Case Series of Nizon-Isidor Syndrome by Heterozygous Variants in MED12L With Further Evidence of Mitotic Instability in One Case With Diploid-Triploid Mosaicism.

Nizon-Isidor syndrome is a rare disorder caused by heterozygous variants in MED12L, with only eight documented cases in the literature. Here, we present three additional cases of this syndrome. Proband 1 was a 7-year-old female who presented with developmental delay, right-leg hemihypertrophy, laryngeal cleft, esotropia, abnormal skin pigmentation, sectoral iris hypopigmentation, dysphagia, periventricular nodular heterotopia, seizures, morbid obesity, and a pelvic kidney.

First clinical diagnosis of FAME3 via commercial Long-Read sequencing reveals mosaic repeat expansion in MARCHF6 gene.

Familial Adult Myoclonic Epilepsy type 3 (FAME3) is a rare autosomal dominant disorder characterized by cortical tremor and epilepsy, caused by a noncoding pentanucleotide repeat expansion (TTTTA/TTTCA) in the MARCHF6 gene. Conventional genetic testing often fails to detect this expansion due to its repetitive structure and intronic location. We evaluated a 61-year-old woman with refractory myoclonic and generalized tonic-clonic seizures, whose prior genetic testing-including exome and genome sequencing-was non-diagnostic.

The Undiagnosed Diseases Network (UDN) Solves Ocular Syndromic Diagnostic Dilemmas.

Purpose: The multicenter NIH-funded Undiagnosed Diseases Network (UDN) exists to diagnose puzzling and newly discovered conditions. We report the UDN's assistance in diagnosing perplexing ocular disorders along with 6 case illustrations.

Design: Retrospective Interventional Case Series.

Circular RNA Profiling Identifies as a -Derived Regulator of Endothelial Proliferation and Stress Responses.

Background: The gene encodes the BMPR-II (bone morphogenetic protein receptor type-II) and is a known regulator of endothelial proliferation, apoptosis, and translational stress responses. While these effects are generally attributed to the actions of BMPR-II protein, we used circular RNA profiling to identify and as new -derived functional RNAs.

Methods: Circular RNAs were profiled by ultradeep RNA sequencing of human pulmonary artery endothelial cells.

RNA-Seq and ChIP-Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes.

Transcription factor rare variants associate with pulmonary arterial hypertension (PAH), particularly in children, and are the second most common cause of heritable PAH. However, TBX4's down-stream targets and the molecular and cellular pathways these targets regulate remain largely unknown in PAH. We combined RNA-seq and ChIP-seq results to identify TBX4 direct targets in lung fibroblasts and pericytes, respectively.

A review of multiple diagnostic approaches in the undiagnosed diseases network to identify inherited metabolic diseases.

Background: The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs.

Resolution of variable expressivity in a multi-generational family using deep clinical phenotyping and models.

Purpose: Variants in result in a rare neurodevelopmental disorder characterized by a variable clinical presentation of symptoms including developmental delay, epilepsy, motor dysfunction, and autism spectrum disorder. haploinsufficiency has been confirmed as the predominant pathway of related neurodevelopmental disorders (NDDs), however, the molecular mechanism underlying the variable clinical presentation remains unclear.

Methods: Here, through work of the Undiagnosed Diseases Network, we identify an undiagnosed individual with an inherited p.

The Genetic Landscape of Familial Pulmonary Fibrosis.

Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction.

The Association between Exposures and Disease Characteristics in Familial Pulmonary Fibrosis.

Heterogeneous characteristics are observed in familial pulmonary fibrosis (FPF), suggesting that nongenetic factors contribute to disease manifestations. To determine the relationship between environmental exposures and disease characteristics of FPF, including the morphological characteristics on chest computed tomography (CT) scan, and timing of FPF symptom onset, lung transplantation, or death. Subjects with FPF with an exposure questionnaire and chest CT were selected from a prospective cohort at Vanderbilt.

Limitations of exome sequencing in detecting rare and undiagnosed diseases.

While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results.

Development and Progression of Radiologic Abnormalities in Individuals at Risk for Familial Interstitial Lung Disease.

The preclinical natural history of progressive lung fibrosis is poorly understood. Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia. Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA.

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. We performed deep targeted resequencing (3.