Primary myelofibrosis with concurrent MPL and atypical JAK2 mutations.

Distinct bone marrow morphology is considered the primary basis for the diagnosis of BCR::ABL1-negative myeloproliferative neoplasms (MPNs). However, presence of a mutually exclusive classical driver mutation in JAK2, CALR, or MPL aids in diagnosing and determining the prognosis of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Few recent studies have reported presence of dual mutations in MPNs and double mutations in patients with PMF have been rarely described.

A Novel EP300 Variant in an African American Girl With Global Developmental Delay and Leukemia.

Background: Pathogenic germline missense and in-frame indel variants in exons 30 or 31 of the EP300 gene are associated with Menke-Hennekam syndrome-2 (MKHK2). The phenotypic spectrum associated with MKHK2 is variable, including neurodevelopmental, respiratory, skeletal, and immunological impairments. Based on their genetic, clinical, and DNA methylation profiles, a recent study proposed three domain-specific subtypes of MKHK: MKHK-ZZ, MKHK-TAZ2, and MKHK-ID4.

A treatment-refractory aggressive MDS-MLD with multiple highly complex chromosome 5 intrachromosomal rearrangements: a case report.

Background: A patient with a myelodysplastic neoplasm exhibited a karyotype with multiple complex chromosome 5 rearrangements. This patient appeared to have a catastrophic cytogenetic event that manifested as a treatment-refractory aggressive form of disease, which lead to patient demise within one year. Both the clinical presentation and disease course were unusual based on the medical history and morphologic findings.

Quality metrics for enhanced performance of an NGS panel using single-vial amplification technology.

Aims: Targeted next-generation sequencing (NGS) panels, which identify genomic alterations, are the stronghold of molecular oncology laboratories. In spite of technological advances, the quantity and quality of DNA from formalin-fixed paraffin-embedded tissue and paucicellular specimens are barriers to successful sequencing. Here, we describe an NGS assay employing single tube stem-loop inhibition mediated amplification technology that delivers highly accurate results with low input DNA.

Expanding the phenotype of deficiency.

Vacuolar ATPases (V-ATPases) are large multisubunit proton pumps conserved among all eukaryotic cells that are involved in diverse functions including acidification of membrane-bound intracellular compartments. The gene encodes an accessory subunit of the vacuolar (V)-ATPase protein pump. Pathogenic variants in have been described in association with a congenital disorder of glycosylation (CDG), which are highly variable, but often characterized by immunodeficiency, hepatopathy, and neurologic manifestations.

Clinical exome sequencing for inherited retinal degenerations at a tertiary care center.

Inherited retinal degenerations are clinically and genetically heterogeneous diseases characterized by progressive deterioration of vision. This study aimed at assessing the diagnostic yield of exome sequencing (ES) for an unselected cohort of individuals with hereditary retinal disorders. It is a retrospective study of 357 unrelated affected individuals, diagnosed with retinal disorders who underwent clinical ES.

3q27.1 microdeletion causes prenatal and postnatal growth restriction and neurodevelopmental abnormalities.

Background: Overlapping microdeletions of chromosome 3q26-3q28 have been reported in eight individuals. The common phenotype observed in these individuals include intrauterine growth restriction, short stature, microcephaly, feeding difficulties, facial dysmorphisms, limb abnormalities and developmental delay. The most striking clinical features shared among all reported cases is prenatal and postnatal growth restriction and neurodevelopmental abnormalities.

A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report.

Background: Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete.

ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years.

Key considerations for comprehensive validation of an RNA fusion NGS panel.

Objectives: Validation of RNA-based NGS assays for the detection of therapeutically targetable gene fusions is challenging. Here, we report systematic validation and quality control monitoring of our targeted fusion panel for the detection of 17 clinically relevant fusion transcripts across several tumor types. We implemented this RNA Fusion Panel as a reflex test for tumors lacking DNA driver mutations.

Targeting SLMAP-ALK-a novel gene fusion in lung adenocarcinoma.

Assessment of gene rearrangements is strongly recommended by the Molecular Testing Guideline for Selection of Lung Cancer Patients proposed by IASLC, AMP, and CAP at the time of diagnosis for patients with advanced stage disease. Non-small-cell lung cancer (NSCLC) with gene rearrangements or the resulting fusion proteins have been, for the most part, successfully targeted with ALK tyrosine kinase inhibitors (TKIs). The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in Recent studies have suggested that EML4-ALK variants may have differential responses to TKIs.

Molecular Basis for Strain Variation in the Saccharomyces cerevisiae Adhesin Flo11p.

FLO11 encodes a yeast cell wall flocculin that mediates a variety of adhesive phenotypes in Saccharomyces cerevisiae. Flo11p is implicated in many developmental processes, including flocculation, formation of pseudohyphae, agar invasion, and formation of microbial mats and biofilms. However, Flo11p mediates different processes in different yeast strains.

DNA Methylation Profiling at Single-Base Resolution Reveals Gestational Folic Acid Supplementation Influences the Epigenome of Mouse Offspring Cerebellum.

It is becoming increasingly more evident that lifestyle, environmental factors, and maternal nutrition during gestation can influence the epigenome of the developing fetus and thus modulate the physiological outcome. Variations in the intake of maternal nutrients affecting one-carbon metabolism may influence brain development and exert long-term effects on the health of the progeny. In this study, we investigated whether supplementation with high maternal folic acid during gestation alters DNA methylation and gene expression in the cerebellum of mouse offspring.

High Gestational Folic Acid Supplementation Alters Expression of Imprinted and Candidate Autism Susceptibility Genes in a sex-Specific Manner in Mouse Offspring.

Maternal nutrients play critical roles in modulating epigenetic events and exert long-term influences on the progeny's health. Folic acid (FA) supplementation during pregnancy has decreased the incidence of neural tube defects in newborns, but the influence of high doses of maternal FA supplementation on infants' brain development is unclear. The present study was aimed at investigating the effects of a high dose of gestational FA on the expression of genes in the cerebral hemispheres (CHs) of 1-day-old pups.

Lifestyle, pregnancy and epigenetic effects.

Rapidly growing evidences link maternal lifestyle and prenatal factors with serious health consequences and diseases later in life. Extensive epidemiological studies have identified a number of factors such as diet, stress, gestational diabetes, exposure to tobacco and alcohol during gestation as influencing normal fetal development. In light of recent discoveries, epigenetic mechanisms such as alteration of DNA methylation, chromatin modifications and modulation of gene expression during gestation are believed to possibly account for various types of plasticity such as neural tube defects, autism spectrum disorder, congenital heart defects, oral clefts, allergies and cancer.

Microarray analysis reveals higher gestational folic Acid alters expression of genes in the cerebellum of mice offspring-a pilot study.

Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring.

Folic acid supplementation in pregnancy and implications in health and disease.

Maternal exposure to dietary factors during pregnancy can influence embryonic development and may modulate the phenotype of offspring through epigenetic programming. Folate is critical for nucleotide synthesis, and preconceptional intake of dietary folic acid (FA) is credited with reduced incidences of neural tube defects in infants. While fortification of grains with FA resulted in a positive public-health outcome, concern has been raised for the need for further investigation of unintended consequences and potential health hazards arising from excessive FA intakes, especially following reports that FA may exert epigenetic effects.

Increasing maternal or post-weaning folic acid alters gene expression and moderately changes behavior in the offspring.

Background: Studies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice.

Single-base resolution of mouse offspring brain methylome reveals epigenome modifications caused by gestational folic acid.

Background: Epigenetic modifications, such as cytosine methylation in CpG-rich regions, regulate multiple functions in mammalian development. Maternal nutrients affecting one-carbon metabolism during gestation can exert long-term effects on the health of the progeny. Using C57BL/6 J mice, we investigated whether the amount of ingested maternal folic acid (FA) during gestation impacted DNA methylation in the offspring's cerebral hemispheres.