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;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 […]
Clinical utility of rapid whole genome sequencing in neonatal patients receiving extracorporeal membrane oxygenation (ECMO)
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 […]
The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships
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 […]
Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies
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 […]
Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis
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 […]
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. 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 […]
Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability
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 […]
Early Newborn Metabolic Patterning and Sudden Infant Death Syndrome
Abstract Importance: Sudden infant death syndrome (SIDS) is a major cause of infant death in the US. Previous research suggests that inborn errors of metabolism may contribute to SIDS, yet the relationship between SIDS and biomarkers of metabolism remains unclear. Objective: To evaluate and model the association between routinely measured newborn metabolic markers and SIDS […]
Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Disease
J Am Soc Nephrol. 2024 Sep 27. doi: 10.1681/ASN.0000000532. Online ahead of print. NO ABSTRACT PMID:39331470 | DOI:10.1681/ASN.0000000532
The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder
Pediatr Neurol. 2024 Sep 21;161:188-193. doi: 10.1016/j.pediatrneurol.2024.09.015. Online ahead of print. ABSTRACT BACKGROUND: RNU4-2 is a newly identified, noncoding gene responsible for a significant proportion of individuals with neurodevelopmental disorders (NDDs). Diagnosis is hampered by the inability of commonly employed clinical testing methods, including exome sequencing and currently formulated multigene panels, to detect variants in […]