Optical genome mapping with genome sequencing identifies subtelomeric Xq28 deletion and inserted 7p22.3 duplication in a male with multisystem developmental disorder.

We report a 17-year-old male with supravalvular stenosis, initial failure to thrive and delayed early development, short stature, acromelia, dysmorphic facial features, hypertelorism, macrocephaly, syringomyelia, hypertension, and anxiety disorder. Fluorescent in situ hybridization (FISH), chromosomal microarray analysis (CMA), and exome sequencing (ES) were nondiagnostic. Combined optical genome mapping (OGM) and genome sequencing (GS) showed a complex rearrangement including an X chromosome with a 22.

Multisite Assessment of Optical Genome Mapping for Analysis of Structural Variants in Constitutional Postnatal Cases.

This study compares optical genome mapping (OGM) performed at multiple sites with current standard-of-care (SOC) methods used in clinical cytogenetics. This study included 50 negative controls and 359 samples from individuals (patients) with suspected genetic conditions referred for cytogenetic testing. OGM was performed using the Saphyr system and Bionano Access software version 1.

The genetic legacy of the Hunyadi descendants.

The Hunyadi family is one of the most influential families in the history of Central Europe in the 14th-16th centuries. The family's prestige was established by Johannes Hunyadi, a Turk-beater who rose to the position of governor of the Kingdom of Hungary. His second son, Matthias Hunyadi, became the elected ruler of the Kingdom of Hungary in 1458.

The genetic origin of Huns, Avars, and conquering Hungarians.

Huns, Avars, and conquering Hungarians were migration-period nomadic tribal confederations that arrived in three successive waves in the Carpathian Basin between the 5 and 9 centuries. Based on the historical data, each of these groups are thought to have arrived from Asia, although their exact origin and relation to other ancient and modern populations have been debated. Recently, hundreds of ancient genomes were analyzed from Central Asia, Mongolia, and China, from which we aimed to identify putative source populations for the above-mentioned groups.

Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes.

BackgroundMyotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.

Third case of Duchenne muscular dystrophy and West syndrome: Expanding the spectrum of the DMD neuropsychiatric phenotype.

Duchenne muscular dystrophy is an X-Linked neuromuscular disorder, and the most common muscular dystrophy. Neuropsychiatric phenotype associated to DMD gene mutations include now low IQ scores, epilepsy, autism, and attention deficit disorder. These have been observed with higher frequency in mutations that disrupt the short isoforms Dp71 and Dp140.

Blood group typing from whole-genome sequencing data.

Many questions can be explored thanks to whole-genome data. The aim of this study was to overcome their main limits, software availability and database accuracy, and estimate the feasibility of red blood cell (RBC) antigen typing from whole-genome sequencing (WGS) data. We analyzed whole-genome data from 79 individuals for HLA-DRB1 and 9 RBC antigens.

Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs.

Background: Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.

Results: We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types.

Clinical Transcriptome Sequencing Confirms Activation of a Cryptic Splice Site in Suspected -Related Disorder.

encodes a brain-specific Ras GTPase activating protein (GAP) that regulates synaptic strength in glutamatergic neurons. Pathogenic variants in this gene are associated with a neurodevelopmental disorder characterized by intellectual and developmental disabilities, generalized epilepsy, hypotonia, and autism spectrum disorders. We describe a young male with suspected -related disorder given clinical overlap and identification of an intronic variant of uncertain significance; clinical transcriptome analysis demonstrated activation of a cryptic acceptor splice site resulting in frameshift and introduction of a stop codon.

Inherited selective cobalamin malabsorption in Komondor dogs associated with a CUBN splice site variant.

Background: Three Komondor dogs in a small family and 3 sporadic cases exhibited a constellation of signs that included juvenile-onset of failure-to-thrive, inappetence, vomiting and/or diarrhea, and weakness. In each we documented dyshematopoiesis, increased anion gap, methylmalonic acidemia/-uria, and serum cobalamin deficiency. Urine protein electrophoresis demonstrated excretion of cubam ligands.

Next-Generation Sequencing and Mutational Analysis: Implications for Genes Encoding LINC Complex Proteins.

Targeted panel, whole exome, or whole genome DNA sequencing using next-generation sequencing (NGS) allows for extensive high-throughput investigation of molecular machines/systems such as the LINC complex. This includes the identification of genetic variants in humans that cause disease, as is the case for some genes encoding LINC complex proteins. The relatively low cost and high speed of the sequencing process results in large datasets at various stages of analysis and interpretation.

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy.

Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis.

Brain-Derived Neurotrophic Factor Elevates Activating Transcription Factor 4 (ATF4) in Neurons and Promotes ATF4-Dependent Induction of .

Activating transcription factor 4 (ATF4) plays important physiologic roles in the brain including regulation of learning and memory as well as neuronal survival and death. Yet, outside of translational regulation by the eIF2α-dependent stress response pathway, there is little information about how its levels are controlled in neurons. Here, we show that brain-derived neurotrophic factor (BDNF) promotes a rapid and sustained increase in neuronal ATF4 transcripts and protein levels.

Ultra-rare mutations in segregate in Caribbean Hispanic families with Alzheimer disease.

Objective: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families.

Methods: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls.

Implementation of next generation sequencing into pediatric hematology-oncology practice: moving beyond actionable alterations.

Background: Molecular characterization has the potential to advance the management of pediatric cancer and high-risk hematologic disease. The clinical integration of genome sequencing into standard clinical practice has been limited and the potential utility of genome sequencing to identify clinically impactful information beyond targetable alterations has been underestimated.

Methods: The Precision in Pediatric Sequencing (PIPseq) Program at Columbia University Medical Center instituted prospective clinical next generation sequencing (NGS) for pediatric cancer and hematologic disorders at risk for treatment failure.

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma.

Background: Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities.

A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading.

Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome.

Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion.

Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle.

Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma.

We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypical ETV6-NTRK3 translocation.