Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations.

The term "recurrent constellations of embryonic malformations" (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging. In this study, genome-wide DNA methylation analysis was conducted on DNA samples obtained from the peripheral blood of 53 individuals with RCEM characterized by clinical features recognized as VACTERL and/or oculoauriculovertebral spectrum association. We identified a common DNA methylation episignature in 40 out of the 53 individuals. Subsequently, a sensitive and specific binary classifier was developed based on the DNA methylation episignature. This classifier can facilitate the use of RCEM episignature as a diagnostic biomarker in a clinical setting. The study also investigated the functional correlation of RCEM DNA methylation relative to other genetic disorders with known episignatures, highlighting the common genomic regulatory pathways involved in the pathophysiology of RCEM.

PRKAG2-Related Lethal Congenital Glycogen Storage Disease of the Heart as Rare Cause of Fetal Hydrops With Bradycardia and Cardiomyopathy: Clinical Report and Literature Review.

Nonimmune foetal hydrops is a prenatal condition associated with significant perinatal mortality. It has so far been associated with over 200 chromosomal and monogenic conditions, most frequently chromosomal aneuploidies and RASopathies. Thorough clinical phenotyping and genetic evaluation are essential to determine the underlying etiology of this clinical entity and guide obstetrical and postnatal management. In this report, we describe the prenatal presentation and postnatal outcome of a pregnancy with Lethal Congenital Glycogen Storage Disease of the Heart, a rare autosomal dominant non lysosomal cardiac glycogenosis caused by a novel de novo likely pathogenic variant in the Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2 (PRKAG2) gene, [NM_016203.3:c.1150A > G, p.(Arg384Gly)]. To this day, only six other molecularly confirmed prenatal presentations of this condition have been reported. This clinical report adds to the knowledge on the prenatal features, clinical evolution, molecular diagnosis and pathological findings of this disorder and underlines the clinical utility of comprehensive molecular testing in the investigation of nonimmune foetal hydrops and fetal cardiomyopathy.