Deletions at 22q11.2 are linked to DiGeorge or velocardiofacial syndrome (VCFS), whose hallmarks include heart, limb, and craniofacial anomalies, as well as learning disabilities and increased incidence of schizophrenia. To assess the potential contribution of 22q11 genes to cognitive and psychiatric phenotypes, we determined the CNS expression of 32 mouse orthologs of 22q11 genes, primarily in the 1.5-Mb minimal critical region consistently deleted in VCFS. None are uniquely expressed in the developing or adult mouse brain. Instead, 27 are localized in the embryonic forebrain as well as aortic arches, branchial arches, and limb buds. Each continues to be expressed at apparently constant levels in the fetal, postnatal, and adult brain, except for Tbx1, ProDH2, and T10, which increase in adolescence and decline in maturity. At least six 22q11 proteins are seen primarily in subsets of neurons, including some in forebrain regions thought to be altered in schizophrenia. Thus, 22q11 deletion may disrupt expression of multiple genes during development and maturation of neurons and circuits compromised by cognitive and psychiatric disorders associated with VCFS.
We asked whether retinoic acid (RA), an established transcriptional regulator in regenerating and developing tissues, acts directly on distinct cell classes in the mature or embryonic forebrain. We identified a subset of slowly dividing precursors in the adult subventricular zone (SVZ) that is transcriptionally activated by RA. Most of these cells express glial fibrillary acidic protein, a smaller subset expresses the epidermal growth factor receptor, a few are terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling positive, and they can be mitotically labeled by sustained rather than acute bromodeoxyuridine exposure. RA activation in similar cells in SVZ-derived neurospheres depends on retinoid synthesis from the premetabolite retinol. The apparent influence of RA on precursors in vitro is consistent with key properties of RA activation in the SVZ; in neurospheres, altered retinoid signaling elicits neither cell death nor an acute increase in cell proliferation. There is apparent continuity of RA signaling in the forebrain throughout life. RA-activated, proliferative precursors with radial glial characteristics are found in the dorsal lateral ganglionic eminence and ventrolateral palliumembryonic rudiments of the SVZ. Thus, endogenous RA signaling distinguishes subsets of neural precursors with glial characteristics in a consistent region of the adult and developing forebrain.
ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.
22q11 deletion syndrome (22qDS), also known as DiGeorge or velocardiofacial syndrome (DGS/VCFS), is a relatively common genetic anomaly that results in malformations of the heart, face and limbs. In addition, patients with 22qDS are at significant risk for psychiatric disorders as well, with one in four developing schizophrenia, and one in six developing major depressive disorders. Like several other deletion syndromes associated with psychiatric or cognitive problems, it has been difficult to determine which of the specific genes in this genomic region may mediate the syndrome. For example, patients with different genomic deletions within the 22q11 region have been found that have similar phenotypes, even though their deletions do not compromise the same set of genes. In this review, we discuss the individual genes found in the region of 22q11 that is commonly deleted in 22qDS patients, and the potential roles each of these genes may play in the syndrome. Although many of these genes are interesting candidates by themselves, we hypothesize that the full spectrum of anomalies associated with 22qDS may result from the combined result of disruptions to numerous genes within the region that are involved in similar developmental or cellular processes.
Background The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset. Methods and Results We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.8% of cases, and variants of uncertain significance in 34.5% of cases. Three patients harbored heterozygous nonsense or splice-site variants in the nucleoporin genes NUP37, NUP43, and NUP188, which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene SYNE1 in a child with severe dilated cardiomyopathy that underwent transplant, as well as in his affected father. To confirm a cardiovascular role for these candidate genes in vivo, we used morpholinos to reduce SYNE1, NUP37, and NUP43 gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a SYNE1 splice-site variant displayed changes in nuclear morphology and protein localization that are consistent with disruption of the nuclear envelope. Conclusions These data expand the repertoire of pathogenic variants associated with cardiovascular disease, and validate the diagnostic and research utility of whole exome sequencing. We identify NUP37, NUP43, and NUP188 as novel candidate genes for cardiovascular disease, and suggest that dysfunction of the nuclear envelope may be an under-recognized component of inherited cardiac disease in some cases.
Pompe disease is a metabolic myopathy with a wide spectrum of clinical presentation. The gold-standard diagnostic test is acid alpha-glucosidase assay on skin fibroblasts, muscle or blood. Identification of two GAA pathogenic variants in-trans is confirmatory. Optimal effectiveness of enzyme replacement therapy hinges on early diagnosis, which is challenging in late-onset form of the disease due to non-specific presentation. Next-generation sequencing-based panels effectively facilitate diagnosis, but the sensitivity of whole-exome sequencing (WES) in detecting pathogenic GAA variants remains unknown. We analyzed WES data from 93 patients with confirmed Pompe disease and GAA genotypes based on PCR/Sanger sequencing. After ensuring that the common intronic variant c.-32-13T > G is not filtered out, whole-exome sequencing identified both GAA pathogenic variants in 77/93 (83%) patients. However, one variant was missed in 14/93 (15%), and both variants were missed in 2/93 (2%). One complex indel leading to a severe phenotype was incorrectly called a nonsynonymous substitution c.-32-13T > C due to misalignment. These results demonstrate that WES may fail to diagnose Pompe disease. Clinicians need to be aware of limitations of WES, and consider tests specific to Pompe disease when WES does not provide a diagnosis in patients with proximal myopathy, progressive respiratory failure or other subtle symptoms.
We used transgenic reporter mice to determine whether brain regions that respond to retinoic acid (RA) during development do so in maturity. We focused on two prominent sites of embryonic RA signaling: the dorsal spinal cord and the olfactory bulb. In the mature dorsal spinal cord, expression of a direct repeat 5 RA response element (DR5-RARE) transgene is seen in interneurons in laminae I and II, as well as in ependymal cells around the central canal. In the olfactory bulb, DR5-RARE transgene-expressing neurons are seen in the mature granule cell and periglomerular layers, as well as in cells in the subventricular zone of the forebrain-the established source for newly generated granule and periglomerular neurons. In addition, there are transgene-labeled neurons in a small number of other brain regions. These include the spinal trigeminal nucleus, area postrema, habenula, amygdala, and the cerebral cortex. Thus, a distinct type of RA-mediated gene expression, detected with the DR5-RARE reporter transgene, defines neurons, subependymal, or ependymal cells in discrete locations throughout the neuraxis. Some of these cells--particularly those in the spinal cord and olfactory bulb--are found in central nervous system regions that receive local RA signals early in development, and retain a significant amount of functional or structural plasticity in the adult.
RanBP1, a velocardiofacial syndrome/DiGeorge syndrome candidate gene, is expressed in the frontonasal processes, branchial arches, aortic arches, and limb buds. At these sites, RanBP1 apparently coincides with neural crest-derived mesenchymal cells. In addition, RanBP1 is expressed in the forebrain as well as in hindbrain regions previously associated with crest-derived mesenchymal cells.
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