A machine learning decision support tool optimizes WGS utilization in a neonatal intensive care unit
Juarez EF, Peterson B, Sanford Kobayashi E, Gilmer S, Tobin LE, Schultz B, Lenberg J, Carroll J, Bai-Tong S, Sweeney NM, Beebe C, Stewart L, Olsen L, Reinke J, Kiernan EA, Reimers R, Wigby K, Tackaberry C, Yandell M, Hobbs C, Bainbridge MN. A machine learning decision support tool optimizes WGS utilization in a neonatal intensive care unit. NPJ Digit Med. 2025 Jan 30
NPJ Digit Med. 2025 Jan 30;8(1):72. doi: 10.1038/s41746-025-01458-9.
ABSTRACT
The Mendelian Phenotype Search Engine (MPSE), a clinical decision support tool using Natural Language Processing and Machine Learning, helped neonatologists expedite decisions to whole genome sequencing (WGS) to diagnose patients in the neonatal intensive care unit. After the MPSE was introduced, utilization of WGS increased, time to ordering WGS decreased, and WGS diagnostic yield increased.
PMID:
39885315 | DOI:
10.1038/s41746-025-01458-9
January 30, 2025
Infant MortalityRPM for NICU and PICUrWGS
A comparative view of human and mouse telencephalon inhibitory neuron development
Chung C, Girgiss J, Gleeson JG. A comparative view of human and mouse telencephalon inhibitory neuron development. Development. 2025 Jan 1
Development. 2025 Jan 1;152(1):dev204306. doi: 10.1242/dev.204306. Epub 2025 Jan 2.
ABSTRACT
Human GABAergic inhibitory neurons (INs) in the telencephalon play crucial roles in modulating neural circuits, generating cortical oscillations, and maintaining the balance between excitation and inhibition. The major IN subtypes are based on their gene expression profiles, morphological diversity and circuit-specific functions. Although previous foundational work has established that INs originate in the ganglionic eminence regions in mice, recent studies have questioned origins in humans and non-human primates. We review the origins of INs in mice and compare with recent findings from primary human prenatal brain tissue culture experiments and lineage analysis from somatic variants in neurotypical human cadavers and human brain organoids. Together, these studies suggest potential primate- or human-specific processes that may have been overlooked in mouse models and could have implications for brain disorders.
PMID:
39745314 | DOI:
10.1242/dev.204306
January 1, 2025
Neurogenomics
Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial
Kingsmore SF, Wright M, Olsen L, Schultz B, Protopsaltis L, Averbuj D, Blincow E, Carroll J, Caylor S, Defay T, Ellsworth K, Feigenbaum A, Gover M, Guidugli L, Hansen C, Van Der Kraan L, Kunard CM, Kwon H, Madhavrao L, Leipzig J, Liang Y, Mardach R, Mowrey WR, Nguyen H, Niemi AK, Oh D, Saad M, Scharer G, Schleit J, Mehtalia SS, Sanford E, Smith LD, Willis MJ, Wigby K, Reimers R. Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial. Am J Hum Genet. 2024 Dec 5
Am J Hum Genet. 2024 Dec 5;111(12):2643-2667. doi: 10.1016/j.ajhg.2024.10.020.
ABSTRACT
Large prospective clinical trials are underway or planned that examine the clinical utility and cost effectiveness of genome-based newborn screening (gNBS). One gNBS platform, BeginNGS, currently screens 53,575 variants for 412 severe childhood genetic diseases with 1,603 efficacious therapies. Retrospective evaluation of BeginNGS in 618,290 subjects suggests adequate sensitivity and positive predictive value (PPV) to proceed to prospective studies. To inform pivotal clinical trial design, we undertook a pilot clinical trial. We enrolled 120 infants in a regional neonatal intensive care unit (NICU) who were not under consideration for rapid diagnostic genome sequencing (RDGS). Each enrollee received BeginNGS and two index tests (California state NBS and RDGS). California NBS identified 4 of 4 true positive (TP) findings (TP rate 3.6%, sensitivity 100%) and 11 false positive (FP) findings (PPV 27%). RDGS identified 41 diagnostic findings in 36 neonates (diagnostic rate 30%). BeginNGS identified 5 of 6 on-target TP disorders (TP rate 4.2%, 95% confidence interval 1%-8%, sensitivity 83%) and no FPs (PPV 100%). Changes in management were anticipated following the return of 27 RDGS results in 25 enrollees (clinical utility [CU] 21%), 3 of 4 NBS TPs (CU 2.7%), and all BeginNGS TPs (CU 4.2%). The incidence of actionable genetic diseases in NICU infants not being considered for RDGS suggests (1) performance of RDGS in ∼20% of admissions misses many genetic diagnoses, (2) NICU enrollment in gNBS trials will greatly increase power to test endpoints, and (3) NICUs may be attractive for early implementation of consented BeginNGS screening.
PMID:
39642868 | DOI:
10.1016/j.ajhg.2024.10.020
December 5, 2024
Newborn ScreeningRPM for NICU and PICUrWGSrWGS Efficacy
Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection
Kingsmore SF, Wright M, Smith LD, Liang Y, Mowrey WR, Protopsaltis L, Bainbridge M, Baker M, Batalov S, Blincow E, Cao B, Caylor S, Chambers C, Ellsworth K, Feigenbaum A, Frise E, Guidugli L, Hall KP, Hansen C, Kiel M, Van Der Kraan L, Krilow C, Kwon H, Madhavrao L, Lefebvre S, Leipzig J, Mardach R, Moore B, Oh D, Olsen L, Ontiveros E, Owen MJ, Reimers R, Scharer G, Schleit J, Shelnutt S, Mehtalia SS, Oriol A, Sanford E, Schwartz S, Wigby K, Willis MJ, Yandell M, Kunard CM, Defay T. Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection. Am J Hum Genet. 2024 Dec 5
Am J Hum Genet. 2024 Dec 5;111(12):2618-2642. doi: 10.1016/j.ajhg.2024.10.021.
ABSTRACT
Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121 days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.
PMID:
39642867 | DOI:
10.1016/j.ajhg.2024.10.021
December 5, 2024
Newborn ScreeningrWGSrWGS Efficacy
Clinical utility of rapid whole genome sequencing in neonatal patients receiving extracorporeal membrane oxygenation (ECMO)
Amin MD, Wigby K, Suttner D, Niemi AK, Guidugli L, Carroll J. Clinical utility of rapid whole genome sequencing in neonatal patients receiving extracorporeal membrane oxygenation (ECMO). J Perinatol. 2024 Nov 27
J Perinatol. 2024 Nov 27. doi: 10.1038/s41372-024-02181-1. Online ahead of print.
ABSTRACT
OBJECTIVE: The objective of this study is to describe the impact of rapid and ultra-rapid whole genome sequencing (rWGS/urWGS) on the care of neonatal intensive care (NICU) patients who require extracorporeal membrane oxygenation (ECMO).
STUDY DESIGN: This is a retrospective cohort study at a single-center NICU in a tertiary children’s hospital. The study population includes NICU patients treated with ECMO from May 2017 to September 2023. Patients were evaluated for whether whole genome was completed, speed of testing (rapid vs. ultra-rapid), diagnostic rate, and clinical utility.
RESULT: Twenty-six (72%) patients had rWGS/urWGS. A diagnosis associated with the patient’s phenotype was made in 12 patients (46%). A change in clinical management was made due to rWGS/urWGS in 10 patients (38%) including avoidance of imaging studies, decisions regarding goals of care, and screening studies.
CONCLUSION: This study demonstrates a high diagnostic rate and clinical utility of rWGS/urWGS for NICU patients requiring ECMO.
PMID:
39604575 | DOI:
10.1038/s41372-024-02181-1
November 27, 2024
rWGS
The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships
Broeren E, Gitau V, Byrne A, Ajuyah P, Balzotti M, Berg J, Bluske K, Bowen BM, Brown MP, Buchanan A, Burns B, Burns NJ, Chandrasekhar A, Chawla A, Chong J, Chopra M, Clause A, DiStefano M, DiTroia S, Elnagheeb M, Girod A, Goel H, Golden-Grant K, Ha T, Hamosh A, Huang J, Hughes M, Jamuar S, Kam S, Kesari A, Koh AL, Lassiter R, Leigh S, Lemire G, Lim JY, Malhotra A, McCurry H, Milewski B, Moosa S, Murray S, Owens E, Palmer E, Palus B, Patel M, Rajkumar R, Ratliff J, Raymond FL, Assis BDRR, Sajan S, Schlachetzki Z, Schmidt S, Stark Z, Strom S, Taylor J, Thaxton C, Thrush D, Toro S, Tshering K, Vasilevsky N, Wayburn B, Webb R, O’Donnell-Luria A, Coffey AJ. The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships. medRxiv [Preprint]. 2024 Nov 20:2024
medRxiv [Preprint]. 2024 Nov 20:2024.11.19.24317561. doi: 10.1101/2024.11.19.24317561.
ABSTRACT
PURPOSE: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders GCEP (SD-GCEP) was formed to address an unmet need.
METHODS: The SD-GCEP applied ClinGen’s framework to evaluate the clinical validity of genes associated with rare syndromic disorders. 111 Gene-Disease Relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated.
RESULTS: From April 2020 through March 2024, 38 precurations were performed on genes with multiple disease relationships and were reviewed to determine if the disorders were part of a spectrum or distinct entities. 14 genes were lumped into a single disease entity and 24 were split into separate entities, of which 11 were curated by the SD-GCEP. A full review of 111 GDRs for 100 genes followed, with 78 classified as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited highlighting where further data are needed. All diseases involved two or more organ systems, while the majority (88/111 GDRs, 79.2%) had five or more organ systems affected.
CONCLUSION: The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes.
PMID:
39606380 | PMC:
PMC11601709 | DOI:
10.1101/2024.11.19.24317561
November 27, 2024
Neurogenomics
Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies
Stehr AM, Lenberg J, Friedman J, Dobbelaere D, Imbard A, Levy J, Donoghue S, Derive N, Stoeva R, Gueguen P, Zech M. Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies. Clin Genet. 2024
Clin Genet. 2024 Oct 5. doi: 10.1111/cge.14622. Online ahead of print.
ABSTRACT
Plasma membrane calcium ATPases (PMCAs) encoded by ATP2B genes have been implicated in Mendelian diseases with ataxia, dystonia, and intellectual disability. Work to date has shown that ATP2B2 (encoding PMCA2) is required for synaptic function and Purkinje-cell integrity in the cerebellum. A recent case series has linked ATP2B2 to a novel entity, characterized by neurodevelopmental and movement phenotypes, in only seven individuals. We called for collaboration to collect five unpublished families affected by the new rare ATP2B2-related condition. Exome-/genome sequencing-identified genotypes included four likely pathogenic/pathogenic heterozygous de novo missense variants and one dominantly inherited end-truncating frameshift allele. The six affected individuals shared features with the described patients including developmental delay, cognitive disturbances, epilepsy, autistic traits, and motor disorders. Striking cerebellar atrophy was observed in one affected individual. In association with hearing loss and movement abnormalities, we report a recurrent p.(Glu457Lys) substitution, previously documented in a neurologically impaired ATP2B2 mouse mutant. Our study further delineates the mutational spectrum and presentation of a human syndrome caused by ATP2B2 variants, confirming the importance of PMCA2 in neurotypical and cerebellar development.
PMID:
39367743 | DOI:
10.1111/cge.14622
November 20, 2024
Neurogenomics
Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis
Cogan G, Zaki MS, Issa M, Keren B, Guillaud-Bataille M, Renaldo F, Isapof A, Lallemant P, Stevanin G, Guillot-Noel L, Courtin T, Buratti J, Freihuber C, Gleeson JG, Howarth R, Durr A, de Sainte Agathe JM, Mignot C. Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis. Hum Genet. 2024 Nov;14
Abstract
Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement.
PMID: 39367212 | DOI: 10.1007/s00439-024-02702-0
November 14, 2024
Neurogenomics
A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases
Kim-McManus O, Gleeson JG, Mignon L, Smith Fine A, Yan W, Nolen N, Demarest S, Berry-Kravis E, Finkel R, Leonard S, Finlayson S, Augustine E, Lyon GJ, Schule R, Yu T. A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases. Nat Commun. 2024 Nov 12;15(1):9802. doi: 10.1038/s41467-024-54077-5. PMID: 39532857; PMCID: PMC11557703.
Nat Commun. 2024 Nov 12;15(1):9802. doi: 10.1038/s41467-024-54077-5.
ABSTRACT
Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.
PMID:
39532857 | DOI:
10.1038/s41467-024-54077-5
November 12, 2024
rWGS Efficacy
Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability
De Hayr L, Blok LER, Dias KR, Long J, Begemann A, Moir RD, Willis IM, Mocera M, Siegel G, Steindl K, Evans CA, Zhu Y, Zhang F, Field M, Ma A, Adès L, Josephi-Taylor S, Pfundt R, Zaki MS, Tomoum H, Gregor A, Laube J, Reis A, Maddirevula S, Hashem MO, Zweier M, Alkuraya FS, Maroofian R, Buckley MF, Gleeson JG, Zweier C, Coll-Tané M, Koolen DA, Rauch A, Roscioli T, Schenck A, Harvey RJ. Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability. Genet Med. 2024 Nov 7
Genet Med. 2024 Nov 7:101253. doi: 10.1016/j.gim.2024.101253. Online ahead of print.
ABSTRACT
PURPOSE: This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in GTF3C3, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.
METHODS: Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.
RESULTS: Twelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 including c.503C>T p.(Ala168Val), c.1268T>C p.(Leu423Pro), c.1436A>G p.(Tyr479Cys), c.2419C>T p.(Arg807Cys), and c.2420G>A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C>T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of Gtf3c3 in Drosophila induced seizure-like behavior, motor impairment, and learning deficits.
CONCLUSION: These findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.
PMID:
39636576 | DOI:
10.1016/j.gim.2024.101253
November 7, 2024
Genetic Neurologic Disease
