) dedicated referral processes for infants who receive high-chance results. These findings demonstrate key system-level considerations and provide a foundation for implementing genomic newborn screening at scale within existing healthcare systems.

Genomic medicine is increasingly being integrated into healthcare systems worldwide, requiring a skilled genomic workforce. Variant interpretation (VI) is crucial to genomic testing, yet there are no agreed professional competencies in VI, career pathways are ill-defined for some professions, and there is limited literature on educational needs and programs. We referenced education theory and curricula from nascent local VI training activities to co-develop learning outcomes in VI with content experts that informed scalable continuing education activities, evaluated using longitudinal cross-sectional surveys. We defined 16 learning outcomes in VI covering fundamental genetics and bioinformatics theory and the stages of variant identification, curation, and classification. The education program included options for self-directed online learning or blended learning (online pre-reading plus workshops). Program reach was 951 individuals (49.2% scientists and 27.8% clinicians). At completion, the majority reported increased understanding of learning outcomes (96.1%, 171/178) and increased confidence in the processes of VI (93.3%, 166/178). The majority (91.7%, 231/252) indicated that the learnings would impact their professional role. Our education program was effective at developing entry-level proficiency in VI across different professions. The learning outcomes can inform multiple aspects of VI education and training programs, including defining the desired level of mastery and program content and aligning evaluation measures. They also provide a basis for an educational framework to inform competencies in VI across multiple professions and for career benchmarking more broadly.

The integration of genomic sequencing into newborn screening (genomic newborn screening; gNBS) has the potential to identify more presymptomatic babies who could benefit from early intervention compared to traditional universal newborn screening (NBS). Realizing these benefits requires careful navigation of ethical, legal, and social implications (ELSI) to minimize harms, promote equity, and maintain trust in NBS programs. The primary objective of this scoping review is to synthesize the ELSI discussed in the gNBS literature, to support implementation and identify knowledge gaps. A secondary objective is to characterize the landscape and contours of the gNBS field. This review, conducted in July 2025, includes academic literature addressing genomic sequencing as a first‑line NBS screen. ELSI were identified within each publication, and these informed the development of a set of decision points with ELSI dimensions within gNBS. A total of 485 publications met inclusion criteria, with the first published in 1987. The volume of publications increased over time, with growing proportions of empirical studies and work associated with gNBS projects, alongside a decreasing proportion of publications from North America. In total, 3781 ELSI considerations were charted using AI-assisted methods, relevant to 59 decision points organized into nine areas. Current scholarship is concentrated on early implementation questions, while long‑term operational needs—such as data stewardship, clinical follow‑up, and sustainable governance—remain underexplored. These gaps, together with limited contributions from many regions due to a multitude of factors, highlight the need for more diverse, empirically grounded, and forward‑looking research to support responsible decisions around gNBS.

Despite advances in sequencing technologies and variant interpretation frameworks, many variants identified in genetic testing, particularly missense variants, remain classified as variants of uncertain significance (VUS), posing ongoing challenges in diagnosis and clinical management. This review explores the ongoing challenges of VUS interpretation in clinical genomics and its impact on patients, clinicians, and healthcare systems. We summarize established strategies that support VUS resolution, including large population reference databases, data-sharing initiatives, computational prediction tools, consensus-based guidelines, deep phenotyping, and functional validation assays. Building on these foundations, we highlight emerging approaches that leverage multi-omics analyses, high-throughput experimental platforms (e.g., saturation genome editing and cell-based morphological assays), and artificial intelligence-driven tools to improve scalability and interpretive accuracy. Together, these complementary approaches aim to reduce uncertainty, increase diagnostic yield, and enhance the clinical utility of genomic testing in both research and precision medicine.