An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism.

Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.

A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.

PURPOSE: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation. METHODS: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts. RESULTS: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding. CONCLUSION: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.

Clinical Exome Studies Have Inconsistent Coverage.

BACKGROUND: Exome sequencing has become a commonly used clinical diagnostic test. Multiple studies have examined the diagnostic utility and individual laboratory performance of exome testing; however, no previous study has surveyed and compared the data quality from multiple clinical laboratories. METHODS: We examined sequencing data from 36 clinical exome tests from 3 clinical laboratories. Exome data were compared in terms of overall characteristics and coverage of specific genes and nucleotide positions. The sets of genes examined included genes in Consensus Coding Sequence (CCDS) (n = 17723), a subset of genes clinically relevant to epilepsy (n = 108), and genes that are recommended for reporting of secondary findings (n = 57; excludes X-linked genes). RESULTS: The average exome nucleotide coverage (≥20×) of each laboratory varied at 96.49% (CV = 3%), 96.54% (CV = 1%), and 91.68% (CV = 4%), for laboratories A, B, and C, respectively. For CCDS genes, the average number of completely covered genes varied at 12184 (CV = 29%), 11687 (CV = 13%), and 5989 (CV = 37%), for laboratories A, B, and C, respectively. With smaller subsets of genes related to epilepsy and secondary findings, the CV revealed low consistency, with a maximum CV seen in laboratory C for both epilepsy genes (CV = 60%) and secondary findings genes (CV = 71%). CONCLUSIONS: Poor consistency in complete gene coverage was seen in the clinical exome laboratories surveyed. The degree of consistency varied widely between the laboratories.

HERV-mediated genomic rearrangement of EYA1 in an individual with branchio-oto-renal syndrome.

Branchio-oto-renal syndrome is characterized by branchial defects, hearing loss, preauricular pits, and renal anomalies. Mutations in EYA1 are the most common cause of branchio-oto-renal and branchio-otic syndromes. Large chromosomal aberrations of 8q13, including complex rearrangements occur in about 20% of these individuals. However, submicroscopic deletions and the molecular characterization of genomic rearrangements involving the EYA1 gene have rarely been reported. Using the array-comparative genomic hybridization, we identified non-recurrent genomic deletions including the EYA1 gene in three patients with branchio-oto-renal syndrome, short stature, and developmental delay. One of these deletions was mediated by two human endogenous retroviral sequence blocks, analogous to the AZFa microdeletion on Yq11, responsible for male infertility. This report describes the expanded phenotype of individuals, resulting from contiguous gene deletion involving the EYA1 gene and provides a molecular description of the genomic rearrangements involving this gene in branchio-oto-renal syndrome.