Our Research

BACKGROUND: Neural tube defects such as spina bifida (SB) are congenital anomalies associated with significant morbidity and mortality worldwide. Environmental factors, particularly folate, modify SB risk. Based on recurrence rates of SB within families, genetic risk also contributes to SB development. However, the effect of maternal folate intake on genetic risk for SB in Bangladesh has not been quantified.

METHODS: Genetic variants were imputed from array data of 112 infants with SB and 116 infants without SB. After quality filtering, genome-wide association was performed on 91 infants with SB and 97 without. Maternal folate intake and maternal nail arsenic concentration were included as covariates and interaction terms (SNP × Folate, SNP × Arsenic) along with maternal age, infant sex, and 10 principal components as covariates.

RESULTS: Two loci had variants nominally associated with SB: one within the coding region of WWOX, including rs7184417 (odds ratio [OR] = 6.20, p = 2.22E-06), and a second in the coding region of ISOC2 (rs4801638; OR = 0.24, p = 5.75E-06). With the gene-folate interaction, a locus in CNTN5 was associated with SB. After including the gene-arsenic interaction, the gene-folate interaction effect was nominally associated with a locus in CTNNA2.

CONCLUSIONS: Inclusion of maternal folate intake as a covariate and interaction term identified three genomic loci that could impact the risk for SB. A fourth locus was identified when maternal arsenic level was included. These nominal associations should be assessed in additional cohorts with larger sample sizes. Novel genes impacted by these loci may interact with previously reported genes for SB.

Umbilical arterial catheters (UAC) in neonates are used for blood pressure monitoring, blood sampling, administration of fluids, nutrition, and medications. As UAC applications evolve, enteral nutrition practices vary in neonates in the presence of a UAC. The theoretical concern for mesenteric ischemia when a UAC is in place led to early nil per os approaches, delaying the initiation of enteral nutrition. More contemporary practices have favored introducing enteral feeding in neonates with UACs. However, there remains a paucity of data to guide clinical practice approaches regarding enteral feeding in neonates with a UAC in place. In this perspective article, we examine the physiological effects of UACs and review existing literature on feeding practices in neonates with a UAC. We offer an approach to managing enteral feeding in neonates with a UAC, addressing the central question: Is routine feeding in neonates with a UAC in place justified in current clinical practice?

Haploinsufficiency of the RNA splicing regulator, RBFOX2 , is linked to congenital heart disease (CHD), yet its pathogenic mechanisms remain unclear. Here, we demonstrate that RBFOX2 is essential for progressing cardiomyocyte (CM) differentiation by shifting exon usage profiles to more mature patterns in sarcomere, cytoskeletal, and focal adhesion genes, including alpha-actinin-2 ( ACTN2 ). This maturation program is initiated by critical levels of RBFOX2 that facilitate autoregulatory splicing at mutually exclusive exons encoding early and late isoforms with distinct functional roles. In heterozygous CMs, autoregulation is disrupted, which skews isoform ratios and generates a dominant-negative product caused by exon co-inclusion. Finally, we demonstrate that overexpression of ACTN2 rescues heterozygous, but not null, phenotypes by restoring contractility, which triggers a mechanosensing feedback loop involving upregulation of RBFOX2 from the wildtype allele and transcriptome maturation. Our data suggest that decreased RBFOX2 dosage and autoregulation impair CM differentiation, contributing to CHD pathogenesis and heart failure susceptibility.

This paper addresses the problem of detecting possible serious bacterial infection (pSBI) of infancy, i.e. a clinical presentation consistent with bacterial sepsis in newborn infants using cranial ultrasound (cUS) images. The captured image set for each patient enables multiview imagery: coronal and sagittal, with geometric overlap. To exploit this geometric relation, we develop a new learning framework, called the intersection-guided Crossview Local-and Image-level Fusion Network (CLIF-Net). Our technique employs two distinct convolutional neural network branches to extract features from coronal and sagittal images with newly developed multi-level fusion blocks. Specifically, we leverage the spatial position of these images to locate the intersecting region. We then identify and enhance the semantic features from this region across multiple levels using cross-attention modules, facilitating the acquisition of mutually beneficial and more representative features from both views. The final enhanced features from the two views are then integrated and projected through the image-level fusion layer, outputting pSBI and non-pSBI class probabilities. We contend that our method of exploiting multi-view cUS images enables a first of its kind, robust 3D representation tailored for pSBI detection. When evaluated on a dataset of 302 cUS scans from Mbale Regional Referral Hospital in Uganda, CLIF-Net demonstrates substantially enhanced performance, surpassing the prevailing state-of-the-art infection detection techniques.

BACKGROUND: Congenital heart disease (CHD) is an important cause of childhood mortality as well as morbidity in children and adults. While genetic risk contributes to the majority of CHD, most individuals with CHD do not have an identified genetic diagnosis. Short tandem repeat (TR) elements are composed of repeated base pair motifs for 2-6 basepairs that are highly polymorphic in length between individuals. These regions had been difficult to study with short read sequencing, and they have not been studied at a large scale in the context of CHD. New software and sequencing platforms have allowed for more accurate TR element genotyping. Therefore, we aimed to identify TR element variants that could impact the expression of known CHD genes.

RESULTS: We identified de novo and inherited TR element variants near known CHD genes in participants with CHD (n = 1,899) in the Pediatric Cardiac Genomics Consortium cohort as well as unaffected participants (n = 1,932) from the Simons Foundation Autism Research Initiative using short-read sequencing followed by variant calling with the gangSTR pipeline. Comparison with long-read sequencing confirmed proband genotypes for 75% (91/120) of the TR element variants identified using short read sequencing. 114 TR element regions had 3 or more de novo TR element variants, compared to an expectation of 74 TR element regions (1.54-fold enrichment, p < 1.5E-5). CHD genes CACNA1C and EVC2 had the strongest enrichment of TR element variants in the CHD cohort, determined by a higher frequency of nearby de novo TR length variants in the CHD cohort compared to the non-CHD cohort. Within CHD trios, there was over-transmission of a TR element variant near Tab 2.

CONCLUSIONS: In a targeted analysis of de novo and transmitted TR element variants in a large cohort of CHD probands, each individual had   1 de novo TR element variant near a CHD gene, and participants with CHD demonstrate clustering of variants within TR element regions. Long-read sequencing confirmed the majority of TR element variants identified using the gangSTR pipeline. De novo variants in known CHD genes were enriched in participants with CHD, with specific enrichment in TR elements near CACNA1C, EVC2, and Tab 2 in the CHD cohort. Many individual TR element variants were in known regulatory regions, but further work is needed to determine their functional impact.