Commentary: Galactosemia Diagnosis by Whole Exome Sequencing Later in Life
Friedman J, Lucas-Del-Pozo S, Moreno-Martinez D, Camprodon-Gomez M, Moreno-Martinez D, Hernandez-Vara J, Kurian MA.
September 16, 2021
Maternal Smoking and Congenital Heart Defects, National Birth Defects Prevention Study, 1997-2011
Bolin EH, Gokun Y, Romitti PA, Tinker SC, Summers AD, Roberson PK, Hobbs CA, Malik S, Botto LD, Nembhard WN
J Pediatr. 2021 Sep 8:S0022-3476(21)00877-5. doi: 10.1016/j.jpeds.2021.09.005. Online ahead of print.
OBJECTIVES: To assess associations between maternal smoking and congenital heart defects (CHDs) in offspring.
STUDY DESIGN: We performed a retrospective case-control study using data for cases of CHD (n=8,339) and non-malformed controls (n=11,020) children from all years (1997-2011) of the National Birth Defects Prevention Study. Maternal self-reported smoking one month before through three months after conception was evaluated as a binary (none, any) and categorical (light, medium, heavy) exposure. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals. Stratified analyses were performed for septal defects according to maternal age, pre-pregnancy body mass index, and maternal race/ethnicity.
RESULTS: Multiple CHDs displayed modest associations with any level of maternal periconceptional smoking independent of potential confounders; the strongest associations were for aggregated septal defects (OR 1.5 [1.3-1.7]), tricuspid atresia (OR 1.7 [1.0-2.7]), and double outlet right ventricle (DORV) (1.5 [1.1-2.1]). TA and DORV also displayed dose-response relationships. Among heavy smokers, the highest odds were again observed for TA (aOR 3.0 [1.5-6.1]) and DORV (aOR 1.5 [1.1-2.2]). Heavy smokers ≥35 years old more frequently had a child with a septal defect when compared with similarly aged non-smokers (aOR 2.3 [1.4-3.9]).
CONCLUSIONS: Maternal periconceptional smoking is most strongly associated with septal defects, TA and DORV; the risk for septal defects is modified by maternal age.
September 16, 2021
Perspectives of Pediatric Providers Regarding Clinical Use of Pharmacogenetics
Avello K, Bell M, Stein Q, Bares V, Landsverk M, Salyakina D, McCafferty-Fernandez J, Kingsmore S, Bedrick A, Bhojwani D, Hoyme HE.
S D Med. 2021 Jul;74(7):294-301.
INTRODUCTION: A major goal of the current personalized medicine era is to utilize pharmacogenetics (PGx) in order to influence how medications and therapies are prescribed by providers. However, disparities for prescribing medications between adults and children exist. Research has shown that children are not just small adults and there are different challenges for pediatric providers in regards to ordering and interpreting PGx tests. The goal of this study was to obtain an initial understanding of current pharmacogenetic testing by pediatric providers, as well as determine perceived barriers.
METHODS: We distributed an online survey to pediatric providers at six different institutions across the U.S.
RESULTS: Of the 252 respondents who completed the survey, 24 percent reported previously ordering PGx tests, however, over 90 percent of respondents reported they would feel more comfortable ordering and interpreting results with the assistance of a pharmacist, geneticist, genetic counselor or PGx expert. Additionally, participants identified specific barriers towards the utilization of PGx testing, as well as suggested solutions to overcome these barriers, including increasing provider education regarding testing, collaboration through a multidisciplinary team approach and established PGx programs.
CONCLUSION: As the pharmacogenetic field continues to demonstrate clinical utility in the pediatric population, it will be important to continuously identify and address barriers that exist for providers to allow for more successful implementation of PGx in the pediatric setting, as well as enhance patient care.
August 31, 2021
RPM for NICU and PICU
Integrative genetic, genomic and transcriptomic analysis of heat shock protein and nuclear hormone receptor gene associations with spontaneous preterm birth
Huusko JM, Tiensuu H, Haapalainen AM, Pasanen A, Tissarinen P, Karjalainen MK, Zhang G, Christensen K, Ryckman KK, Jacobsson B, Murray JC, Kingsmore SF, Hallman M, Muglia LJ, Rämet M.
Sci Rep. 2021 Aug 24;11(1):17115. doi: 10.1038/s41598-021-96374-9.
Heat shock proteins are involved in the response to stress including activation of the immune response. Elevated circulating heat shock proteins are associated with spontaneous preterm birth (SPTB). Intracellular heat shock proteins act as multifunctional molecular chaperones that regulate activity of nuclear hormone receptors. Since SPTB has a significant genetic predisposition, our objective was to identify genetic and transcriptomic evidence of heat shock proteins and nuclear hormone receptors that may affect risk for SPTB. We investigated all 97 genes encoding members of the heat shock protein families and all 49 genes encoding nuclear hormone receptors for their potential role in SPTB susceptibility. We used multiple genetic and genomic datasets including genome-wide association studies (GWASs), whole-exome sequencing (WES), and placental transcriptomics to identify SPTB predisposing factors from the mother, infant, and placenta. There were multiple associations of heat shock protein and nuclear hormone receptor genes with SPTB. Several orthogonal datasets supported roles for SEC63, HSPA1L, SACS, RORA, and AR in susceptibility to SPTB. We propose that suppression of specific heat shock proteins promotes maintenance of pregnancy, whereas activation of specific heat shock protein mediated signaling may disturb maternal-fetal tolerance and promote labor.
August 26, 2021
Detecting methylation quantitative trait loci using a methylation random field method
Lyu C, Huang M, Liu N, Chen Z, Lupo PJ, Tycko B, Witte JS, Hobbs CA, Li M.
Brief Bioinform. 2021 Aug 19:bbab323. doi: 10.1093/bib/bbab323. Online ahead of print.
DNA methylation may be regulated by genetic variants within a genomic region, referred to as methylation quantitative trait loci (mQTLs). The changes of methylation levels can further lead to alterations of gene expression, and influence the risk of various complex human diseases. Detecting mQTLs may provide insights into the underlying mechanism of how genotypic variations may influence the disease risk. In this article, we propose a methylation random field (MRF) method to detect mQTLs by testing the association between the methylation level of a CpG site and a set of genetic variants within a genomic region. The proposed MRF has two major advantages over existing approaches. First, it uses a beta distribution to characterize the bimodal and interval properties of the methylation trait at a CpG site. Second, it considers multiple common and rare genetic variants within a genomic region to identify mQTLs. Through simulations, we demonstrated that the MRF had improved power over other existing methods in detecting rare variants of relatively large effect, especially when the sample size is small. We further applied our method to a study of congenital heart defects with 83 cardiac tissue samples and identified two mQTL regions, MRPS10 and PSORS1C1, which were colocalized with expression QTL in cardiac tissue. In conclusion, the proposed MRF is a useful tool to identify novel mQTLs, especially for studies with limited sample sizes.
August 24, 2021
To Be or No B2: A Rare Cause of Stridor and Weakness in a Toddler
Aliya L. Frederick, MD, PhD, Jennifer H. Yang, MD, Sarah Schneider, MD, Alexis Quade, MD, Lucia Guidugli, PhD, CGMBS, Kristen Wigby, MD, Melissa Cameron, MD
Child Neurol Open. 2021 Aug 5;8:2329048X211030723. doi: 10.1177/2329048X211030723. eCollection 2021 Jan-Dec.
We present a case of a young child with a rare metabolic disorder whose clinical presentation resembled that of autoimmune myasthenia gravis. The differential diagnosis was expanded when autoantibody testing was negative and the patient did not respond to standard immunomodulatory therapies. Rapid whole genome sequencing identified 2 rare variants of uncertain significance in the SLC52A3 gene shown to be in compound heterozygous state after parental testing. Biallelic mutations in SLC52A3 are associated with Riboflavin Transporter Deficiency, which in its untreated form, results in progressive neurodegeneration and death. Supplementation with oral riboflavin has been shown to limit disease progression and improve symptoms in some patients. When the diagnosis is suspected, patients should be started on supplementation immediately while awaiting results from genetic studies.
August 17, 2021
Rapid whole genome sequencing in critically ill children: Shifting from unease to evidence, education and equitable implementation
Linda S. Franck, RN, PhD, David Dimmock, MD, FACMG DABP, Charlotte Hobbs, MD, PhD, Stephen F. Kingsmore, MD, DSc
August 17, 2021
Developmental and temporal characteristics of clonal sperm mosaicism
Xiaoxu Yang, Martin W. Breuss, Xin Xu, Danny Antaki, Kiely N. James, Valentina Stanley, Laurel L. Ball, Renee D. George, Sara A. Wirth, Beibei Cao, An Nguyen, Jennifer McEvoy-Venneri, Guoliang Chai, Shareef Nahas, Lucitia Van Der Kraan, Yan Ding, Jonathan Sebat, Joseph G. Gleeson
Cell. 2021 Aug 7:S0092-8674(21)00883-7. doi: 10.1016/j.cell.2021.07.024. Online ahead of print.
Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.
August 17, 2021
Exome sequencing of child-parent trios with bladder exstrophy: Findings in 26 children
Pitsava G, Feldkamp ML, Pankratz N, Lane J, Kay DM, Conway KM, Shaw GM, Reefhuis J, Jenkins MM, Almli LM, Olshan AF, Pangilinan F, Brody LC, Sicko RJ, Hobbs CA, Bamshad M, McGoldrick D, Nickerson DA, Finnell RH, Mullikin J, Romitti PA, Mills JL
Am J Med Genet A. 2021 Aug 5. doi: 10.1002/ajmg.a.62439. Online ahead of print.
Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.
August 9, 2021
Gene DiscoveryRare Disease
Emergence of an early SARS-CoV-2 epidemic in the United States
Mark Zeller, Karthik Gangavarapu, Catelyn Anderson, Allison R. Smither, John
A. Vanchiere, Rebecca Rose, Daniel J. Snyder, Gytis Dudas, Alexander Watts,
Nathaniel L. Matteson, Refugio Robles-Sikisaka, Maximilian Marshall, Amy K.
Feehan, Gilberto Sabino-Santos, Jr., Antoinette R. Bell-Kareem, Laura D. Hughes,
Manar Alkuzweny, Patricia Snarski, Julia Garcia-Diaz, Rona S. Scott, Lilia I. Melnik,
Raphaëlle Klitting, Michelle McGraw, Pedro Belda-Ferre, Peter DeHoff, Shashank
Sathe, Clarisse Marotz, Nathan D. Grubaugh, David J. Nolan, Arnaud C. Drouin,
Kaylynn J. Genemaras, Karissa Chao, Sarah Topol, Emily Spencer, Laura Nicholson,
Stefan Aigner, Gene W. Yeo, Lauge Farnaes, Charlotte A. Hobbs, Louise C. Laurent,
Rob Knight, Emma B. Hodcroft, Kamran Khan, Dahlene N. Fusco, Vaughn S. Cooper,
Phillipe Lemey, Lauren Gardner, Susanna L. Lamers, Jeremy P. Kamil, Robert F.
Garry, Marc A. Suchard, Kristian G. Andersen
Emergence of an early SARS-CoV-2 epidemic in the United States, Cell (2021), The emergence of the COVID-19 epidemic in the United States (U.S.) went largely undetected due to inadequate testing. New Orleans experienced one of the earliest and fastest accelerating outbreaks, coinciding with Mardi Gras. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large-scale events accelerate 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 had limited diversity compared to other U.S. states, and that one introduction of SARS-CoV-2 led to almost all of the early 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 the festival dramatically accelerated transmission. 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 epidemics.
PMID:33564781 | DOI:10.1101/2021.02.05.21251235
August 9, 2021