medRxiv [Preprint]. 2025 Nov 28:2025.11.26.25341098. doi: 10.1101/2025.11.26.25341098. ABSTRACT Sudden Unexpected Infant Death (SUID), the third leading cause of infant death, has increasing incidence and multifactorial etiology. Identification of preventative interventions has hitherto been hindered by etiologic studies limited to genetic or environmental effects in isolation. Here we report a multifactorial genome x environment analysis of SUID risk. Births in San Diego County California from 2005-2018 were linked to hospital discharge summaries and death files, yielding 212 SUID cases and 620,392 infants alive at age 1 year. Whole genome sequencing (WGS) identified probable and possible genetic etiologies in 16% and 48% of SUID cases, respectively. Genetic risks were extremely heterogeneous with 144 loci contributing 173 risks in 57% of SUID cases. Genetic risk was very strong (Prevalence Risk Ratio, PRR >99) or strong (PRR 3.7 – 99) in 12% and 34% of SUID cases, respectively. Six of sixteen significant environmental risks lost significance when SUID cases without strong or very strong genetic risk were compared with infants alive at age 1 year, while SUID risk associated with prenatal cannabis increased from adjusted hazard ratio (aHR) 3.7 to 6.0, other substance abuse from aHR 2.6 to 3.5, and black race from aHR 1.9 to 2.5. Thus, genome x environment analysis of a large cohort unveiled etiologic heterogeneity and hidden SUID risks, highlighting cannabis and genetic diseases as strong risk factors. Since preventative or therapeutic interventions were available for 83% of genetic risks, newborn screening by WGS has potential for substantial SUID reduction. Educational campaigns for SUID should emphasize perinatal cannabis avoidance. ONE SENTENCE SUMMARY: Multifactorial genome x environment analysis of a large cohort identified heterogeneous etiology in Sudden Unexpected Infant Death and unveiled strong risks from prenatal cannabis and genetic diseases. PMID:41358299 | PMC:PMC12676543 | DOI:10.1101/2025.11.26.25341098

Am J Med Genet A. 2025 Nov 26:e70007. doi: 10.1002/ajmga.70007. Online ahead of print. ABSTRACT SLC30A9 mutations are linked to Birk-Landau-Perez syndrome, which is characterized by neurodevelopmental and renal disease, thought to result from impaired zinc homeostasis. In this report, we describe a patient with a homozygous likely pathogenic SLC30A9 variant with atypical chorio-retinal degeneration, suggesting retinal involvement in SLC30A9-associated diseases. The patient has bilateral sensorineural hearing loss, developmental delay, intellectual disability, abnormal balance, and Tourette syndrome. Ophthalmic manifestations include vascular attenuation, optic disc pallor, and pigmentation. In addition, the patient is noted to have high myopia. Our case highlights the importance of broad genetic testing in diagnosing rare multi-systemic disorders. Further research into the molecular mechanisms by which SLC30A9 results in photoreceptor disease is essential to understand its role in retinal degeneration and to develop potential therapeutic strategies. PMID:41293997 | DOI:10.1002/ajmga.70007

BMJ Open. 2025 Nov 13;15(11):e098609. doi: 10.1136/bmjopen-2024-098609. ABSTRACT INTRODUCTION: In the last 60 years, newborn bloodspot screening (NBS) has expanded as a public health intervention from a single severe childhood genetic disease (SCGD) to up to as many as 80 SCGD and testing of ~40 million newborns/year worldwide. However, the gap between current NBS and its potential to increase the efficiency, effectiveness and global equity of healthcare delivery for SCGD is large and rapidly growing. There are now effective therapeutic interventions-drugs, diets, devices and surgeries-for up to 2000 SCGD. Since almost all SCGD can be identified by bloodspot genome sequencing, it has been a longstanding goal to supplement current NBS with genome sequencing-based NBS (gNBS) for all eligible SCGD. We recently described a novel gNBS platform (named Begin Newborn Genome Sequencing (BeginNGS)) with the potential to overcome several major challenges to gNBS (cost, scalability, false positives and an unprepared healthcare workforce). A pilot clinical trial of BeginNGS for 412 SCGD in a level IV neonatal intensive care unit (NICU) had a true positive rate of 4.2%, sensitivity of 83%, positive predictive value of 100% and clinical utility rate of 4.2%, indicating readiness of the platform for use in a powered, multicentre study. METHODS AND ANALYSIS: The BeginNGS study is a single group, international, multicentre, adaptive clinical trial to compare utility, acceptability, feasibility and cost-effectiveness of BeginNGS gNBS (experimental intervention) with standard NBS (control). A minimum of 10 000 neonates (aged <28 days, maximum of 100 000) will be enrolled across 25 racial, ethnic and ancestry populations and five enrolment site types (high-risk obstetrician offices, labour induction office visits, newborn nurseries, NICUs and well-baby visits). BeginNGS is gNBS for circa 2000 SCGD (currently 508 SCGD). The primary objective of the trial is to generate equitable evidence to support broad implementation of gNBS. Enrolled newborns receive both interventions (BeginNGS and standard of care NBS). Newborns who screen positive receive confirmatory testing and medical follow-up for at least 1 year to obtain outcomes data. The primary outcome measure is clinical utility, defined as the proportion of diagnoses identified by BeginNGS and state NBS during infancy that are likely to benefit (likely to have an improved outcome) from treatment. We hypothesise that BeginNGS has a greater rate of clinical utility than standard NBS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, equitable and ethical by addition or removal of SCGD and genetic variants, population enrichment (for under-represented racial, ethnic and ancestral groups) and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of gNBS, providing greater power to test utility in ultra-rare SCGD. Parents will be approached (in person, via phone or via electronic communication) to provide informed consent to enrol their newborns prenatally, postnatally in newborn nurseries or NICUs or at well baby outpatient visits. This study is part of phase III of the BeginNGS programme. Patient and public voices have been engaged in the design and execution of each BeginNGS phase through individuals and groups joining the BeginNGS consortium and participating in the family and community engagement work group. gNBS has the potential to transform the way we diagnose and treat childhood genetic diseases. Preliminary data suggest that national adoption of BeginNGS for all births has the potential to improve outcomes of >50 000 US children per year. ETHICS AND DISSEMINATION: This study was approved by the WCG Clinical institutional review board on 14 February 2024, and the most recent amendment approved on 7 October 2025 (approval number 20235517). Study findings will be shared through research consortium workshops, national and international conferences, community presentations and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT06306521. PMID:41238356 | DOI:10.1136/bmjopen-2024-098609

Cell Stem Cell. 2025 Nov 3:S1934-5909(25)00374-1. doi: 10.1016/j.stem.2025.10.006. Online ahead of print. ABSTRACT Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches. PMID:41187745 | DOI:10.1016/j.stem.2025.10.006

J Pediatr. 2025 Oct 31:114889. doi: 10.1016/j.jpeds.2025.114889. Online ahead of print. ABSTRACT OBJECTIVE: To compare 1-year healthcare costs and quality-adjusted life years (QALYs) for two diagnostic strategies in critically ill infants with suspected genetic disorders: 1) early rapid genome sequencing (within 7 days of admission) for all infants, and 2) early targeted neonatal gene sequencing (NewbornDx) for all infants, followed by later rGS (after 7 days) for undiagnosed infants. STUDY DESIGN: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a multicenter, prospective study that enrolled 400 hospitalized infants under one year of age with suspected genetic disorders. All participants underwent both rGS and NewbornDx. Using patient-level GEMINI data and 2023 Medicare rates, we developed a decision tree to compare total costs and QALYs over a 1-year period for these two hypothetical testing strategies. RESULTS: The diagnostic yield and upfront testing costs were higher for rGS (49%; $12,297) than NewbornDx (27%; $2,449; p<0.05). As neither early testing nor diagnosis significantly affected QALYs, we conducted a cost-minimization analysis, focusing solely on cost differences between strategies. Over one year, early rGS was estimated to save $158,592 per patient (95% CI: $63,701-$253,292) compared with early NewbornDx with later rGS if necessary. CONCLUSIONS: Early rGS results in substantial healthcare cost savings, highlighting the need to expand reimbursement to improve access early in a hospitalization for critically ill infants. PMID:41177396 | DOI:10.1016/j.jpeds.2025.114889

HGG Adv. 2025 Oct 25:100539. doi: 10.1016/j.xhgg.2025.100539. Online ahead of print. ABSTRACT Human development is a complex process that requires precise control of gene expression through regulatory proteins. Recently, heterozygous variants in PRR12, encoding a proline-rich regulatory protein, were found to cause a variable phenotype involving developmental delay/cognitive impairment, neuropsychiatric diagnoses, structural eye anomalies, congenital heart and kidney defects, and poor growth. QSER1, encoding glutamine- and serine-rich protein 1, represents a paralog of PRR12 that shares 28% overall identity at the protein level and stronger conservation (43%) in the C-terminal region. QSER1 deficiency in human embryonic stem cells causes hypermethylation of many key transcription factor genes, implicating it in the development of multiple organs. Here we present three unrelated individuals with neurodevelopmental phenotypes, variable other multisystem anomalies, and heterozygous variants in QSER1. This includes two novel de novo frameshift alleles (p.(Lys1565Argfs*36) and p.(Phe896fs*28)), and one ultra-rare canonical splice site variant resulting in a combination of abnormal transcripts, frameshift (p.(Glu1393Glyfs*26)) and in-frame deletion of a conserved amino acid (p.(Glu1393del)), supported by in silico predictions and minigene assays. In situ hybridization revealed dynamic and broad expression of qser1 in zebrafish embryos, including a strong presence in the developing brain. These data suggest a possible role for QSER1/qser1 in vertebrate development and human disease. PMID:41139957 | DOI:10.1016/j.xhgg.2025.100539

Birth Defects Res. 2025 Oct;117(10):e2533. doi: 10.1002/bdr2.2533. ABSTRACT BACKGROUND: Spina bifida (SB), a common neural tube defects (NTDs), has a complex genetic architecture that remains incompletely understood. Although prior studies have identified rare, deleterious single nucleotide variants (SNVs) in SB, broader contributions to risk remain unclear. Here, we investigated shared genetic risk among 256 SB probands compared with 395 ancestry-matched controls using an unbiased sequencing approach. METHODS: We performed an exome-wide association study (ExWAS) of 46,887 SNVs with minor allele frequencies (MAF) > 0.001 to identify single-variant associations, followed by gene-based burden tests to assess the cumulative effect of SNVs within genes, using all variants and then restricting to rare variants (MAF < 0.05). Both burden tests were repeated in 510 unaffected parents to evaluate excess mutational burden relative to controls. RESULTS: Across all analyses, 16 genes were associated with SB: SRCIN1, PDE4DIP, XCL2, CTAGE10P, GLB1L3, PMS2P4, HSPA4, GLB1L2, FAM90A1, PLA1A, HLA-A, SPIRE2, TVP23B, CHD5, FOXA2, and PIF1. ExWAS identified 11 significant SNVs, nine of which were common (MAF > 0.05). The unrestricted burden test identified seven genes; four remained significant when restricted to rare variants, and two additional genes emerged only in that subset. Five burden-associated genes were not detected in the ExWAS, suggesting cumulative variant effects. Four burden-associated genes also showed enrichment in parents, supporting inherited risk. Three of these showed suggestive transmission disequilibrium (p values ≤ 0.10) and one was attributed to multiple SNVs. CONCLUSION: These results provide new insight into the multifactorial genetic landscape of SB and highlight the importance of unbiased approaches in constructing genetic models of NTD. PMID:41013918 | DOI:10.1002/bdr2.2533

J Med Genet. 2025 Oct 8:jmg-2025-110631. doi: 10.1136/jmg-2025-110631. Online ahead of print. ABSTRACT BACKGROUND: Pathogenic gain-of-function or dominant-negative effect missense variations in ACTB are associated with a neurodevelopmental disorder characterised by intellectual disability (ID), seizures, sensorineural hearing loss, cerebral, renal and ocular abnormalities and dysmorphic features (Baraitser-Winter cerebrofrontofacial syndrome). ACTB encodes beta-actin, a highly conserved protein involved in cell motility, structure and integrity. Deletions including ACTB, and, more rarely, single-nucleotide loss-of-function variants in ACTB have been described in patients with a distinct phenotype including developmental delay, ID, microcephaly, growth restriction, cardiac and renal abnormalities and dysmorphic features. METHODS: We collected 14 individuals and 1 fetus carrying a heterozygous deletion including ACTB, and 4 individuals with a heterozygous truncating variant. Genotypic and phenotypic data were analysed. Furthermore, a comprehensive review of all cases reported to date was also undertaken. RESULTS: Twelve out of 17 individuals presented with ID, and 3 out of 17 with learning disabilities. Speech delay and behavioural abnormalities were observed in 15 out of 17 and 12 out of 17 individuals, respectively, motor delay in 9 out of 17 and growth restriction in 9 out of 18. Most of the individuals (13/18) had recognisable dysmorphic features. 11 anomalies were de novo, except for 1 deletion inherited from the mother. The size of the deletion varied from 125 kb to 1.6 Mb and could result from a fork stalling and template switching. CONCLUSION: This study allowed us to better characterise the phenotype associated with the haploinsufficiency of ACTB, underlying the high prevalence of neurodevelopmental disorders (ID, speech and motor delay, behavioural abnormalities) and growth restriction in this recognisable syndrome. PMID:41062261 | DOI:10.1136/jmg-2025-110631

Biol Psychiatry. 2025 Sep 30:S0006-3223(25)01485-4. doi: 10.1016/j.biopsych.2025.09.010. Online ahead of print. ABSTRACT BACKGROUND: Genetic testing may provide important diagnostic information for individuals with schizophrenia, but the frequency with which clinically significant variants are identified across different testing approaches has not been systematically evaluated. METHODS: We conducted a systematic review and meta-analysis searching MEDLINE, EMBASE, and APA PsycINFO (January 2007-June 2023) for studies reporting results of clinical genetic testing in schizophrenia. Two independent reviewers performed abstract/title screening, full-text review, and data extraction following PRISMA guidelines. A random-effects model was used to estimate the pooled and platform-specific proportions of individuals with pathogenic or likely pathogenic variants, with heterogeneity assessed using the I² statistic. RESULTS: Analysis of 31 studies (20,476 participants) showed that 6% (95% CI: 4% to 7%) of individuals with schizophrenia had a clinically significant genetic variant identified. Detection rates were 6% (95% CI: 4% to 8%) for chromosomal microarray, 5% (95% CI: -0.02% to 12%) for exome sequencing, and 7% (95% CI: 2% to 12%) for genome sequencing. Substantial heterogeneity was observed across studies (I² = 95.9%). Geographic representation was limited, with no studies from Latin America, South Asia, or Africa. CONCLUSIONS: Genetic testing identifies clinically informative variants in approximately 6% of individuals with schizophrenia. However, substantial heterogeneity across studies and limited geographic representation underscore the need for more standardized testing approaches and broader population sampling in future genetic research on schizophrenia. PMID:41038604 | DOI:10.1016/j.biopsych.2025.09.010

Nat Commun. 2025 Aug 7;16(1):7267. doi: 10.1038/s41467-025-61712-2. ABSTRACT Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform in-depth analyses on individual patients with ultra-rare diseases. The increasing sizes of ultra-rare disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development. The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale case-based diagnostic analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We further release a software package, RaMeDiES, enabling automated cross-analysis of deidentified sequenced cohorts for new diagnostic and research discoveries. Gene-level findings and variant-level information across the cohort are available in a public-facing browser ( https://dbmi-bgm.github.io/udn-browser/ ). These results show that case-level diagnostic efforts should be supplemented by a joint genomic analysis across cohorts. PMID:40770127 | DOI:10.1038/s41467-025-61712-2