-Associated Ocular Albinism in a Hispanic Family and Review of the Literature.

While ocular albinism (OA) is usually associated with reduced vision, nystagmus, and foveal hypoplasia, there is phenotypic variability in iris and fundus hypopigmentation. Hemizygous pathogenic/likely pathogenic (P/LP) variants in at X: 151.56-151.

Genetic Investigation and Transcriptome Profiling in a Nuclear Family With Peutz-Jeghers Syndrome.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder hallmarked by mucocutaneous melanocytic macules and gastrointestinal hamartomatous polyposis associated with germline/somatic pathogenic variants in the tumor suppressor . PJS is clinically heterogeneous; however, the relationship between clinical phenotype and genotype remains elusive. Here, we report a family with PJS that harbors a heterozygous whole gene deletion combined with a heterozygous variant in that segregates with mucocutaneous pigmentation in the family.

Monozygotic twins discordant for juvenile dermatomyositis: clinical, serological and gene expression studies.

Background: Juvenile Dermatomyositis (JDM) is a rare pediatric autoimmune disease involving a combination of environmental and genetic susceptibility factors. Monozygotic twins provide a unique opportunity to examine disease-specific gene expression as they share the same DNA. The goal of this study is to characterize gene expression differences between monozygotic twins discordant for JDM.

Hemophagocytic Lymphohistiocytosis with Predominant T-Lymphocytes in Young Child: An Unusual Presentation of Evolving Acute Myeloid Leukemia.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening condition commonly observed in young children. Distinguishing primary HLH from secondary HLH, such as malignancy-associated HLH, can be challenging, potentially leading to misdiagnosis and inappropriate treatment. A 16-month-old female presented with fever, decreased appetite, and rhinorrhea.

Novel SMARCA4 Variant in an Infant With Atypical Teratoid Rhabdoid Tumor.

Atypical teratoid/rhabdoid tumors (AT/RT) are malignant central nervous system (CNS) tumors. Typically, AT/RT is classified as SMARCB1 (INI-1) deficient or as SMARCA4 (BRG1) deficient. In this case, we describe a unique case of AT/RT with a novel SMARCA4 missense variant identified on next-generation sequencing but retained expression of INI-1 and BRG-1 on immunohistochemistry.

B-cell lymphoblastic leukemia/lymphoma with mutated N159Y: clinical and genetic features of an emerging entity.

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A Case of Non-Syndromic Congenital Cataracts Caused by a Novel Variant in the C-Terminal DNA-Binding Domain-Case Report and Literature Review.

The gene encodes a transcription factor in which pathogenic variants have been associated with both isolated and syndromic congenital cataracts. We aim to review the variants in the C-terminal DNA-binding domain associated with non-syndromic congenital cataracts and describe a patient with a novel, disease-causing de novo missense variant. Published reports of C-terminal variants and their associated congenital cataracts and ophthalmic findings were reviewed.

Homozygosity for disease-causing variants in AMT and GLDC in a patient with severe nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is a relatively well-characterized inborn error of metabolism that results in a combination of lethargy, hypotonia, seizures, developmental arrest, and, in severe cases, death early in life. Three genes encoding components of the glycine cleavage enzyme system-GLDC, AMT, and GCSH-are independently associated with NKH. We report on a patient with severe NKH in whom the homozygous pathogenic variant in AMT (NM_000481.

Expansion of the phenotypic spectrum associated with pathogenic missense variation in DHX16.

Pathogenic heterozygous variants in DHX16 have been recently identified in association with a variety of clinical features, including neuromuscular disease, sensorineural hearing loss, ocular anomalies, and other phenotypes. All DHX16 disease-causing variants previously reported in affected individuals are missense in nature, nearly all of which were found to be de novo. Here we report on a patient with neuromuscular disease, hearing loss, retinal degeneration, and previously unreported phenotypic features including mitochondrial deficiency and primary ovarian insufficiency, in whom a novel de novo likely pathogenic variant in DHX16 NM_003587.

ROS1 Alterations as a Potential Driver of Gliomas in Infant, Pediatric, and Adult Patients.

Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion-positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1 fusion gliomas along with the characterization and meta-analysis of new and published cases.

Transitional care and clinical management of adolescents, young adults, and suspected new adult patients with congenital central hypoventilation syndrome.

Purpose: With contemporaneous advances in congenital central hypoventilation syndrome (CCHS), recognition, confirmatory diagnostics with PHOX2B genetic testing, and conservative management to reduce the risk of early morbidity and mortality, the prevalence of identified adolescents and young adults with CCHS and later-onset (LO-) CCHS has increased. Accordingly, there is heightened awareness and need for transitional care of these patients from pediatric medicine into a multidisciplinary adult medical team. Hence, this review summarizes key clinical and management considerations for patients with CCHS and LO-CCHS and emphasizes topics of particular importance for this demographic.

A performance evaluation study: Variant annotation tools - the enigma of clinical next generation sequencing (NGS) based genetic testing.

Dramatically expanding our ability for clinical genetic testing for inherited conditions and complex diseases such as cancer, next generation sequencing (NGS) technologies are allowing for rapid interrogation of thousands of genes and identification of millions of variants. Variant annotation, the process of assigning functional information to DNA variants based on the standardized Human Genome Variation Society (HGVS) nomenclature, is a fundamental challenge in the analysis of NGS data that has led to the development of many bioinformatic algorithms. In this study, we evaluated the performance of 3 variant annotation tools: Alamut® Batch, Ensembl Variant Effect Predictor (VEP), and ANNOVAR, benchmarked by a manually curated ground-truth set of 298 variants from the medical exome database at the Molecular Diagnostics Laboratory at Lurie Children's Hospital.

3D Printed gelatin film with extract.

Active packaging, such as edible film with antibacterial properties, can help extend the shelf life of food. The research aimed to develop a 3D printed gelatin edible film by using glycerol and extract (GAE). Mechanical properties of gelatin gel, physical, mechanical, and antimicrobial properties of edible film with glycerol and GAE were determined.

Utility and Outcomes of the 2019 American College of Medical Genetics and Genomics-Clinical Genome Resource Guidelines for Interpretation of Copy Number Variants with Borderline Classifications at an Academic Clinical Diagnostic Laboratory.

In 2019, the American College of Medical Genetics and Genomics and the Clinical Genome Resource published updated technical standards for the interpretation and reporting of copy number variants (CNVs), introducing a semiquantitative classification system to improve standardization and consistency between laboratories. Evaluation of these guidelines' performance will inform laboratories about the impact of their implementation into clinical practice. A total of 145 difficult-to-classify CNVs, originally assessed by an academic molecular diagnostic laboratory, were re-interpreted/classified according to the American College of Medical Genetics and Genomics-Clinical Genome Resource guidelines.

Genetic changes associated with relapse in favorable histology Wilms tumor: A Children's Oncology Group AREN03B2 study.

Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation.

Cytology-histology correlation of myoepithelial tumors harboring EWSR1-POU5F1 fusions: A report of two cases.

Myoepithelial tumors (MET) constitute a group of neoplasms with a variety of morphologic, immunophenotypic, and molecular features. Approximately half of MET of soft tissue harbor EWSR1 gene rearrangements with a subset showing EWSR1-POU5F1 fusions and demonstrating distinctive tendency towards aggressive behavior in children. Histologically, EWSR1-POU5F1-positive MET typically show clear-cell morphology with malignant features including marked pleomorphism and atypical mitotic figures.

Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy.

Background Pediatric dilated cardiomyopathy (DCM) is a well-known clinical entity; however, phenotype-genotype correlations are inadequately described. Our objective was to provide genotype associations with life-threatening cardiac outcomes in pediatric DCM probands. Methods and Results We performed a retrospective review of children with DCM at a large pediatric referral center (2007-2016), excluding syndromic, chemotherapy-induced, and congenital heart disease causes.

Genomic Autopsy of Sudden Deaths in Young Individuals.

Importance: Postmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information.

Objective: To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families.

Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype-phenotype correlation in congenital central hypoventilation syndrome (CCHS).

Purpose: CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established.

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children.

Introduction: Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood.

Methods: We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years.

Transcript analysis for variant classification resolution in a child with primary ciliary dyskinesia.

Transcriptional analysis can be utilized to reconcile variants of uncertain significance, particularly those predicted to impact splicing. Laboratory analysis of the predicted mRNA transcript may allow inference of the in vivo impact of the variant and aid prediction of its clinical significance. We present a patient with classical features of primary ciliary dyskinesia (PCD) who was identified to have compound heterozygous variants in the gene (c.