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

Elife. 2022 Jul 5;11:e78459. doi: 10.7554/eLife.78459.

ABSTRACT

BACKGROUND: De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring.

METHODS: As a cohort study, in three independent couples undergoing in vitro fertilization, we first identified male gonadal mosaicism through deep whole genome sequencing. We then confirmed variants and assessed their transmission to preimplantation blastocysts (32 total) through targeted ultra-deep genotyping.

RESULTS: Across 55 gonadal mosaic variants, 15 were transmitted to blastocysts for a total of 19 transmission events. This represented an overall predictable but slight undertransmission based upon the measured mutational abundance in sperm. We replicated this conclusion in an independent, previously published family-based cohort.

CONCLUSIONS: Unbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations. This-in turn-could help to reduce their impact on miscarriages and pediatric disease.

FUNDING: No external funding was received for this work.

PMID:35787314 | DOI:10.7554/eLife.78459

Brain. 2022 Jun 30:awac164. doi: 10.1093/brain/awac164. Online ahead of print.

ABSTRACT

Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a ‘reeling’ gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.

PMID:35769015 | DOI:10.1093/brain/awac164

Brain. 2022 Jun 23:awac223. doi: 10.1093/brain/awac223. Online ahead of print.

ABSTRACT

The endocannabinoid system is a highly conserved and ubiquitous signaling pathway with broad ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia, and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNAseq showed clear expression of the truncated transcript and no differences were found between mutant and wild type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique pediatric syndrome. Because enzymatic activity was preserved, the observed mis-localization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.

PMID:35737950 | DOI:10.1093/brain/awac223

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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

Mov Disord. 2022 Apr 5. doi: 10.1002/mds.29006. Online ahead of print.

ABSTRACT

BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine.

OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia.

METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire.

RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening.

CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.

PMID:35384065 | DOI:10.1002/mds.29006

Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome

J Med Genet. 2022 Mar 1:jmedgenet-2021-108375. doi: 10.1136/jmedgenet-2021-108375. Epub ahead of print. PMID: 35232796.

Abstract

Background: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome.

Methods: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients’ phenotypes.

Results: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS.

Conclusion: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.

PMID: 35232796 | DOI: 10.1136/jmedgenet-2021-108375

Front Cell Dev Biol. 2022 Feb 28;10:783762. doi: 10.3389/fcell.2022.783762. eCollection 2022.

ABSTRACT

The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.

PMID:35295849 | PMC:PMC8918504 | DOI:10.3389/fcell.2022.783762

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