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Congenital diaphragmatic hernia (CDH) is often detectable prenatally. Advances in genetic testing have made it possible to obtain a molecular diagnosis in many fetuses with CDH. Here, we review the aneuploidies, copy number variants (CNVs), and single genes that have been clearly associated with CDH. We suggest that array-based CNV analysis, with or without a chromosome analysis, is the optimal test for identifying chromosomal abnormalities and CNVs in fetuses with CDH. To identify causative sequence variants, whole exome sequencing (WES) is the most comprehensive strategy currently available. Whole genome sequencing (WGS) with CNV analysis has the potential to become the most efficient and effective means of identifying an underlying diagnosis but is not yet routinely available for prenatal diagnosis. We describe how to overcome and address the diagnostic and clinical uncertainty that may remain after genetic testing, and review how a molecular diagnosis may impact recurrence risk estimations, mortality rates, and the availability and outcomes of fetal therapy. We conclude that after the prenatal detection of CDH, patients should be counseled about the possible genetic causes of the CDH, and the genetic testing modalities available to them, in accordance with generally accepted guidelines for pretest counseling in the prenatal setting.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Identifying the etiology of an acute respiratory infection in children is a well-known challenge. In this study, we evaluated the correlation between salivary C-reactive protein (CRP) and its serum counterpart, which is known to be higher in bacterial infections but necessitates a venipuncture. Salivary and serum CRPs were measured in children with an acute respiratory illness, aged 2 months to 18 years. Pearson's correlation coefficients were used to measure correlation. Discrimination of the salivary CRP levels for predicting serum levels above 100 mg/L was calculated and compared to serum CRP levels. Sensitivity and specificity were similarly calculated. Salivary CRP was measured in 104 samples. Levels correlated significantly and positively with serum CRP levels (r = 0.670, p

PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and missense constrained, and has been identified as a candidate gene for autism spectrum disorder (ASD). We describe 16 individuals from 12 families who carry deletions involving PAX5 and surrounding genes, de novo frameshift variants that are likely to trigger nonsense-mediated mRNA decay, a rare stop-gain variant, or missense variants that affect conserved amino acid residues. Four of these individuals were published previously but without detailed clinical descriptions. All these individuals have been diagnosed with one or more neurodevelopmental phenotypes including delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. Seizures were documented in four individuals. No recurrent patterns of brain magnetic resonance imaging (MRI) findings, structural birth defects, or dysmorphic features were observed. Our findings suggest that PAX5 haploinsufficiency causes a neurodevelopmental disorder whose cardinal features include DD, variable ID, and/or ASD.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of personal epigenomes, for ∼25 tissues and >10 assays in four donors (>1500 open-access functional genomic and proteomic datasets, in total). Each dataset is mapped to a matched, diploid personal genome, which has long-read phasing and structural variants. The mappings enable us to identify >1 million loci with allele-specific behavior. These loci exhibit coordinated epigenetic activity along haplotypes and less conservation than matched, non-allele-specific loci, in a fashion broadly paralleling tissue-specificity. Surprisingly, they can be accurately modelled just based on local nucleotide-sequence context. Combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci and enables models for transferring known eQTLs to difficult-to-profile tissues. Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

A family with DYRK1B LOF variant offering to expand the phenotype beyond the metabolic syndrome.

Fibroblast growth factor receptor-like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf-Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf-Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left-sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.

Identifying the etiology of an acute respiratory infection in children is a well-known challenge. In this study, we evaluated the correlation between salivary C-reactive protein (CRP) and its serum counterpart, which is known to be higher in bacterial infections but necessitates a venipuncture. Salivary and serum CRPs were measured in children with an acute respiratory illness, aged 2 months to 18 years. Pearson's correlation coefficients were used to measure correlation. Discrimination of the salivary CRP levels for predicting serum levels above 100 mg/L was calculated and compared to serum CRP levels. Sensitivity and specificity were similarly calculated. Salivary CRP was measured in 104 samples. Levels correlated significantly and positively with serum CRP levels (r = 0.670, p0.001). Area under the curve for predicting serum CRP levels of 100 mg/L was 0.848. For a salivary CRP concentration above 32,610 ng/L, the sensitivity and specificity were 69% and 93%, respectively, for accurately predicting a serum CRP level ≥100 mg/L.Conclusions: Salivary CRP can be used in the pediatric acute setting due to its high specificity for predicting elevated serum levels without the need for venipuncture. Further studies are required to achieve higher sensitivity rates. What is known: • Salivary C-reactive protein has shown correlation to its serum counterpart, mainly in healthy children, adults, and ill neonates. What is new: • In a large population of children with acute respiratory illness, aged 2 months to 18 years, salivary C-reactive protein showed high specificity for predicting elevated serum levels, thus indicating its potential as a diagnostic tool.

Background In recent years, therapeutic drug monitoring (TDM) of anti–tumor necrosis factor alpha (anti-TNFα) agents has been commonly utilized. We aimed to investigate its effect on long-term drug retention and clinical outcomes in pediatric patients with Crohn’s disease (CD). Methods The medical records of pediatric CD patients receiving anti-TNFα agents from 2007 to 2018 were reviewed retrospectively. Patients were stratified to those who initiated anti-TNFα treatment between 2007 and 2012, an era when TDM was not available (TDM-), and patients who initiated anti-TNFα treatment between 2013 and 2018, with at least 1 TDM during firstline anti-TNFα treatment (TDM+). The main outcome measures included time to first anti-TNFα discontinuation (drug retention), flares, and hospitalizations per year of first anti-TNFα treatment, treatment intensification rate, and surgical resection rate. Results One hundred ninety-seven patients were included (n = 98, TDM-; n = 99, TDM+; median [interquartile range] age, 12.6 [10.1–14.2] years; females 68 [35%]). Compared with the TDM- group, the TDM+ group had a longer drug retention time (mean ± SE, 45.0 ± 2.7 vs 33.5 ± 2.4 months; P = 0.001), lower hospitalization rate per patient per year (mean ± SE, 0.51 ± 0.7 vs 0.92 ± 0.81; P < 0.001), and higher treatment intensification rate (70% vs 18%; P < 0.001). Surgical resection rate was not significantly different. Analysis of the entire cohort showed a longer retention time for adalimumab vs infliximab (45.3 ± 2.8 vs 34.8 ± 2.5 months; P = 0.007). Conclusions TDM-based treatment enables longer drug retention time, reflecting better utilization of anti-TNFα agents, with several additional favorable outcomes.

Fibroblast growth factor receptor-like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf-Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf-Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left-sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.

The medical workforce shortage worldwide varies for different residencies.To determine future gaps in medical specialties in Israel by means of a model and to identify trends and considerations among medical students when they choose their residencies.The gap (Gi) assessment model was based upon current demand (Di) and existing (Ei) status for each residency, using the formula [Gi = (Di-Ei)/Ei]. Ei represented the proportion of specific residencies in 2006-2010 out of all Israeli residency graduates and Di was based on questionnaires filled out by medical students at Sackler and Hadassah medical schools in Tel Aviv and Jerusalem, respectively (N = 909).The largest relative shortages (Gi ranges from -1 to 1) were in Pathology (G = -1), Rehabilitation Medicine (-0.9), Radiology (-0.8), Family Medicine (-0.8) and Anesthesiology (-0.8). The highest relative demands were in Surgical subspecialties (2.9) and Obstetrics/Gynecology (OB/GYN) (1.6). More females than males chose residencies in OB/GYN (19.5% vs. 7.1%, P0.001) and Pediatrics (28.1% vs. 15.4%, P0.001). Surgery subspecialties (9% vs. 23.7%, P0.001) were male-predominant. The workload consideration was rated higher among females, while income was rated higher among males. Among students in clinical years, compared to pre-clinical, there was a decline in the selection of some professions, including Surgical subspecialties (9.7% vs. 19.5%, P0.001).The suggested model, based on a survey of demand and current or projected future needs, can be used to assess gaps and plan early interventions. Programs at the level of medical school may affect residency preferences. The decline in selection of surgical professions and the increasing workload as a consideration for residency choice should be given attention.