The potential integration of whole genome sequencing (WGS) into the UK newborn screening programme (NBS) represents a major advancement in population health genomics. Multiple studies have assessed professionals' opinion...The potential integration of whole genome sequencing (WGS) into the UK newborn screening programme (NBS) represents a major advancement in population health genomics. Multiple studies have assessed professionals' opinions on the healthcare system's readiness for this change. Parental and public views are under-represented and limited regional and national assessments have been undertaken. This study systematically reviews qualitative literature exploring public and parental views of genomic newborn screening (gNBS) to identify potential barriers and enablers of its uptake. Using thematic synthesis of seventeen studies from five countries, key themes emerged around preconceptions about individual's benefits and costs of engaging and assumptions about the design of gNBS services. Participants generally recognised the benefits of early diagnosis and medical intervention but expressed concerns about psychological impacts, data privacy, and the scope of screened conditions. Views were shaped by limited public understanding of genomics, with misconceptions potentially influencing consent decisions. This research highlights a preference for flexible, tiered screening options and the importance of inclusive, multimodal communication strategies delivered pre- and perinatally by trusted healthcare professionals. Equitable access and robust privacy protections were identified as critical for public trust. These findings underscore the importance of co-designing gNBS implementation with stakeholders to ensure informed, voluntary participation and maximise public health benefits. This systematic review informs policymakers and healthcare providers about public attitudes, which are essential for shaping ethically responsible and socially acceptable genomic screening programmes.
Spinal muscular atrophy (SMA) is a rare autosomal recessive condition caused by biallelic loss of the SMN1 gene that results in severe lower motor neuron degeneration in childhood. Targeted pre-symptomatic treatments hav...Spinal muscular atrophy (SMA) is a rare autosomal recessive condition caused by biallelic loss of the SMN1 gene that results in severe lower motor neuron degeneration in childhood. Targeted pre-symptomatic treatments have been shown to dramatically improve outcomes, supporting the inclusion of SMA in newborn screening programmes. However, ~95% of infantile-onset cases are caused by homozygous deletions of exon 7-8 of the SMN1 gene, which is challenging to detect using short-read next-generation DNA sequencing technology due to the high sequence similarity between SMN1 and its nearby paralog SMN2. Here, we evaluate the performance of an SMN-specific variant caller in ~490,000 adults with whole-genome sequence data in UK Biobank. We also perform a phenome-wide association study (PheWAS) of 4782 diseases and traits for SMN1 deletion carriers. We show that the SMNCopyNumberCaller performs extremely well, identifying 8856 (1.8%) heterozygous carriers and just two (0.0004%) individuals with homozygous SMN1 deletions, of whom one had been diagnosed with SMN1-SMA. From the PheWAS, we found novel associations between SMN1/2 copy number and the level of several circulating proteins encoded or regulated by genes near the SMN locus, further validating the accuracy of the caller. Our results suggest that using a specialist variant caller can accurately determine SMN1/2 copy number from short-read DNA sequencing technology, achieving a very high specificity (~100%) for homozygous SMN1 deletions. The number of false positive results for SMN1-SMA is therefore likely to be extremely low when using short-read whole-genome sequencing at a population level.
De Wachter M, van der Lei MB, Decleve A
… +31 more, De Man K, Elinck E, Schoonjans AS, Gouy E, Januel L, Monin P, Labalme A, Shillington A, Goel H, Taylor JP, Neas K, Koolen DA, Lecoquierre F, Goldenberg A, Brunet T, Brugger M, Luo M, Krygier M, Mazurkiewicz-Bełdzińska M, Degoutin M, Beneteau C, Goizet C, Weaver DD, Farrow EG, Lee A, Gadea RN, Ceulemans B, de Witte PAM, Copmans D, Jansen AC, Kooy RF
CMIP, a c-maf inducing protein that plays a key role in cytoskeletal remodeling, neuronal migration and synaptic formation, was first associated with specific language impairment and autism through the identification of...CMIP, a c-maf inducing protein that plays a key role in cytoskeletal remodeling, neuronal migration and synaptic formation, was first associated with specific language impairment and autism through the identification of a deletion in a single patient in 2012. Since then, only two additional individuals with CMIP deletions have been reported, both sharing features of autism and gastrointestinal features. However, a firm causal relationship between variants in CMIP and neurodevelopmental disorders has not yet been established. In this multicentre cohort study, we identified 25 individuals, from 17 unrelated families, with CMIP-related neurodevelopmental disorders, 22 of whom have not been previously reported. Of these, seven individuals carried heterozygous loss-of-function CMIP single-nucleotide variants, while the other 18 individuals had a complete or partial deletion of CMIP, some involving adjacent genes. The clinical phenotype was variable with a high prevalence of developmental delay (20/25), autism spectrum disorder features (13/25), attention-deficit/hyperactivity disorder features (11/25) and other psychiatric disorders (15/25). Epilepsy was present in nine individuals (9/25), of whom three had therapy-resistant seizures. To study the pathogenicity of CMIP variants, a cmip mutant zebrafish model carrying a premature stop codon was investigated. These mutants showed temperature-dependent altered locomotor activity suggestive of seizure-like behavior, which was confirmed by spontaneous epileptiform discharges in cmip mutant zebrafish larvae. Our patient cohort and the zebrafish data establish CMIP as a gene implicated in neurodevelopmental and neuropsychiatric disorders. We recommend inclusion of CMIP in the genetic work-up of neurodevelopmental delay, with or without autism or psychiatric disorders and epilepsy.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterised by bone fragility and frequent fractures. While current treatments aim to preserve bone mass, there is no cure. Boost Brittle Bones Before Birth (BOOS...Osteogenesis imperfecta (OI) is a rare genetic disorder characterised by bone fragility and frequent fractures. While current treatments aim to preserve bone mass, there is no cure. Boost Brittle Bones Before Birth (BOOSTB4) is an international clinical trial investigating postnatal (n = 15) and prenatal plus postnatal (n = 3) infusions of fetal mesenchymal stem cells as a potential treatment for severe OI. Each BOOSTB4 participant received four stem cell doses at four-month intervals. Here we explore the experiences of parents and of healthcare professionals involved in BOOSTB4. In this qualitative study, one or both parents of children participating in BOOSTB4 took part after the second dose (T1: 16 families, 22 participants) and at least 6 months after the final dose (T2: 12 families, 16 participants). Professionals delivering BOOSTB4 participated in one interview (n = 13). Data were analysed using codebook thematic analysis. Decisions to participate in the trial were influenced by the potential for improved prognosis and limited alternative therapies. Parents felt reassurance because they were taking action and gratitude for access to expertise in OI. Balancing hope, expectations and uncertainty around treatment efficacy was challenging. Parents also expressed disappointment and uncertainty about treatment ending. Practical challenges included travel for treatment with a child with OI or late in pregnancy. Professionals noted the difficulty in managing parental expectations and the regulatory and logistical barriers of an international trial. Findings emphasised the need for clear communication before, during and after the trial, transparent information and trial designs that accommodate the needs of individual families.
Reproductive genetic carrier screening (RGCS) is increasingly available and publicly funded in some jurisdictions. There is a pressing need for user-centric resources to support decision-making. We conducted a scoping re...Reproductive genetic carrier screening (RGCS) is increasingly available and publicly funded in some jurisdictions. There is a pressing need for user-centric resources to support decision-making. We conducted a scoping review using the Joanna Briggs Institute framework with the aim of mapping studies published between 2014 and 2025 examining individual and reproductive couple perspectives on RGCS. Searches were conducted in Medline, Embase, PubMed and Web of Science. Studies were categorised by design and descriptive characteristics. Eighty-nine studies were included. Research documented motivations for accepting or declining RGCS and the interplay of systemic, structural and personal factors related to decision-making. Investigation of educational needs emphasized moving beyond clinical framing to reflect experiential knowledge. Multiple touchpoints were identified across the service implementation pathway, revealing opportunities for fit-for-purpose resource integration; and perspectives from those with experiential knowledge of genetic conditions added unique insights. However, population diversity was low, with limited research from rural, regional and/or remote locations, diverse family structures, people with intellectual disability or neurodiversity and cultural and linguistically diverse communities. This review maps individual and reproductive couple perspectives on RGCS and offers six expert recommendations for resource development. A key call to action is to engage priority populations in future RGCS research to avoid deepening health inequities.
Genomic newborn screening (gNBS) has the potential to generate information that remains relevant across the lifespan, yet little is known about how families who have directly experienced gNBS, understand its long-term ro...Genomic newborn screening (gNBS) has the potential to generate information that remains relevant across the lifespan, yet little is known about how families who have directly experienced gNBS, understand its long-term role and value. This study analysed the results of eight focus groups with 32 parents whose children had received findings from gNBS (through the BabyScreen+ study, a population-based Australian gNBS pilot programme), to explore how they conceptualise the use of genomic information beyond infancy (which we refer to as extended genomic sequencing, or eGS). Parents described a complex interplay of factors including treatability, severity, certainty, and personal capacity to manage information that shaped their desire to receive results. Using the Health Belief Model as a lens, we show how parental reflections mapped to constructs such as perceived benefits, barriers, severity, susceptibility, self-efficacy, and cues to action. However, parents' reasoning was dynamic rather than static, illustrating how shifts in clinical options or family circumstances influence decision making over time. Overall, our findings demonstrate that families view gNBS data as a potential lifetime resource and support the need for flexible consent pathways, ongoing counselling, and governance frameworks that anticipate both the benefits and burdens of genomic information. This work offers timely insights to inform ethical implementation of eGS in Australia and contributes to international discussions about integrating genomic sequencing into population-level screening.
Chaurasia A, Shukla A, Pande S
… +23 more, Purushothama G, Ashokan AK, Majethia P, Kaur N, Upadhyai P, Quadri N, Bhavani GS, Narayanan DL, Nayak SS, Nampoothiri S, Sabir AH, Mohammed AA, Shaw S, Hartill VL, Watson CM, Johnson CA, Alshammari A, Fry AE, Poulter JA, Newman WG, Kasher PR, Banka S, Girisha KM
Systematic analysis of copy number variants (CNVs) in large datasets is challenging, and there are limited studies of homozygous copy number losses in rare disease exomes. Here, we leveraged the genomic uniqueness and re...Systematic analysis of copy number variants (CNVs) in large datasets is challenging, and there are limited studies of homozygous copy number losses in rare disease exomes. Here, we leveraged the genomic uniqueness and relative under-representation of the Indian population in the current public genomic databases and identified 42,386 possible homozygous losses (median 20 per individual) in a heterogeneous cohort of 2021 individuals with suspected Mendelian disorders, who had undergone exome sequencing using 12 different capture kits in a resource-limited setting. Employing a genomic position loss-count-based approach, we filtered 1224 rare homozygous loss calls in 718 individuals (median 1 per individual) for further analysis, thus significantly reducing the analysis burden. Clinical correlation and validation of these rare calls enabled 10 new diagnoses in 240 unsolved individuals. This led to a two-fold increase in diagnosis owing to homozygous deletions. Further analysis of the data and identification of additional affected individuals through collaboration led to identification of biallelic FILIP1 and FAM177A1 variants as causes of a syndromic arthrogryposis and a neuromuscular disorder respectively. Both conditions were recently reported as ultra-rare recessive disorders, thus validating our approach. We also show that biallelic loss-of-function TFCP2L1 variants cause chronic kidney disease and VPS36 variants cause a severe recessive neurodevelopmental disorder characterised by microcephaly, motor delay, agenesis of the corpus callosum, cerebellar atrophy, seizures, hypotonia, spasticity and early death. Overall, these results demonstrate a scalable approach to screen homozygous losses for improving diagnostic yield and discovering disease-genes in large exome cohorts.
High-throughput genome and exome sequencing have uncovered numerous intronic variants in disease genes, yet predicting their impact on pre-mRNA splicing is still challenging. While deep learning tools have improved varia...High-throughput genome and exome sequencing have uncovered numerous intronic variants in disease genes, yet predicting their impact on pre-mRNA splicing is still challenging. While deep learning tools have improved variant prioritization, their ability to detect atypical regulatory mechanisms remains unknown. We combined predictions from multiple complementary splicing prediction tools with functional RNA studies to evaluate the splicing consequences of intronic variants identified in patients with neurodegenerative diseases. Nine intronic variants with uncertain impact on splicing were selected, including six deep-intronic variants, two non-canonical splice-site variants, and one canonical splice-site variant associated with an atypical phenotype. Three variants were predicted to disrupt a donor splice site, five to create a cryptic donor splice site, and one was located close to a putative acceptor site. Transcript analysis in blood revealed splicing abnormalities in eight of the nine cases. All algorithms failed at least once: deep learning tools missed specific donor site losses or cryptic splice-site activation events, while motif-based approaches failed to predict some donor site activation or generated false-positive predictions. The only variant not directly located in a splice site was predicted to activate a deep intronic splicing enhancer. Motif-based tools suggested the creation of an SRSF2 protein-dependent enhancer. Functional studies based on minigene assays support a role for SRSF2 in promoting pseudoexon inclusion. These findings highlight the complementarity of splicing prediction tools and the need to integrate them into diagnostic pipelines, with transcript-level confirmation remaining critical for accurate pathogenicity assessment.
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 con...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.
The long-term psychosocial outcomes of reproductive genetic carrier screening (RGCS) have yet to be adequately quantified. We examined long-term psychosocial outcomes of RGCS within the Australian Reproductive Genetic Ca...The long-term psychosocial outcomes of reproductive genetic carrier screening (RGCS) have yet to be adequately quantified. We examined long-term psychosocial outcomes of RGCS within the Australian Reproductive Genetic Carrier Screening Project ('Mackenzie's Mission'), where 9107 reproductive couples had RGCS for ~1300 genes and 175 (1.9%) received a new increased chance result. We administered a survey at approximately three to five years (mean = 3.7) post-result, capturing attitudes toward the result, state anxiety (using the STAI-6) and decision regret for all participants, plus empowerment and decisional conflict for participants with an increased chance result. Using STAI-6 data from previous surveys, we used linear mixed models to examine change in state anxiety over time. Participants with a low chance result (n = 2512) had low state anxiety, minimal decision regret and felt reassured by their result. For participants with an increased chance result (n = 86), increased state anxiety after result disclosure gradually decreased, almost returning to baseline by 3-5 years post-result. This group also had high empowerment, minimal decision regret, low decisional conflict regarding reproductive choices and positive attitudes about the utility of their increased chance result. Predictors of clinically meaningful state anxiety at 3-5 years post-result were: having an increased chance result, higher trait anxiety and having a child with a medical condition/disability. Findings highlight that large-panel RGCS is valuable for reproductive planning. Elevated state anxiety after increased chance result disclosure aligns with other reproductive genetic screening and decreases over time. It is important that RGCS programmes provide appropriate, longitudinal psychosocial support to promote the reproductive empowerment of all who participate.
Nathan V, Akbar H, McInerney-Leo A
… +8 more, Gilroy D, Henders A, Naresh R, Choudhury N, Waqar M, Shah S, Yanes T, South Asian Genes and Health in Australia (SAGHA) research team
Komatsu K, Sugie A, Nitta Y
… +11 more, Osaka J, Mansoor Hussain UH, Kubota M, Shimozawa N, Carter MT, J G Zwijnenburg P, Waisfisz Q, Boschann F, Horn D, Nakashima M, Saitsu H
Pathogenic variants of genes encoding initiation factors can cause neurological diseases, including neurodevelopmental disorders and brain abnormalities. The eukaryotic translation initiation factor 1 A, X-linked (EIF1AX...Pathogenic variants of genes encoding initiation factors can cause neurological diseases, including neurodevelopmental disorders and brain abnormalities. The eukaryotic translation initiation factor 1 A, X-linked (EIF1AX) is a gene located at Xp22.12 that plays an important role in the regulation of translation initiation. Here, we identified de novo hemizygous EIF1AX variants in male individuals with neurodevelopmental disorders and explored their possible involvement in these neurological disorders. We performed trio-based exome or whole genome sequencing in four families. The pathogenicity of EIF1AX variants was evaluated using a molecular dynamic simulation and transgenic Drosophila models. We identified four de novo hemizygous EIF1AX variants in four male individuals with variable neurodevelopmental delay, dysmorphic features, behavioral problems, ophthalmological abnormalities, and structural abnormalities in the brain. One variant was predicted to cause a splicing alteration, and minigene analysis confirmed exon skipping leading to the generation of a premature termination codon. In transgenic Drosophila harboring wild-type (WT) EIF1AX or the three other EIF1AX missense variants, overexpression of WT and the p.(Asn17Asp) variant caused structural abnormalities in the compound eye, whereas the p.(Lys64Glu) and p.(Asp90Gly) variants significantly reduced these eye abnormalities. In addition, WT overexpression resulted in significant axonal toxicity in the Drosophila optic nerve, causing a significant reduction in the number of axons, whereas all mutants showed only a mild reduction in axonal number. Our findings indicated that all variants resulted in different degrees of EIF1AX loss-of-function. Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males.
Solanes-Cabús A, Castillo-Manzano C, Rofes P
… +15 more, Pérez-Marco S, Isach J, Oñate G, Teruel I, Crous-Bou M, Lleuger-Pujol R, Salinas M, de Cid R, Del Valle J, Feliubadaló L, Portela G, Navarro M, Brunet J, Comas D, Lázaro C
We hypothesized that the BRCA1 c.68_69del variant is highly prevalent among individuals with Roma ancestry from Spain due to a founder effect, as in the Ashkenazi Jewish population, where targeted screening has proven to...We hypothesized that the BRCA1 c.68_69del variant is highly prevalent among individuals with Roma ancestry from Spain due to a founder effect, as in the Ashkenazi Jewish population, where targeted screening has proven to be cost-effective. We conducted two cross-sectional prevalence studies in self-reported Roma adults from a community-based and a nationwide sample. To assess variant origin, we reconstructed haplotypes in carriers with Roma, Indian, Ashkenazi Jewish and European ancestry, and compared haplotype sharing and mutation-age estimates. BRCA1 c.68_69del variant was detected in 3.6% (16/440) of the community-based Roma sample and 0.8% (2/258) of the nationwide Roma sample. Roma carriers shared extended haplotypes (1.4-16.9 Mb) with carriers of presumed European and Ashkenazi Jewish ancestry, supporting a common founder, whereas minimal overlap (65 kb) with the Indian-ancestry carrier suggested an independent origin, despite the Roma population's Indian origin. Mutation-age estimates were 925 years ago in non-Roma carriers and 600 years ago in Roma carriers. Shared haplotypes support an Iberian founder later enriched in Roma, likely leading to a high prevalence of BRCA1 c.68_69del in Spanish Roma and supporting targeted genetic screening within this community.
Kim Y, Jang J, Ryu KS
… +16 more, Chae JH, Ko JM, Kim MJ, Lee S, Moon J, Lee JS, Lee H, Cho SI, Chae SW, Lim H, Lim H, Sung H, Youn S, Lee H, Lee JS, Seong MW
Global developmental delay (GDD) and intellectual disability (ID) are frequently caused by genetic factors, yet many patients remain undiagnosed even after whole exome sequencing (WES). This study aimed to apply Optical...Global developmental delay (GDD) and intellectual disability (ID) are frequently caused by genetic factors, yet many patients remain undiagnosed even after whole exome sequencing (WES). This study aimed to apply Optical Genome Mapping (OGM) and Illumina Complete Long Reads (ICLR) in pediatric patients with unexplained GDD/ID after WES and propose a practical diagnostic strategy for clinical implementation. We conducted OGM and ICLR on 87 pediatric patients with unexplained GDD/ID despite prior WES. Discordant cases underwent further validation using gap-PCR or PacBio long-read sequencing. A minigene assay was also performed to confirm the pathogenicity of an intronic variant. Of the 87 patients, 6 were found to carry pathogenic or likely pathogenic variants, including 4 structural variants (SVs) and 2 single nucleotide variants (SNVs). OGM and ICLR provided additional diagnostic yields of 4.71% and 6.98%. OGM was effective in detecting complex rearrangements, whereas ICLR performed well in cases with overlapping structural variants. For all SV burden, ICLR detected 8 SVs (mean 0.09 ± 0.33 per sample), and OGM identified 8 SVs (mean 0.09 ± 0.29 per sample), showing comparable results. This study demonstrates the complementary utility of ICLR and OGM in detecting diverse classes of pathogenic variants in GDD/ID. ICLR was advantageous for detecting non-coding SNVs, as well as for providing accurate breakpoint resolution in SVs, while OGM was effective for complex rearrangements and repetitive regions. These findings support a stepwise diagnostic strategy in which ICLR may be considered as an early second-tier test for WES-negative GDD/ID cases.
While prostate cancer (PrCa) is highly heritable, the genes associated with PrCa survival after diagnosis remain poorly understood. We aimed to identify genes associated with PrCa-specific survival through transcriptome-...While prostate cancer (PrCa) is highly heritable, the genes associated with PrCa survival after diagnosis remain poorly understood. We aimed to identify genes associated with PrCa-specific survival through transcriptome-wide association studies (TWAS) using genetic predictors of gene expression in the prostate. We used the Transcriptome-Integrated Genetic Association Resource (TIGAR) to train expression prediction models separately using normal prostate, primary tumor, and metastatic tumor tissues. We performed TWAS using these models in data from the Malmö Diet and Cancer (MDC) study (discovery) and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (validation). We identified and validated seven genes associated with PrCa-specific survival at a common locus on chromosome 1. We found two genes using prediction models from normal prostate tissues and five with models from metastatic tumor tissues. Elevated RCC1 expression is linked to a shorter time to biochemical recurrence, while higher PHACTR4 expression was observed in tumors with a higher Gleason grade. The study is limited to European ancestry and can only show associations. Further research across other populations and experiments to establish causality will be needed. Our multi-tissue study identified novel genes associated with PrCa survival, particularly RCC1 and PHACTR4, providing new insights for potential genomic markers for PrCa survival.