A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2-Related Mitochondrial Disorder.

POLG2 encodes an accessory subunit in DNA polymerase gamma that is required for mitochondrial DNA synthesis. Monoallelic pathogenic variants in POLG2 are associated primarily with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 4 (PEOA4, MIM #610131). We report a rare case of severe infantile hepatocerebral syndrome associated with biallelic variants in POLG2.

Integrative exome sequencing and machine learning identify MICB and interferon pathway genes as contributors to SSc risk.

Objectives: Systemic sclerosis (SSc) is a complex autoimmune disease with both known and unidentified genetic contributors. While genome-wide association studies (GWAS) have implicated multiple loci, many reside in noncoding regions. We aimed to identify novel protein-coding variants and pathogenic pathways using exome sequencing (ES) integrated with an Evolutionary Action-Machine Learning (EAML) framework, single-cell RNA sequencing (scRNA-seq), and expression quantitative trait locus (eQTL) analysis.

Diagnostic Yield of Exome Sequencing for Pregnancies With and Without Fetal Anomalies and for Stillbirth.

Objective: Exome sequencing (ES) benefits the genetic work-up for fetuses with structural anomalies, but data on its utility for fetuses without anomalies and stillbirths is more limited. We report our experience with prenatal ES for all three indications.

Method: We retrospectively reviewed results from 344 trio-ES performed for fetuses with structural anomalies (N = 262), stillbirths (N = 39), and fetuses without anomalies (N = 43), many of which had a relevant family history.

Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis.

Introduction: The molecular diagnosis of mitochondrial disorders is complicated by phenotypic variability, genetic heterogeneity, and the complexity of mitochondrial heteroplasmy. Next-generation sequencing (NGS) of the mitochondrial genome in combination with a targeted panel of nuclear genes associated with mitochondrial disease provides the highest likelihood of obtaining a comprehensive molecular diagnosis. To assess the clinical utility of this approach, we describe the results from a retrospective review of patients having dual genome panel testing for mitochondrial disease.

Clinical validation of RNA sequencing for Mendelian disorder diagnostics.

Despite rapid advancements in clinical sequencing, over half of diagnostic evaluations still lack definitive results. RNA sequencing (RNA-seq) has shown promise in research settings for bridging this gap by providing essential functional data for accurate interpretation of diagnostic sequencing results. However, despite advanced research pipelines, clinical translation of diagnostic RNA-seq has not yet been realized.

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing.

De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies.

Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.

De Novo Chromosomes 3q and 5q Chromothripsis Leads to a 5q14.3 Microdeletion Syndrome Presentation: Case Report and Review of the Literature.

5q14.3 microdeletion syndrome (MIM#613443) is a neurodevelopmental disorder (NDD) involving copy number loss of multiple genes including Myocyte enhancer factor 2C (MEF2C) gene in the q14.3 region of chromosome 5.

Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.

The 3-methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of inborn errors of metabolism defined biochemically by detectable elevation of 3-methylglutaconic acid (3-MGA) in the urine. In type 1 (or primary) 3-MGA-uria, distal defects in the leucine catabolism pathway directly cause this elevation. Secondary 3-MGA-uria syndromes, however, are unrelated to leucine metabolism-specific defects but share a common biochemical phenotype of elevated 3-MGA.

Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps.

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) ( = 9) or srGS ( = 3) and resolve nine of them.

Neurodevelopmental Disorder Caused by Deletion of , a lncRNA Gene.

encodes a human long noncoding RNA (lncRNA) adjacent to , a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with haploinsufficiency.

Comparing the Diagnostic Yield of Germline Exome Versus Panel Sequencing in the Diverse Population of the Texas KidsCanSeq Pediatric Cancer Study.

Purpose: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population.

Patients And Methods: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel.

Project GIVE: using a virtual genetics service platform to reduce health inequities and improve access to genomic care in an underserved region of Texas.

Background: The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services.

Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing.

Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations.

Novel mutation leading to splice donor loss in a conserved site of gene causes Duchenne muscular dystrophy with cryptorchidism.

Background: As one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants.

Methods: In this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men.

Reducing Time to Diagnosis of Rare Genetic Diseases in a Medically Underserved Hispanic Population- Lessons Learned for Meaningful Engagement.

Background: The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley at the Texas-Mexico border is predominantly Hispanic with a high poverty rate and an increased prevalence of birth defects, with very limited access to genetics services.

Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.

Background: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta.

De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities.

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders.

Disease modeling of ADAMTS9-related nephropathy using kidney organoids reveals its roles in tubular cells and podocytes.

Introduction: Mutations in cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria.