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

A clinical and genotype-phenotype analysis of MACF1 variants

  • Dekker J, Schot R, Aldinger KA, Everman DB, Washington C, Jones JR, Sullivan JA, Spillmann RC, Shashi V, Vitobello A, Denommé-Pichon AS, Mosca-Boidron AL, Perrin L, Auvin S, Zaki MS, Gleeson JG, Meave N, Wallace C, Nambot S, Delanne J, Ruggiero SM, Helbig I, Fitzgerald MP, Leventer RJ, Grange DK, Argilli E, Sherr EH, Prakash S, Neilson DE, Nicita F, Sferra A, Bertini ES, Aiello C, Brockmann K, Kuranov AB, Kaulfuss S, Basit S, Alluqmani M, Almatrafi A, Friedman JM, Guimond C, Mohammed F, Sharma P, Goel D, Wirth T, Anheim M, Bahena P, Koparir A, Kolokotronis K, Vona B, Haaf T, Kunstmann E, Maroofian R, Sczakiel HL, Boschann F, Misra-Isrie M, Louie RJ, Stolerman ES, Sanchez-Lara PA, Mergler S, Oegema R, Zarate YA, Kariminejad A, Tajsharghi H, Zeidler S, Kievit AJA, Bouman A, Cappuccio G, Brunetti-Pierri N, Stuurman KE, Swols DM, Tekin M, Upadia J, Martin DM, Craven D, Hiatt SM, van de Pol LA, D'Arco F, Margot H, Wilke M, Yousefi S, Barakat TS, van Veghel-Plandsoen MM, Aronica E, Anink J, Rogers SL, Slep KC, Doherty D, Dobyns WB, Mancini GMS.

Am J Hum Genet. 2025 Sep 3:S0002-9297(25)00320-9. doi: 10.1016/j.ajhg.2025.08.010. Online ahead of print.

ABSTRACT

Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity.

PMID:40925378 | DOI:10.1016/j.ajhg.2025.08.010

Follow-up and outcome of patients with primary BH4 deficiencies

  • Nardecchia F, Manti F, De Giorgi A, Galosi S, Friedman J, Leuzzi V.

Front Neurol. 2026 Jul 16;17:1793300. doi: 10.3389/fneur.2026.1793300. eCollection 2026.

ABSTRACT

BH4 deficiencies may occur with or without hyperphenylalaninemia (HPA). If identified early through neonatal screening for PKU, the clinical follow-up aims to prevent the onset of typical disease symptoms. In contrast, for the conditions not associated with HPA, diagnosis usually occurs once symptoms manifest, and follow-up focuses on monitoring the treatment’s effectiveness in restoring normal neurological function. Except for pterin-4-alpha-carbinolamine dehydratase defect (PCCDd), the core symptoms and natural course of these diseases involve neurodevelopmental impairment and movement disorders. Current information on clinical follow-up and outcome comes from retrospective observational studies, with standardized measures used in only a few of them. Serial clinical observations focusing on the two most consistent areas of neurological impairment are the best predictors of outcome and the main follow-up targets. Available clinical data, often aggregating early- and late-treated patients, show that the best clinical outcome occurs in autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (AD-GTPCHd). In contrast, for recessive conditions, prognosis is variably associated with both the timing of treatment (autosomal recessive [AR]-GTPCHd, 6-pyruvoyltetrahydropterin synthase [PTPS]d, sepiapterin [SR]d, q-dihydropyridine reductase [DHPR]d) and the severity of metabolic derangement (AR-GTPCHd, PTPSd). Neurocognitive, psychiatric, and sleep disorders are currently underestimated and can occur in children and adults, affecting social adaptation and quality of life. Among metabolic alterations, blood Phe levels, when altered, warrant regular monitoring. CSF evaluation can be considered in subjects unresponsive to treatment or with an unexpected clinical course. CSF 5-MTHF monitoring should be reserved for patients with DHPRd experiencing neurological deterioration and seizures. Monitoring prolactin levels, when altered, may assist in personalizing pharmacological treatment. Serum magnesium and glucose are metabolic markers that should be assessed in PDCCd. Brain MRI monitoring is recommended for patients experiencing unusual courses, epilepsy, and neurological deterioration (particularly in PTPSd and DHPRd). A DAT scan is advised for those with AD-GTPCH who present or develop Parkinsonism, and EEG monitoring should be conducted for every patient with epilepsy or suspected seizures. For future clinical studies, it is mandatory that the clinical assessment adopt standardized tools that score impairment across neurological and behavioral domains, taking the patient’s age into account.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=1144143, identifier (CRD420251144143).

PMID:42534655 | PMC:PMC13422167 | DOI:10.3389/fneur.2026.1793300

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy

  • Falabella M, Lopez Calcerrada S, Aref J, Gao J, Macken WL, Pizzamiglio C, Kabiljo R, Francavilla AL, Gaignard P, Pouzet A, Levy J, Barcia G, Leighton JK, Chronopoulou E, Pierre G, Köksal Özgül R, Dursun A, Halligan R, Mundy H, Raza Alvi J, Sultan T, Craigen WJ, Emrick L, Rosenfeld JA, Elmakkawy G, Kim J, Gleeson JJ, Rad A, Oprea G, Hussain M, Rehman KU, Riaz S, Taylor RW, Procaccio V, Zaki MS, Fernandez-Vizarra E, Pierri CL, Hanna MG, Houlden H, Maroofian R, Ugalde C, Taanman JW, Pitceathly RDS.

Nat Commun. 2026 May 30. doi: 10.1038/s41467-026-73455-9. Online ahead of print.

ABSTRACT

Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential.

PMID:42218136 | DOI:10.1038/s41467-026-73455-9

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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

Comprehensive Genotypic, Phenotypic, and Biochemical Characterization of GOT2 Deficiency: A Progressive Neurodevelopmental Disorder with Epilepsy and Abnormal Movements

  • German HM, Zaki MS, Usmani MA, Karagoz I, Efthymiou S, Abdel-Hamid MS, Arabiyat HA, Ghaffar A, Shahzad M, van Bokhoven H, Ahmed ZM, Yaghini O, Hosseini N, Majidinezhad M, Alavi S, Bosma M, Broeks MH, Türkdoğan D, Suri M, Laura de Godoy L, Verhoeven-Duif NM, Riazuddin S, Gleeson JG, Alves C, Jans JJM, Riazuddin S, Houlden H, Maroofian R.

Genet Med. 2025 Sep 22:101587. doi: 10.1016/j.gim.2025.101587. Online ahead of print.

ABSTRACT

PURPOSE: Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle (MAS), a key regulator of intracellular redox homeostasis. Recently, five patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy.

METHODS: We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency.

RESULTS: Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed two severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation.

CONCLUSION: These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of DEE, and propose novel biomarkers for diagnosis and treatment.

PMID:41001736 | DOI:10.1016/j.gim.2025.101587

PIGC-related encephalopathy: Lessons learned from 18 new probands

  • Bayat A, Borroto MC, Salian S, Zaki MS, Benkerroum H, Elbendary HM, Nguyen TTM, Sadek AA, Carli D, Brusco A, Ferrero GB, Tartaglia M, Hay E, Krey I, A Jamra R, Bartolomaeus T, Knaus A, Gleeson JG, Houlden H, Dominik N, Jackson A, Douzgou Houge S, Banka S, Mohammadi-Asl J, Hajjari M, Azizimalamiri R, Nourbakhsh P, Neissi M, Scardamaglia A, Li D, Kinoshita T, Maroofian R, Murakami Y, Campeau PM.

Eur J Hum Genet. 2025 Sep 17. doi: 10.1038/s41431-025-01923-9. Online ahead of print.

ABSTRACT

PIGC encodes a protein essential for the biosynthesis of glycophosphatidylinositol-anchored proteins (GPI-APs). So far, three families with biallelic PIGC variants have been reported to exhibit developmental delay/intellectual disability and seizures. Our aim was to further elucidate the clinical and biomolecular characteristics of PIGC pathogenic or likely pathogenic variants. We established a cohort of 18 previously unreported probands. Clinical data were collected, and causative variants were identified though genome/exome sequencing. Variants were modelled in silico using AlphaFold2. Flow cytometry was performed to analyze the cell-surface expression of GPI-APs. The probands displayed a severe neurodevelopmental disorder characterized by developmental and cognitive impairment, early-onset and treatment-resistant seizures, and premature death affecting 10 out of 18 individuals (median age of 40 months, ranging from 40 days to 7 years). Additional features included brain imaging abnormalities (14/15), hypotonia (15/18), and skeletal anomalies (5/17). One patient exhibited mildly elevated alkaline phosphatase levels. All harbored biallelic PIGC variants, with 14 out of 18 of those being homozygous variants. Analysis of samples derived from probands and cellular models showed reduced cell surface levels of GPI-APs. This study confirms the association of PIGC biallelic variants with refractory seizures, severe developmental and cognitive impairments, and highlights their association with childhood-onset mortality. Additionally, it shows that dysfunctional PIGC results in defective biosynthesis of GPI-AP.

PMID:40962973 | DOI:10.1038/s41431-025-01923-9

Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy

  • Kim-McManus O, Mignon L, Douville J, Pu H, Parisien C, Glass S, Bennett CF, Celso J, Robbins K, Ung H, Olson H, Kingsmore SF, Petrou S, Crooke ST, Gleeson JG, Berry-Kravis E

Nat Med. 2026 Jul 21. doi: 10.1038/s41591-026-04527-y. Online ahead of print.

ABSTRACT

SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient’s phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 .

PMID:42481851 | DOI:10.1038/s41591-026-04527-y

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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.

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