Clinical Variants in C. elegans Expressing Human STXBP1 Reveals a Novel Class of Pathogenic Variants and Classifies Variants of Uncertain Significance
Genetics in Medicine Open (2023), doi: https://doi.org/10.1016/j.gimo.2023.100823. Abstract Purpose: Modeling disease variants in animals is useful for drug discovery, understanding disease pathology, as well as classifying variants of uncertain significance (VUS) as pathogenic or benign. Methods Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), we performed a Whole-gene Humanized Animal Model (WHAM) procedure to replace […]
SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission
Brain. 2023 Jul 17:awad235. doi: 10.1093/brain/awad235. Online ahead of print. ABSTRACT SLC4A10 is a plasma-membrane bound transporter which utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ […]
Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder
JAMA. 2023 Jul 11;330(2):161-169. doi: 10.1001/jama.2023.9350. ABSTRACT IMPORTANCE: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results. OBJECTIVE: To compare outcomes of genomic sequencing with those of a […]
Assessing Diversity in Newborn Genomic Sequencing Research Recruitment: Race/Ethnicity and Primary Spoken Language Variation in Eligibility, Enrollment, and Reasons for Declining
Clin Ther. 2023 Jul 8:S0149-2918(23)00220-5. doi: 10.1016/j.clinthera.2023.06.014. Online ahead of print. ABSTRACT PURPOSE: Diagnostic genomic research has the potential to directly benefit participants. This study sought to identify barriers to equitable enrollment of acutely ill newborns into a diagnostic genomic sequencing research study. METHODS: We reviewed the 16-month recruitment process of a diagnostic genomic research […]
Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness
Sci Adv. 2023 Jun 30;9(26):eadf2860. doi: 10.1126/sciadv.adf2860. Epub 2023 Jun 30. ABSTRACT Cell cycle dysregulation is prerequisite for cancer formation. However, it is unknown whether the mode of dysregulation affects disease characteristics. Here, we conduct comprehensive analyses of cell cycle checkpoint dysregulation using patient data and experimental investigations. We find that ATM mutation predisposes the […]
Biallelic loss of function variants in WBP4 , encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome
medRxiv. 2023 Jun 27:2023.06.19.23291425. doi: 10.1101/2023.06.19.23291425. Preprint. ABSTRACT Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WBP4 (WW Domain Binding Protein 4) is part of the early spliceosomal complex, and was not described before in the context of human pathologies. Ascertained through GeneMatcher we identified eleven patients from […]
BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients
Eur J Hum Genet. 2023 Jun 21. doi: 10.1038/s41431-023-01410-z. Online ahead of print. ABSTRACT BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular […]
A gene-based association test of interactions for maternal-fetal genotypes identifies genes associated with nonsyndromic congenital heart defects
Genet Epidemiol. 2023 Jun 21. doi: 10.1002/gepi.22533. Online ahead of print. ABSTRACT The risk of congenital heart defects (CHDs) may be influenced by maternal genes, fetal genes, and their interactions. Existing methods commonly test the effects of maternal and fetal variants one-at-a-time and may have reduced statistical power to detect genetic variants with low minor […]
Response to Grosse et al
Am J Hum Genet. 2023 Jun 1;110(6):1017. doi: 10.1016/j.ajhg.2023.05.004. NO ABSTRACT PMID:37267897 DOI:10.1016/j.ajhg.2023.05.004
Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome
N Engl J Med. 2023 May 31. doi: 10.1056/NEJMoa2202318. Online ahead of print. ABSTRACT BACKGROUND: Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high. METHODS: We evaluated four patients from three unrelated families with an […]