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

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

Essential genetic testing in movement disorders – results from a Delphi study

  • Carvalho V, Guedes LC, Gatto E, Rodriguez-Violante M, Klein C, Rodriguez-Porcel F, Morgante F, Rossi M, Miranda M, Ganos C, Riboldi GM, Cesarini M, Darling A, Skorvanek M, van de Warrenburg B, Shalash A, Cossu G, Friedman J, Albanese A, Cardozo A, Lohmann K, Thaler A, Stamelou M, Saunders-Pullman R, Marras C, Sarva H, Bhatia KP, Ferreira JJ.

Parkinsonism Relat Disord. 2026 May 22;148:108367. doi: 10.1016/j.parkreldis.2026.108367. Online ahead of print.

ABSTRACT

BACKGROUND: While genetic testing in Movement Disorders (MD) has expanded enormously, access to genetic testing and genetic counseling remains asymmetric at the global scale. Guidance on efficient testing strategies for clinicians, governments and stakeholders is crucial.

OBJECTIVES: Establish a list of genetic movement disorders considered essential as determined by a group of MD experts.

METHODS: All genes associated with MD were searched using the OMIM and MDS Gene database. We collected all additional tests available at 4 different laboratories from the EuroGentest database. The results were compiled in 6 questionnaires. A genetic test was considered essential if molecular testing had a direct impact in the management of the patient, including treatment of the disease or its comorbidities, or genetic counseling of the patient and family members. Two Delphi rounds were conducted asking MD experts which specific tests they considered essential in an adult MD clinic.

RESULTS: Fifty-nine disorders were considered essential to genetically identify by the MD experts. This included 25 genes associated with ataxia, 15 with parkinsonism, 14 with dystonia, eight with chorea, five with paroxysmal disorders, four with myoclonus, four with hereditary spastic paraparesis, and one with tremor. Sixteen disorders reached 100% consensus among experts: Huntington’s disease, PxMD-PPRT2, Wilson’s disease, DYT-SGCE, DYT-THAP1, DYT-TOR1A, DYT/PARK-GCH1, Fragile-X Tremor-ataxia syndrome, PARK-GBA, PARK-LRRK2, PARK-PINK1, PARK-PRKN, PARK-SNCA, Cerebrotendinous Xanthomatosis, Ataxia-Telangiectasia, and Niemann-Pick disease type C.

CONCLUSION: This study provides a list of genetic MD that should be molecularly tested in adult centers with a compatible phenotype according to a group of MD experts.

PMID:42202611 | DOI:10.1016/j.parkreldis.2026.108367

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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

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

Disease insights from brain somatic mosaicism

  • Chung C, Nedunuri R, Gleeson JG.

Exp Mol Med. 2026 Apr 8. doi: 10.1038/s12276-024-01331-x. Online ahead of print.

ABSTRACT

Brain somatic mosaicism (BSM) refers to genome variation within brain cells that results from accumulated postzygotic mutations. These mutations can be used to understand cell lineage, molecular dynamics and disease processes. Unlike most other organs, brain cells are mostly fixed in position and not replaced throughout life. Thus, assessing mosaic variants (MVs) within the brain, including their spread and cell type-specific distributions and correlations with aging and cellular health, can reveal insights into neurodevelopmental, neuropsychiatric and neurodegenerative diseases. Extracting genetic material from human surgical brain resections, pregnancy remnants, or postmortem samples can reveal the origins of brain cells and uncover the effects of aging and disease on genomic integrity. Technological advances combining high-read-depth bulk sequencing, isolation of specific brain cell types, and single-cell multiomics can both detect and quantify MVs with good precision and recall. Research exploiting brain MVs is revolutionizing the understanding of the origins, mechanisms and potential treatments for brain conditions.

PMID:41951903 | DOI:10.1038/s12276-024-01331-x

Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies

  • Leitão E, Santini A, Cogne B, Essid M, Athanasiadou M, LaFlamme CW, Marijon P, Bernard V, Jousselin K, Chatron N, Barcia G, Keren B, Mignot C, Charles P, Besnard T, Paluch R, de Sainte Agathe JM, Almanza Fuerte EP, Sengupta S, Milh M, Ramond F, Allan T, An I, Araujo C, Arpin S, Austin-Tse C, Auvin S, Baer S, Bahi-Buisson N, Bak M, Barth M, Baulac S, Bednarek-Weirauch N, Begemann M, Bennett MF, Bensabath U, Bézieau S, Bhouri R, Biehler M, Hammer TB, Bogoin J, Bonanno E, Boussion S, Bris C, Brosseau-Beauvir A, Bruel AL, Briand-Suleau A, Buratti J, Celse T, Chambon P, Chemaly N, Chesneau B, Colin E, Colmard M, Colson C, Conrad S, Courtin T, Creveaux I, Cullier AC, Dang LT, de Saint Martin A, de Vanssay de Blavous Legendre C, Demeer B, Denommé-Pichon AS, Diekhoff P, DiTroia S, Doco-Fenzy M, Dubourg C, Dubucs C, Ducreux S, Dufour L, Duquet R, Durand B, El Chehadeh S, Elbracht M, Faivre L, Faoucher M, Faudet A, Forlani S, Fradin M, Gaignard P, Ganne B, Garde A, Géraud J, Gill D, Goldenberg A, Grabli D, Grisel C, Gueden S, Gueguen P, Guerrot AM, Guichet A, Haack TB, Härting N, Häusler MG, Heide S, Herget T, Héron B, Héron D, Herwig J, Heulin M, Holling T, Houdayer C, Isidor B, Jacquette A, Januel L, Jean-Marçais N, Kaiser FJ, Kaya S, King C, Konyukh M, Kraft F, Krause J, Kirstetter R, Kuechler A, Kurth I, Kutsche K, Labalme A, Laloy JS, Laugel V, Le Bricquir F, Lèbre AS, Lebrun M, Leguern E, Levy J, Lieffering N, Lyonnet S, Lüthy K, Macdonald SMW, Mansour-Hendili L, Maraval J, Marquardt I, Mattausch C, Mercier S, Messaoud O, Morel G, Mortreux J, Munnich A, Nabbout R, Nambot S, Navarro V, Neale A, Nguyen L, Nizon M, Nowak F, O'Leary MC, Odent S, Ojeda NM, Olin V, Olivieri S, Õunap K, Pais LS, Panagiotakaki E, Patat O, Perrin-Sabourin L, Petit F, Philippe C, Piton A, Planes M, Poirsier C, Pouzet A, Prouteau C, Quéméner-Redon S, Renaud M, Richard AC, Rio M, Rivier C, Robin-Renaldo F, Rollier P, Rossi M, Roubertie A, Ruault V, Rupin-Mas M, Saugier-Veber P, Saunier A, Saneto R, Sarrazin E, Sarret C, Schaefer E, Schluth-Bolard C, Schneider A, Schumann I, Seplyarskiy VB, Spranger S, Smol T, Sturm M, Sunyaev SR, Sperelakis-Beedham B, Stenton SL, Stock F, Tharreau M, Torun D, Toulouse J, Thiyagarajah H, Valence S, Valleix S, Van-Gils J, Villard L, Ville D, Villeneuve N, Vitobello A, Waernessyckle A, Wagner J, Weber Y, Wieczorek D, Witkowski T, Yadavilli M, Yammine T, Zaafrane-Khachnaoui K, Zaki MS, Ziegler A, Bramswig NC, Lermine A, Nicolas G, Gleeson JG, Sadleir LG, Hildebrand MS, Scheffer IE, Whiffin N, O'Donnell-Luria A, Mefford HC, Blanc P, Thevenon J, Charbonnier C, Charenton C, Depienne C, Lesca G, Nava C.

Nat Genet. 2026 Mar 30. doi: 10.1038/s41588-026-02547-5. Online ahead of print.

ABSTRACT

Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.

PMID:41912934 | DOI:10.1038/s41588-026-02547-5

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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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