Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans.

PURPOSE: Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown. METHODS: We used exome sequencing to uncover ADD1 variants associated with intellectual disability (ID) and brain malformations. We studied ADD1 splice isoforms in mouse and human neocortex development with RNA sequencing, super resolution imaging, and immunoblotting. We investigated 4 variant ADD1 proteins and heterozygous ADD1 cells for protein expression and ADD1-ADD2 dimerization. We studied Add1 functions in vivo using Add1 knockout mice. RESULTS: We uncovered loss-of-function ADD1 variants in 4 unrelated individuals affected by ID and/or structural brain defects. Three additional de novo copy number variations covering the ADD1 locus were associated with ID and brain malformations. ADD1 is highly expressed in the neocortex and the corpus callosum, whereas ADD1 splice isoforms are dynamically expressed between cortical progenitors and postmitotic neurons. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. CONCLUSION: Our human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or ID.

Clinical Bioinformatics in Precise Diagnosis of Mitochondrial Disease.

Clinical bioinformatics system is well-established for diagnosing genetic disease based on next-generation sequencing, but requires special considerations when being adapted for the next-generation sequencing-based genetic diagnosis of mitochondrial diseases. Challenges are caused by the involvement of mitochondrial DNA genome in disease etiology. Heteroplasmy and haplogroup are key factors in interpreting mitochondrial DNA variant effects. Data resources and tools for analyzing variant and sequencing data are available at MSeqDR, MitoMap, and HmtDB. Revised specifications of the American College of Medical Genetics/Association of Molecular Pathology standards and guidelines for mitochondrial DNA variant interpretation are proposed by the MSeqDr Consortium and community experts.

MSeqDR: A Centralized Knowledge Repository and Bioinformatics Web Resource to Facilitate Genomic Investigations in Mitochondrial Disease.

MSeqDR is the Mitochondrial Disease Sequence Data Resource, a centralized and comprehensive genome and phenome bioinformatics resource built by the mitochondrial disease community to facilitate clinical diagnosis and research investigations of individual patient phenotypes, genomes, genes, and variants. A central Web portal (https://mseqdr.org) integrates community knowledge from expert-curated databases with genomic and phenotype data shared by clinicians and researchers. MSeqDR also functions as a centralized application server for Web-based tools to analyze data across both mitochondrial and nuclear DNA, including investigator-driven whole exome or genome dataset analyses through MSeqDR-Genesis. MSeqDR-GBrowse genome browser supports interactive genomic data exploration and visualization with custom tracks relevant to mtDNA variation and mitochondrial disease. MSeqDR-LSDB is a locus-specific database that currently manages 178 mitochondrial diseases, 1,363 genes associated with mitochondrial biology or disease, and 3,711 pathogenic variants in those genes. MSeqDR Disease Portal allows hierarchical tree-style disease exploration to evaluate their unique descriptions, phenotypes, and causative variants. Automated genomic data submission tools are provided that capture ClinVar compliant variant annotations. PhenoTips will be used for phenotypic data submission on deidentified patients using human phenotype ontology terminology. The development of a dynamic informed patient consent process to guide data access is underway to realize the full potential of these resources.

Fetal akinesia deformation sequence due to a congenital disorder of glycosylation.

Congenital disorders of Glycosylation (CDG) are increasingly emerging as a major underlying etiology for patients with complex neurogenetic malformations and dysmorphic features. We describe a newborn female with arthrogryposis multiplex due to fetal akinesia secondary to CDG-DPAGT1. Pregnancy was complicated by reduced fetal movements. At birth, the patient was evaluated for intrauterine growth restriction, bilateral cataracts, and multiple joint contractures. She had markedly reduced spontaneous movements, hypotonia, weak cry, and poor suck. She had ventilator-dependent central respiratory depression. Brain MRI showed delayed myelination and an incomplete cerebellar vermis. Transferrin isoelectric focusing was suggestive of a type I congenital disorder of glycosylation. Sequencing revealed a homozygous missense mutation in dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1), exon 3, p.Leu118Val, consistent with DPAGT1-CDG. There have been seventeen previously reported cases of DPAGT1-CDG, including two similar cases with multiple contractures. This case highlights the importance of considering congenital disorders of glycosylation in the differential diagnosis for arthrogryposis.