Biomarkers.

Background: Synuclein Aggregate Assays (SAA) in cerebrospinal fluid (CSF) and in skin biopsy have been shown to successfully identify underlying synuclein (Lewy body) pathology in patients with Parkinson's disease. Data in Lewy Body Dementia (LBD) is limited, particularly with pathologic confirmation and staging of underlying Lewy body pathology, and other co-pathologies.

Method: Utilizing data and biofluids from participants in the U.

Biomarkers.

Background: Alzheimer's disease (AD) is a pathologically heterogeneous disease making it a challenge to develop effective treatments. Emerging evidence suggests that there are pathological differences between women and men with AD. More biomarkers are needed to enhance sex-specific precision medicine in AD.

Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons.

Solute carrier family 6 member 1 (SLC6A1) is abundantly expressed in the developing brain even before the CNS is formed. Its encoded GABA transporter 1 (GAT-1) is responsible for the reuptake of GABA into presynaptic neurons and glia, thereby modulating neurotransmission. GAT-1 is expressed globally in the brain, in both astrocytes and neurons.

Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism.

Background: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD).

Characterization of the GABRB2-Associated Neurodevelopmental Disorders.

Objective: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2, coding for the γ-aminobutyric acid type A (GABA ) receptor subunit β2.

Methods: We recruited and systematically evaluated 25 individuals with variants in GABRB2, 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system.

Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy.

Purpose: We aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting.

Methods: We analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6994 panels with another 8588 recently published panels as well as exome-wide de novo variants in 1942 individuals with NDD+E and 10,937 controls.

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children.

Objective: It is recognised that 5% - 10 % of children with macrocephaly and autism spectrum disorder (ASD) and/or intellectual disability (ID) have a heterozygous pathogenic mutation in the tumour suppressor gene that is associated with PTEN hamartoma tumour syndrome. However, the clinical features and course in children with a pathogenic mutation are unclear and have not been well documented.

Study Objectives: We undertook a retrospective chart review of children (< 18  years) with pathogenic mutations to ascertain clinical findings, clinical course and possible outcomes.

Microbiomic differences in tumor and paired-normal tissue in head and neck squamous cell carcinomas.

Background: While the role of the gut microbiome in inflammation and colorectal cancers has received much recent attention, there are few data to support an association between the oral microbiome and head and neck squamous cell carcinomas. Prior investigations have been limited to comparisons of microbiota obtained from surface swabs of the oral cavity. This study aims to identify microbiomic differences in paired tumor and non-tumor tissue samples in a large group of 121 patients with head and neck squamous cell carcinomas and correlate these differences with clinical-pathologic features.

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy.

Objective: The early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage-gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872.

Systemic connective tissue features in women with fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic disease associated with hypertension, headache, dissection, stroke, and aneurysm. The etiology is unknown but hypothesized to involve genetic and environmental components. Previous studies suggest a possible overlap of FMD with other connective tissue diseases that present with dissections and aneurysms.

Cowden syndrome: recognizing and managing a not-so-rare hereditary cancer syndrome.

Cowden syndrome (CS) is an autosomal dominant hereditary cancer syndrome causing increased risk for breast, thyroid, renal, uterine, and other cancers as well as benign neoplasias and neurodevelopmental concerns. Timely diagnosis of affected patients is key, as early recognition allows for high-risk screening and other preventative measures prior to a patient enduring multiple cancer diagnoses. This review will highlight the cardinal features of CS and management recommendations for affected patients.

Vitamin E protects against lipid peroxidation and rescues tumorigenic phenotypes in cowden/cowden-like patient-derived lymphoblast cells with germline SDHx variants.

Purpose: Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid, and other cancers. Germline variations in succinate dehydrogenase genes (SDHx) occur in approximately 10% PTEN mutation-negative CS and CS-like (CSL) individuals (SDH(var+)). We previously showed that SDHx variants result in elevated reactive oxygen species (ROS), disruption of nicotinamide adenine dinucleotide (NAD) equilibrium, and destabilization of p53 hence apoptosis resistance in CS/CSL patient-derived lymphoblastoid cells.

Molecular testing: improving patient care through partnering with laboratory genetic counselors.

The utility of molecular diagnostics in clinical practice has been steadily increasing and is expected to continue to do so as the applications of genomic medicine increase. The goal of this article was to describe the roles and responsibilities of genetic counselors who work in the customer service area of molecular diagnostics laboratories. In this role, genetic counselors provide recommendations to clinicians on issues that are specific to DNA-based testing.