Further Delineation of the ALG9-CDG Phenotype

ALG9-CDG is one of the less frequently reported types of CDG. Here, we summarize the features of six patients with ALG9-CDG reported in the literature and report the features of four additional patients. The patients presented with drug-resistant infantile epilepsy, hypotonia, dysmorphic features, failure to thrive, global developmental disability, and skeletal dysplasia. One patient presented with nonimmune hydrops fetalis. A brain MRI revealed global atrophy with delayed myelination. Exome sequencing identified a novel homozygous mutation c.1075G>A, p.E359K of the ALG9 gene. The results of our analysis of these patients expand the knowledge of ALG9-CDG phenotype

Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease

PURPOSE:To compare the efficacy of whole genome sequencing (WGS) with targeted next-generation sequencing (NGS) in the diagnosis of inherited retinal disease (IRD).DESIGN:Case series.PARTICIPANTS:A total of 562 patients diagnosed with IRD.METHODS:We performed a direct comparative analysis of current molecular diagnostics with WGS. We retrospectively reviewed the findings from a diagnostic NGS DNA test for 562 patients with IRD. A subset of 46 of 562 patients (encompassing potential clinical outcomes of diagnostic analysis) also underwent WGS, and we compared mutation detection rates and molecular diagnostic yields. In addition, we compared the sensitivity and specificity of the 2 techniques to identify known single nucleotide variants (SNVs) using 6 control samples with publically available genotype data.MAIN OUTCOME MEASURES:Diagnostic yield of genomic testing.RESULTS:Across known disease-causing genes, targeted NGS and WGS achieved similar levels of sensitivity and specificity for SNV detection. However, WGS also identified 14 clinically relevant genetic variants through WGS that had not been identified by NGS diagnostic testing for the 46 individuals with IRD. These variants included large deletions and variants in noncoding regions of the genome. Identification of these variants confirmed a molecular diagnosis of IRD for 11 of the 33 individuals referred for WGS who had not obtained a molecular diagnosis through targeted NGS testing. Weighted estimates, accounting for population structure, suggest that WGS methods could result in an overall 29% (95% confidence interval, 15-45) uplift in diagnostic yield.CONCLUSIONS:We show that WGS methods can detect disease-causing genetic variants missed by current NGS diagnostic methodologies for IRD and thereby demonstrate the clinical utility and additional value of WGS.Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved