RCIGM logo featuring kite with a DNA tail
RCIGM logo featuring kite with a DNA tail

Neurogenomics

Research

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

TMEM161B modulates radial glial scaffolding in neocortical development

  • Wang L, Heffner C, Vong KL, Barrows C, Ha YJ, Lee S, Lara-Gonzalez P, Jhamb I, Van Der Meer D, Loughnan R, Parker N, Sievert D, Mittal S, Issa MY, Andreassen OA, Dale A, Dobyns WB, Zaki MS, Murray SA, Gleeson JG.

Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2209983120. doi: 10.1073/pnas.2209983120. Epub 2023 Jan 20.

ABSTRACT

TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.

PMID:36669109 DOI:10.1073/pnas.2209983120

Stem Cell-Based Organoid Models of Neurodevelopmental Disorders

  • Wang L, Owusu-Hammond C, Sievert D, Gleeson JG.

Biol Psychiatry. 2023 Jan 24:S0006-3223(23)00039-2. doi: 10.1016/j.biopsych.2023.01.012. Online ahead of print.

ABSTRACT

The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell-based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging.

PMID:36759260 DOI:10.1016/j.biopsych.2023.01.012

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

  • Chung C, Yang X, Bae T, Vong KI, Mittal S, Donkels C, Westley Phillips H, Li Z, Marsh APL, Breuss MW, Ball LL, Garcia CAB, George RD, Gu J, Xu M, Barrows C, James KN, Stanley V, Nidhiry AS, Khoury S, Howe G, Riley E, Xu X, Copeland B, Wang Y, Kim SH, Kang HC, Schulze-Bonhage A, Haas CA, Urbach H, Prinz M, Limbrick DD Jr, Gurnett CA, Smyth MD, Sattar S, Nespeca M, Gonda DD, Imai K, Takahashi Y, Chen HH, Tsai JW, Conti V, Guerrini R, Devinsky O, Silva WA Jr, Machado HR, Mathern GW, Abyzov A, Baldassari S, Baulac S; Focal Cortical Dysplasia Neurogenetics Consortium; Brain Somatic Mosaicism Network; Gleeson JG.

Nat Genet. 2023 Jan 12. doi: 10.1038/s41588-022-01276-9. Online ahead of print.

ABSTRACT

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

PMID:36635388 DOI:10.1038/s41588-022-01276-9

View More Publications

News

View All News

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

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

  • Palmer EE, Pusch M, Picollo A, Forwood C, Nguyen MH, Suckow V, Gibbons J, Hoff A, Sigfrid L, Megarbane A, Nizon M, Cogné B, Beneteau C, Alkuraya FS, Chedrawi A, Hashem MO, Stamberger H, Weckhuysen S, Vanlander A, Ceulemans B, Rajagopalan S, Nunn K, Arpin S, Raynaud M, Motter CS, Ward-Melver C, Janssens K, Meuwissen M, Beysen D, Dikow N, Grimmel M, Haack TB, Clement E, McTague A, Hunt D, Townshend S, Ward M, Richards LJ, Simons C, Costain G, Dupuis L, Mendoza-Londono R, Dudding-Byth T, Boyle J, Saunders C, Fleming E, El Chehadeh S, Spitz MA, Piton A, Gerard B, Abi Warde MT, Rea G, McKenna C, Douzgou S, Banka S, Akman C, Bain JM, Sands TT, Wilson GN, Silvertooth EJ, Miller L, Lederer D, Sachdev R, Macintosh R, Monestier O, Karadurmus D, Collins F, Carter M, Rohena L, Willemsen MH, Ockeloen CW, Pfundt R, Kroft SD, Field M, Laranjeira FER, Fortuna AM, Soares AR, Michaud V, Naudion S, Golla S, Weaver DD, Bird LM, Friedman J, Clowes V, Joss S, Pölsler L, Campeau PM, Blazo M, Bijlsma EK, Rosenfeld JA, Beetz C, Powis Z, McWalter K, Brandt T, Torti E, Mathot M, Mohammad SS, Armstrong R, Kalscheuer VM.

Mol Psychiatry. 2022 Nov 16. doi: 10.1038/s41380-022-01852-9. Online ahead of print.

ABSTRACT

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

PMID:36385166 DOI:10.1038/s41380-022-01852-9

Cord blood adiponectin and leptin are associated with a lower risk of stunting during infancy

  • Park S, Vargas Z, Zhao A, Baltazar PI, Friedman JF, McDonald EA.

Sci Rep. 2022 Sep 6;12(1):15122. doi: 10.1038/s41598-022-19463-3.

ABSTRACT

Undernutrition is responsible for up to 45% of deaths in children under five, with low- and middle-income countries disproportionately affected. Adipokines are known modulators of metabolism and have been linked to growth rates and neurocognition during infancy. We examined the relationship(s) between cord blood adiponectin and leptin and both longitudinal growth and cognition during the first year of life using generalized estimating equations. Infants were classified as underweight (weight-for-age z-score [WAZ]), stunted (height-for-age z-score [HAZ]) or wasted (weight-for-height z-score [WHZ]) using WHOAnthro software. Cord blood adiponectin and leptin levels were highly correlated (r = 0.35, P < 0.0001) and positively associated with birth WAZ (r = 0.34 and r = 0.45, P < 0.0001, respectively). Adipokines were independently, inversely associated with weight gain. Infants in the highest quintile of adipokine production had a lower risk of being stunted, while neither was associated with lower WAZ or WHZ in final adjusted models. Cognition was not found to be independently related to cord blood leptin or adiponectin. The negative association with adipokines and rate of weight gain during infancy may reflect heightened nutritional status at birth rather than a direct hormonal influence. The relationship between leptin or adiponectin and longitudinal length gains suggests that both adipokines may promote linear growth during infancy.

PMID:36068284 | DOI:10.1038/s41598-022-19463-3

Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts

  • Leskoske KL, Garcia-Mansfield K, Sharma R, Krishnan A, Rusert JM, Mesirov JP, Wechsler-Reya RJ, Pirrotte P.

J Proteome Res. 2022 Aug 17. doi: 10.1021/acs.jproteome.2c00203. Online ahead of print.

ABSTRACT

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.

PMID:35977718 | DOI:10.1021/acs.jproteome.2c00203

View More Publications

News

Discovery of Endocannabinoid Gene Mutation Leads to Identification of  New, Rare Pediatric Neurological Disease

In a study published in the October 2022 issue of BRAIN, researchers from Rady Children’s Institute for Genomic Medicine (RCIGM®) and the University of California San Diego School of Medicine describe their discovery of a new clinical syndrome, Neuro-Ocular DAGLA-related Syndrome (NODRS), in children with termination variants in the diacylglycerol lipase alpha (DAGLA) gene which encodes an enzyme in the brain that is involved in the signaling pathway of the endocannabinoid (eCB) system.

View All News

Want to Learn More?

View Our Publications
RCIGM logo featuring kite with a DNA tail

Partner With Us

Order a Test

About Us

STAY UP TO DATE

© 2023 Rady Children's Institute for Genomic Medicine.

Follow Us
Icon-linkedin Twitter

Contact Us About BeginNGS