Scientific Publications

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322 Results

2021

Abnormal SCID Newborn Screening and Spontaneous Recovery Associated with a Novel Haploinsufficiency IKZF1 Mutation

Kuehn HS, Gloude NJ, Dimmock D, Tokita M, Wright M, Rosenzweig SD, Collins C.

J Clin Immunol. 2021 Apr 14. doi: 10.1007/s10875-021-01035-1. Online ahead of print. ABSTRACT PURPOSE: IKAROS, encoded by IKZF1, is a member of the IKAROS family of zinc-finger transcription factors playing critical roles in lymphocyte development, differentiation, and tumor suppression. Several studies demonstrated that IKZF1 mutations affecting DNA binding or homo-/hetero-dimerization are mostly associated with common variable immunodeficiency, combined immunodeficiency, or hematologic manifestations. Herein we report a likely de novo, nonsense IKZF1 mutation (p.C182*) in a baby with low T cell receptor excision circles (TREC) identified by newborn screening testing for severe combined immunodeficiency. The patient also presented a profound B cell deficiency at birth. METHODS: Genetic, functional, immunologic, and clinical outcome data associated with this patient and her mutation were evaluated. RESULTS: Mutant p.C182* was detected in the cytoplasm of the patient’s primary cells, in contrast to wild type (WT) IKAROS protein, only detected in the nucleus. Functional in vitro assessments revealed that p.C182* was less stable than WT IKAROS protein and failed to bind to its target DNA binding sequence and dimerize with WT IKAROS protein, resulting in impaired pericentromeric targeting and transcriptional repression by means of haploinsufficiency. During follow-up, while a spontaneous recovery of TREC and T cells was observed, B cells improved but not to sustained normal ranges. CONCLUSIONS: Patients with IKAROS-associated diseases can present with SCID-like TREC values through newborn screening testing. IKZF1 mutations should be added to the low TREC differential, although spontaneous recovery has to be considered. PMID:33855675 | DOI:10.1007/s10875-021-01035-1

April 15, 2021

Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia

Ghosh SG, Breuss MW, Schlachetzki Z, Chai G, Ross D, Stanley V, Sonmez FM, Topaloglu H, Zaki MS, Hosny H, Gad S, Gleeson JG.

Eur J Hum Genet. 2021 Apr 6. doi: 10.1038/s41431-021-00832-x. Online ahead of print.

ABSTRACT

HEAT repeats are 37-47 amino acid flexible tandem repeat structural motifs occurring in a wide variety of eukaryotic proteins with diverse functions. Due to their ability to undergo elastic conformational changes, they often serve as scaffolds at sites of protein interactions. Here, we describe four affected children from two families presenting with pontocerebellar hypoplasia manifest clinically with neonatal seizures, severe intellectual disability, and motor delay. Whole exome sequencing identified biallelic variants at predicted splice sites in intron 31 of HEATR5B, encoding the HEAT repeat-containing protein 5B segregating in a recessive fashion. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. HEATR5B is expressed during brain development in human, and we failed to recover live-born homozygous Heatr5b knockout mice. Taken together, our results implicate loss of HEATR5B in pontocerebellar hypoplasia.

PMID:33824466 | DOI:10.1038/s41431-021-00832-x

April 7, 2021
Neurogenomics

Comprehensive identification of somatic nucleotide variants in human brain tissue

Wang Y, Bae T, Thorpe J, Sherman MA, Jones AG, Cho S, Daily K, Dou Y, Ganz J, Galor A, Lobon I, Pattni R, Rosenbluh C, Tomasi S, Tomasini L, Yang X, Zhou B, Akbarian S, Ball LL, Bizzotto S, Emery SB, Doan R, Fasching L, Jang Y, Juan D, Lizano E, Luquette LJ, Moldovan JB, Narurkar R, Oetjens MT, Rodin RE, Sekar S, Shin JH, Soriano E, Straub RE, Zhou W, Chess A, Gleeson JG, Marquès-Bonet T, Park PJ, Peters MA, Pevsner J, Walsh CA, Weinberger DR; Brain Somatic Mosaicism Network, Vaccarino FM, Moran JV, Urban AE, Kidd JM, Mills RE, Abyzov A.

Genome Biol. 2021 Mar 29;22(1):92. doi: 10.1186/s13059-021-02285-3. ABSTRACT BACKGROUND: Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells. RESULTS: Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees. CONCLUSIONS: This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases. PMID:33781308 | PMC:PMC8006362 | DOI:10.1186/s13059-021-02285-3

March 30, 2021
Neurogenomics

Metagenomic Next-Generation Sequencing for Pathogen Detection and Transcriptomic Analysis in Pediatric Central Nervous System Infections

Ramchandar N, Coufal NG, Warden AS, Briggs B, Schwarz T, Stinnett R, Xie H, Schlaberg R, Foley J, Clarke C, Waldeman B, Enriquez C, Osborne S, Arrieta A, Salyakina D, Janvier M, Sendi P, Totapally BR, Dimmock D, Farnaes L. 

Open Forum Infect Dis. 2021 Mar 6;8(6):ofab104. doi: 10.1093/ofid/ofab104. eCollection 2021 Jun. ABSTRACT BACKGROUND: Pediatric central nervous system (CNS) infections are potentially life-threatening and may incur significant morbidity. Identifying a pathogen is important, both in terms of guiding therapeutic management and in characterizing prognosis. Usual care testing by culture and polymerase chain reaction is often unable to identify a pathogen. We examined the systematic application of metagenomic next-generation sequencing (mNGS) for detecting organisms and transcriptomic analysis of cerebrospinal fluid (CSF) in children with central nervous system (CNS) infections. METHODS: We conducted a prospective multisite study that aimed to enroll all children with a CSF pleocytosis and suspected CNS infection admitted to 1 of 3 tertiary pediatric hospitals during the study timeframe. After usual care testing had been performed, the remaining CSF was sent for mNGS and transcriptomic analysis. RESULTS: We screened 221 and enrolled 70 subjects over a 12-month recruitment period. A putative organism was isolated from CSF in 25 (35.7%) subjects by any diagnostic modality. Metagenomic next-generation sequencing of the CSF samples identified a pathogen in 20 (28.6%) subjects, which were also all identified by usual care testing. The median time to result was 38 hours. CONCLUSIONS: Metagenomic sequencing of CSF has the potential to rapidly identify pathogens in children with CNS infections. PMID:34104666 | PMC:PMC8180245 | DOI:10.1093/ofid/ofab104

March 21, 2021

Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Klöckner C, Sticht H, Zacher P, Popp B, Babcock HE, Bakker DP, Barwick K, Bonfert MV, Bönnemann CG, Brilstra EH; Care4Rare Canada Consortium, Chung WK, Clarke AJ, Devine P, Donkervoort S, Fraser JL, Friedman J, Gates A, Ghoumid J, Hobson E, Horvath G, Keller-Ramey J, Keren B, Kurian MA, Lee V, Leppig KA, Lundgren J, McDonald MT, McLaughlin HM, McTague A, Mefford HC, Mignot C, Mikati MA, Nava C, Raymond FL, Sampson JR, Sanchis-Juan A, Shashi V, Shieh JTC, Shinawi M, Slavotinek A, Stödberg T, Stong N, Sullivan JA, Taylor AC, Toler TL, van den Boogaard MJ, van der Crabben SN, van Gassen KLI, van Jaarsveld RH, Van Ziffle J, Wadley AF, Wagner M, Wigby K, Wortmann SB, Zarate YA, Møller RS, Lemke JR, Platzer K. Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy. Genet Med. 2021 Apr;23(4):796. doi: 10.1038/s41436-020-01090-w. Erratum for: Genet Med. 2021 Apr;23(4):653-660. PMID: 33686260.

Genet Med. 2021 Mar 8. doi: 10.1038/s41436-020-01090-w. Online ahead of print. PMID:33686260 | DOI:10.1038/s41436-020-01090-w

March 9, 2021

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

Patel J, Bircan E, Tang X, Orloff M, Hobbs CA, Browne ML, Botto LD, Finnell RH, Jenkins MM, Olshan A, Romitti PA, Shaw GM, Werler MM, Li J, Nembhard WN; National Birth Defects Prevention Study.

PLoS Genet. 2021 Mar 8;17(3):e1009413. doi: 10.1371/journal.pgen.1009413. eCollection 2021 Mar. ABSTRACT Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16×10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80×10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28×10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77×10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways. PMID:33684136 | PMC:PMC7971842 | DOI:10.1371/journal.pgen.1009413

March 8, 2021

Author Correction: Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Ghosh SG, Breuss MW, Schlachetzki Z, Chai G, Ross D, Stanley V, Sonmez FM, Topaloglu H, Zaki MS, Hosny H, Gad S, Gleeson JG.

Nat Commun. 2021 Feb 15;12(1):1192. doi: 10.1038/s41467-021-21448-1.

NO ABSTRACT

PMID:33589599 | PMC:PMC7884391 | DOI:10.1038/s41467-021-21448-1

February 16, 2021
Neurogenomics

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study

Maron JL, Kingsmore SF, Wigby K, Chowdhury S, Dimmock D, Poindexter B, Suhrie K, Vockley J, Diacovo T, Gelb BD, Stroustrup A, Powell CM, Trembath A, Gallen M, Mullen TE, Tanpaiboon P, Reed D, Kurfiss A, Davis JM.

JAMA Pediatr. 2021 Feb 15:e205906. doi: 10.1001/jamapediatrics.2020.5906. Online ahead of print. ABSTRACT IMPORTANCE: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. OBJECTIVE: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. DESIGN, SETTING, AND PARTICIPANTS: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. INTERVENTIONS: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. MAIN OUTCOMES AND MEASURES: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. RESULTS: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. CONCLUSIONS AND RELEVANCE: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood. PMID:33587123 | PMC:PMC7885094 | DOI:10.1001/jamapediatrics.2020.5906

February 15, 2021

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Au KS, Hebert L, Hillman P, Baker C, Brown MR, Kim DK, Soldano K, Garrett M, Ashley-Koch A, Lee S, Gleeson J, Hixson JE, Morrison AC, Northrup H.

Sci Rep. 2021 Feb 11;11(1):3639. doi: 10.1038/s41598-021-83058-7. ABSTRACT Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort. PMID:33574475 | PMC:PMC7878900 | DOI:10.1038/s41598-021-83058-7

February 12, 2021

Emergence of an early SARS-CoV-2 epidemic in the United States

Zeller M, Gangavarapu K, Anderson C, Smither AR, Vanchiere JA, Rose R, Dudas G, Snyder DJ, Watts A, Matteson NL, Robles-Sikisaka R, Marshall M, Feehan AK, Sabino-Santos G, Bell-Kareem A, Hughes LD, Alkuzweny M, Snarski P, Garcia-Diaz J, Scott RS, Melnik LI, Klitting R, McGraw M, Belda-Ferre P, DeHoff P, Sathe S, Marotz C, Grubaugh N, Nolan DJ, Drouin AC, Genemaras KJ, Chao K, Topol S, Spencer E, Nicholson L, Aigner S, Yeo GW, Faranes L, Hobbs CA, Laurent LC, Knight R, Hodcroft EB, Khan K, Fusco DN, Cooper VS, Lemey P, Gardner L, Lamers SL, Kamil JP, Garry RF, Suchard MA, Andersen KG.

medRxiv [Preprint]. 2021 Feb 8:2021.02.05.21251235. doi: 10.1101/2021.02.05.21251235. PMID: 33564781; PMCID: PMC7872376.

Abstract

The emergence of the early COVID-19 epidemic in the United States (U.S.) went largely undetected, due to a lack of adequate testing and mitigation efforts. The city of New Orleans, Louisiana experienced one of the earliest and fastest accelerating outbreaks, coinciding with the annual Mardi Gras festival, which went ahead without precautions. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large, crowded events may have accelerated early transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana initially had limited sequence diversity compared to other U.S. states, and that one successful introduction of SARS-CoV-2 led to almost all of the early SARS-CoV-2 transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras and that the festival dramatically accelerated transmission, eventually leading to secondary localized COVID-19 epidemics throughout the Southern U.S.. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate COVID-19 epidemics on a local and regional scale. PMID: 33564781 | PMCID: PMC7872376 | DOI: 10.1101/2021.02.05.21251235

February 5, 2021

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