Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects' phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.

Background: Human papillomavirus (HPV) 16 and 18 are associated with cervical carcinogenesis through an interaction between HPV oncogenic proteins and cell cycle regulatory genes. However, the exact pathogenetic mechanisms are not determined yet.

Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common. We reviewed the clinical features and management as well as the molecular basis of Alagille syndrome.

Currently, the industry-wide trend for viable air sampling in indoor environmental investigations is to use sampling times between 2 and 4 min in duration. Our results support the routine use of a 6-min sampling time where low spore loads are expected, resulting in improved limits of detection.

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The potential damage to man-made structures associated with earthquake-induced liquefaction has been demonstrated in catastrophic fashion over the past 40-50 years. The phenomenon of liquefaction of relatively clean, poorly graded, sands is well understood. However, the same cannot be said for cases when finegrained materials are present within the sand matrix. A resolution of what appears in some reported studies as conflicting observations related to the effect of fines on cyclic resistance is of concern, particularly for land reclamation projects and sea fills where the material source is variable and may contain significant levels of fines. The nature of the fines themselves may have a measurable effect on the matrix behavior. The work presented herein explores the effect of silt and clay-size carbonaceous fines on the liquefaction susceptibility of sand. The choice of fines was guided by the conditions associated with the Lebanon coastal reclamation projects, where limestone/marlstone quarry source materials are dominant. The results obtained confirm the significant effect of fines on the cyclic resistance. They also confirm the existence of a limit fines content and a plasticity index threshold and establish their effect on observed behavior.

Traditional approaches to prenatal genetic diagnosis for common presentations such as short femurs or intrauterine growth restriction are imperfect, and whole-exome sequencing is an emerging option. Mucolipidosis type II (I-cell disease) is an ultra-rare autosomal recessive lysosomal storage disorder with the potential for prenatal-onset skeletal and placental manifestations. We describe the prenatal signs in two recent unrelated patients with confirmed diagnoses soon after birth. In both cases, parents were consanguineous but there was no known family history of mucolipidosis type II. False reassurance was provided after negative testing for another disease with overlapping prenatal manifestations already present in one of the families, emphasizing that offspring of consanguineous parents can be at risk for more than one recessive condition. Our experience illustrates the potential advantages in expanding prenatal applications of WES for the identification of rare single gene disorders in offspring of consanguineous unions.

What's Already Known About This Topic? There are no publications linking prenatally detected hepatic arteriovenous malformations (AVM) with the diagnosis of hereditary hemorrhagic telangiectasia (HHT). To date only one case series reported symptomatic neonatal hepatic AVMs, none of which were detected prenatally. What Does This Study Add? We report two siblings with molecularly confirmed HHT who presented with symptomatic hepatic AVMs, one of which was detected prenatally. This report suggests that prenatal or neonatal hepatic AVMs merit evaluation for HHT.