Copy-number variants in the ACMG secondary finding genes: A reporting framework for clinical cytogeneticists.

Purpose: To determine the pathogenicity and frequency of copy-number variants (CNV) in the 81 secondary finding (SFv3.2) genes recommended by the American College of Medical Genetics and Genomics (ACMG).

Methods: Review of published evidence on pathogenicity of partial or complete copy-number losses or gains in ACMG SFv3.

The challenges and opportunities of offering and integrating training in clinical molecular genetics and clinical cytogenetics: A survey of LGG Fellowship Program Directors.

Purpose: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model.

Methods: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time.

Case report: Early use of whole exome sequencing unveils HNRNPU-related neurodevelopmental disorder and answers additional clinical questions through reanalysis.

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient's symptoms remained elusive.

Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial.

Background: Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding.

Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program.

Background: Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF).

Objectives: As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families.

Patients/methods: 62 index cases with a pre-existing diagnosis of type 3 VWD were analyzed.

Copy number alterations involving 59 ACMG-recommended secondary findings genes.

In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single-nucleotide variants (SNVs) are observed in one of 59 genes associated with a life-threatening, medically actionable condition. Little is known about the incidence and sensitivity of chromosomal microarray analysis (CMA) for detection of pathogenic copy number variants (CNVs) comprising medically-actionable genes. Clinical CMA has been performed on 8865 individuals referred for molecular cytogenetic testing.

Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation.

Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1.

Common sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with type 1 VWD.

Background: Genetic variation in the gene is associated with von Willebrand factor (VWF) and factor VIII (FVIII) levels in healthy individuals.

Objectives: We hypothesized that sequence variants associated with higher VWF or FVIII could impact the diagnosis of type 1 von Willebrand disease (VWD).

Methods: We examined VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF propeptide (VWFpp), and FVIII levels along with gene sequencing in 256 healthy control and 97 type 1 VWD subjects as part of a cross-sectional study.

Importance of complete phenotyping in prenatal whole exome sequencing.

Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory.

Maternal GRB10 microdeletion is a novel cause of cystic placenta: Spectrum of genomic changes in the etiology of enlarged cystic placenta.

Introduction: The genetics and pathology of diploid complete and triploid partial hydatidiform moles have been well established. Enlarged cystic placenta often indicates an underlying etiology and is frequently associated with adverse pregnancy outcome. Several imprinted genes are strongly expressed in placental tissues and essential for normal placental growth and development.

A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders.

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs.

Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States.

von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1 VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD remains the subject of debate. In order to study the spectrum of type 1 VWD in the United States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD without stringent laboratory diagnostic criteria.

Crucial role for the VWF A1 domain in binding to type IV collagen.

Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions.

VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population.

Diagnosis and classification of VWD is aided by molecular analysis of the VWF gene. Because VWF polymorphisms have not been fully characterized, we performed VWF laboratory testing and gene sequencing of 184 healthy controls with a negative bleeding history. The controls included 66 (35.

Von Willebrand disease in the United States: a perspective from Wisconsin.

Von Willebrand disease (VWD) is a common bleeding disorder with prevalence in the United States of 0.01 to 1% and a prevalence in the region around Milwaukee, Wisconsin, of at least 0.025%.

Molecular determination of RHD zygosity: predicting risk of hemolytic disease of the fetus and newborn related to anti-D.

Objective: Development of an accurate molecular method for paternal RHD zygosity to predict risk to a fetus for hemolytic disease of the fetus and newborn (HDFN) related to anti-D.

Methods: Quantitative fluorescence polymerase chain reaction (QF-PCR) was used to detect RHD exons 5 and 7, using RHCE exon 7 as an internal control. The genotype and zygosity were determined from the peak area ratios of RHD exon 5 or 7 to RHCE exon 7.

High-throughput red blood cell antigen genotyping using a nanofluidic real-time polymerase chain reaction platform.

Background: Serologic testing of donors to obtain antigen-negative blood for transfusion is limited by availability and quality of reagents. Where sequence variant information is available, molecular typing platforms can be used to determine the presence of a variant allele and offer a high-throughput format correlated to the blood group antigen. We have investigated a flexible high-throughput platform to screen blood donors for antigen genotypes in the African American population.

Behavioral, biochemical, and genetic analysis of iron metabolism in high-intensity blood donors.

Background: Individuals donating whole blood 13 times in a 2-year period without development of iron deficiency anemia (superdonors) are a self-selected population that is deferred for low hematocrit (Hct) level less frequently than other donors.

Study Design And Methods: Iron metabolism was assessed in 138 superdonors through a questionnaire and measurement of Hct, serum ferritin, serum hepcidin, and serum growth differentiation factor 15 (GDF15). Genetic testing for HFE and JAK-2 mutations was also performed.

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

ACMG previously developed recommendations for standards for interpretation of sequence variations. We now present the updated revised recommendations. Here, we describe six interpretative categories of sequence variations: (1) sequence variation is previously reported and is a recognized cause of the disorder; (2) sequence variation is previously unreported and is of the type which is expected to cause the disorder; (3) sequence variation is previously unreported and is of the type which may or may not be causative of the disorder; (4) sequence variation is previously unreported and is probably not causative of disease; (5) sequence variation is previously reported and is a recognized neutral variant; and (6) sequence variation is previously not known or expected to be causative of disease, but is found to be associated with a clinical presentation.

Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival.

Type 1 von Willebrand disease (VWD) is characterized by a partial quantitative deficiency of von Willebrand factor (VWF). Few VWF gene mutations have been identified that cause dominant type 1 VWD. The decreased survival of VWF in plasma has recently been identified as a novel mechanism for type 1 VWD.

Genetic mutations in von Willebrand disease identified by DHPLC and DNA sequence analysis.

Von Willebrand disease (VWD) is a common inherited bleeding disorder caused by quantitative (types 1 and 3) and qualitative (type 2) defects in von Willebrand factor (VWF). The VWF gene is a large gene containing 52 exons; except for type 2 VWD, the majority of mutations causing VWD are not localized to specific exons. We have used denaturing high performance liquid chromatography (DHPLC) to scan the coding region of the VWF gene for sequence variations.