variants in the non-coding spliceosomal snRNA gene are a frequent cause of syndromic neurodevelopmental disorders.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA as a novel syndromic NDD gene.

Genomic Diagnoses for Ectopic Intracerebral Calcifications.

Background And Objectives: Ectopic intracerebral calcifications (EICs) in the basal ganglia, thalamus, cerebellum, or white matter are seen in a variety of disease states or may be found incidentally on brain imaging. The clinical significance and proportion of cases attributable to an underlying genetic cause is unknown.

Methods: This retrospective cohort study details the clinical, imaging, and genomic findings of 44 patients with EICs who had no established diagnosis despite extensive medical workup.

Neurofilament light chain in cerebrospinal fluid as a novel biomarker in evaluating both clinical severity and therapeutic response in Niemann-Pick disease type C1.

Purpose: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder caused by pathogenic variants in NPC1. Disease progression is monitored using the NPC Neurological Severity Scale, but there are currently no established validated or qualified biomarkers. Neurofilament light chain (NfL) is being investigated as a biomarker in multiple neurodegenerative diseases.

Adults with lysosomal storage diseases in the undiagnosed diseases network.

Objectives: To review the referral and clinical characteristics of adult patients diagnosed with lysosomal storage diseases (LSD) through the Undiagnosed Diseases Network (UDN).

Methods: Retrospective review of both application and evaluation records for adults admitted to the UDN with a final diagnosis of a lysosomal storage disease.

Results: Ten patients were identified.

Inherited disorders of complex lipid metabolism: A clinical review.

Over 80 human diseases have been attributed to defects in complex lipid metabolism. A majority of them have been reported recently in the setting of rapid advances in genomic technology and their increased use in clinical settings. Lipids are ubiquitous in human biology and play roles in many cellular and intercellular processes.

Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia Type 2.

Glutaric acidemia type 2 (GA2), also called multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4-C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin-containing dehydrogenases to Coenzyme Q (CoQ ) of the mitochondrial electron transport chain (ETC). We report a patient who was originally reported as the first case with primary myopathic CoQ deficiency when he presented at 11.

A family with spinocerebellar ataxia and retinitis pigmentosa attributed to an mutation.

Objective: To identify the genetic cause of autosomal dominant spinocerebellar ataxia and retinitis pigmentosa in a large extended pedigree.

Methods: Clinical studies were done at 4 referral centers. Ten individuals in the same extended family participated in at least a portion of the study.

Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.

Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen.