Distinct Neurocognitive Profiles and Clinical Phenotypes Associated with Copy Number Variation at the 22q11.2 Locus

O’Hora, Kathleen; Kushan-Wells, Leila; Hoftman, Gil D.; Jalbrzikowski, Maria; Gur, R.C.; Gur, Ruben C.; Bearden, Carrie E.

doi:10.1101/2023.05.12.23289905

Cited by 3 publications

References 65 publications

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Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

Schleifer,

O’Hora,

Fung

et al. 2023

Preprint

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The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in 22qDel (n=96, 53.1% female), 22qDup (n=37, 45.9% female), and TD controls (n=80, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the effect of 22q11.2 gene dosage was examined using linear mixed models. Age-related changes were characterized with general additive mixed models (GAMMs). Positive gene dosage effects (22qDel < TD < 22qDup) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age- related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

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Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

Schleifer,

O’Hora,

Fung

et al. 2023

Preprint

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Beyond IQ: Executive function deficits and their relation to functional, clinical, and neuroimaging outcomes in 3q29 deletion syndrome

Pollak,

Sefik,

Aberizk

et al. 2024

Preprint

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Background3q29 deletion syndrome (3q29del) is a rare (∼1:30,000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function deficits in 47% of individuals with 3q29del; however, the nuances of executive function in this population have not been described.MethodsWe used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world executive functioning in a cohort of 32 individuals with 3q29del (62.50% male, mean age=14.50±8.26 years). High-resolution structural magnetic resonance imaging was performed on a subset of participants (n=24).ResultsWe found global deficits in executive function; individuals with 3q29del scored significantly higher than the population mean on the BRIEF Global Executive Composite (GEC) and all subscales. 81.25% of study subjects (n=26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were significantly higher among 3q29del participants with a diagnosis of ADHD, and BRIEF GEC T scores were significantly associated with schizophrenia spectrum symptoms as measured by the SIPS. The BRIEF-2 ADHD Form accurately (sensitivity=86.70%) classified individuals with 3q29del based on ADHD diagnosis status, highlighting its potential use as a screener for ADHD in this population. BRIEF GEC T scores were significantly correlated with cerebellar white matter and subregional cerebellar cortex volumes.ConclusionsTogether, these data expand our understanding of the phenotypic spectrum of 3q29del and identify executive function as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

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Spotted around the web: Synthetic embryos; Angelman gene therapy

Adams¹,

McMurray²

2023

Spectrum

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WEEK OF JUNE 26 THautistic adults are more likely than non-autistic ones to have experienced falls, bodily injuries, poisonings and self-harm, in addition to various health conditions, according to a population-based study in Sweden. The Lancet Healthy Longevity An assessment tool that asks children about their participation and engagement in daily activities -a simplified version of "Picture My Participation" -has been validated in a Chinese-speaking population of autistic and non-autistic children. Scandinavian Journal of Occupational Therapy Both deletions and duplications of the 22q11.2 chromosomal region can give rise to autism, but they have distinct neurocognitive profiles, according to a preprint. medRxiv An organization that runs 130 autism treatment centers in the United States, funded by a private equity firm, has filed for bankruptcy. Spectrum has previously covered the ramifications of private investment in nursing homes and other care facilities. Reuters A machine-learning technique called 'federated learning' makes it possible to screen datasets for people who may have autism without plugging their information into a centralized server, thereby skirting privacy issues. Scientific Reports Naturalistic environments and situations in the laboratory are helping neuroscientists decode animal behavior. Nature Biotech companies are tackling chromosomal conditions such as Angelman and Phelan-McDermid syndromes. Earlier this year, Spectrum reported on an RNA therapy for Angelman syndrome as modeled in monkeys. Labiotech Two research groups developed synthetic embryos, or embryoids, from human stem cells, prompting ethical concerns. Spectrum reported on embryoids made from mouse stem cells in October. Nature The Swiss drug company Roche has discontinued its work on rugonersen, a gene therapy for Angelman syndrome, after disappointing results from a phase 1 clinical trial.Spectrum covered preclinical data on the therapy in August. FAST U.S. Food and Drug Administration issued its first clinical trial guidelines for

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Distinct Neurocognitive Profiles and Clinical Phenotypes Associated with Copy Number Variation at the 22q11.2 Locus

Cited by 3 publications

References 65 publications

Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

Beyond IQ: Executive function deficits and their relation to functional, clinical, and neuroimaging outcomes in 3q29 deletion syndrome

Spotted around the web: Synthetic embryos; Angelman gene therapy

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