Neurogenomics

Cracking
the Code

Identifying the cause of neurological disorders and early intervention are key to reducing the devastating brain damage that can occur. 

Neurological disorders can be caused both by inherited and random gene variations. Often, the first sign of a disorder in a newborn is unexplained seizures. 

RCIGM is involved in both foundational and translational research.

Neurodevelopmental Genetics

RCIGM investigations into inherited brain disorders focus on poorly understood conditions in neuronal development where the application of human genetics, wet-lab disease modeling and cell biology can be used to develop new treatments.
190227RadySeminar

Joseph Gleeson, MD

RCIGM Director of Neurodevelopmental Genetics Endowed Chair

Joseph Gleeson, MD, is the RCIGM Director of Neurodevelopmental Genetics Endowed Chair. Among his current research projects is a genetic investigation of the genetic mechanisms underlying spina bifida, the most common structural defect of the central nervous system.

In 2020 Dr. Gleeson along with other researchers at UC San Diego School of Medicine, in collaboration with Rady Children’s Institute for Genomic Medicine, were awarded an $8.3 million grant from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development to further illuminate the causes of spina bifida.

Dr. Gleeson also heads the Neurogenetics Laboratory at UC San Diego and is the Director of the Center for Brain Development. He is the 2020 recipient of the Bernard Sachs Award from the Child Neurology Society. In 2017, he was the first recipient of the Constance Lieber Prize for Innovation in Developmental Neuroscience.

Publications

Nat Med. 2021 Jul 9. doi: 10.1038/s41591-021-01443-1. Online ahead of print.

ABSTRACT

Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.

PMID:34244682 | DOI:10.1038/s41591-021-01443-1

Genet Med. 2021 Jun 25. doi: 10.1038/s41436-021-01239-1. Online ahead of print.

ABSTRACT

PURPOSE: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo.

METHODS: Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish.

RESULTS: We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts.

CONCLUSION: Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.

PMID:34172899 | DOI:10.1038/s41436-021-01239-1

Nat Commun. 2021 May 7;12(1):2558. doi: 10.1038/s41467-021-22627-w.

ABSTRACT

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.

PMID:33963192 | DOI:10.1038/s41467-021-22627-w

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Genetic Neurologic Disease

Neurologic Movement Disorders

RCIGM focuses on translational research in pediatric neurologic movement disorders, particularly those resulting from genetic or metabolic conditions. 

Investigations into genetic underpinnings of neurologic movement disorders is led by Jennifer Friedman, MD. Her work involves sequencing children with unexplained neurologic disease to identify diagnosis and treatment options.

Dr. Friedman’s research is aimed at ending the diagnostic odyssey by bringing diagnoses to patients and families; shortening the therapeutic odyssey by delivering precision neurologic care and identifying novel genes for rare neurologic disorders.

headshot of Dr. Jenni Friedman

Jennifer Friedman, MD

Dr. Jennifer Friedman is the Translational Medicine Director for the Precision Medicine Clinic at Rady Children’s Hospital, where she is also a senior staff neurologist. In addition, she serves as clinical professor in the UC San Diego Departments of Neurosciences and Pediatrics. 

Dr. Friedman is a diplomate of the American Board of Psychiatry and Neurology. She is a member of the American Academy of Neurology, the Movement Disorder Society, the Tourette Syndrome Association, and the Phi Beta Kappa National Honor Society. 

Publications

Mol Genet Genomic Med. 2021 Jun 2:e1623. doi: 10.1002/mgg3.1623. Online ahead of print.

ABSTRACT

BACKGROUND: Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS.

METHODS: A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole-exome sequencing, was screened for causal variants with whole-genome sequencing (WGS).

RESULTS: WGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV-irradiation.

CONCLUSION: The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing.

PMID:34076366 | DOI:10.1002/mgg3.1623

Madelyn A Gillentine

Genome Med. 2021 Apr 19;13(1):63. doi: 10.1186/s13073-021-00870-6.

ABSTRACT

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

CONCLUSIONS: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

PMID:33874999   DOI:10.1186/s13073-021-00870-6

J Inherit Metab Dis. 2021 Jan 14. doi: 10.1002/jimd.12360. Online ahead of print.

ABSTRACT

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

PMID:33443316 | DOI:10.1002/jimd.12360

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