Research models of neurodevelopmental disorders: The right model in the right place

Damianidou, Eleni; Mouratidou, Lidia; Kyrousi, Christina

doi:10.3389/fnins.2022.1031075

Cited by 5 publications

(2 citation statements)

References 261 publications

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“…Also, we identified several matches in GeneMatcher for future studies. Functional studies also come with limitations in that the results cannot always be extrapolated to humans (Damianidou et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2024

Hum. Genet.

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Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.

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Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2024

Hum. Genet.

View full text Add to dashboard Cite

show abstract

“…Also, we identi ed several matches in GeneMatcher for future studies. Functional studies also come with limitations in that the results cannot always be extrapolated to humans (Damianidou et al, 2022).…”

Section: Study Limitationsmentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2023

Preprint

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Background Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Methods Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. Results We identified clinically significant variants in five probands, resulting in a 9.4% (5/53) molecular diagnostic yield. Those variants were in CHD3, PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. However, we detected positive associations between neurodevelopmental difficulties and PRS for educational attainment and cognitive performance within the families (p = 0.006 and 0.02, respectively). We did not detect significant associations between PRS for language quantitative measures and their corresponding PRS. Conclusion Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the conditions.

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Characterizing the neuroimmune environment of offspring in a novel model of maternal allergic asthma and particulate matter exposure

Tamayo,

Osman,

Schwartzer

et al. 2023

J Neuroinflammation

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Inflammation during pregnancy is associated with an increased risk for neurodevelopmental disorders (NDD). Increased gestational inflammation can be a result of an immune condition/disease, exposure to infection, and/or environmental factors. Epidemiology studies suggest that cases of NDD are on the rise. Similarly, rates of asthma are increasing, and the presence of maternal asthma during pregnancy increases the likelihood of a child being later diagnosed with NDD such as autism spectrum disorders (ASD). Particulate matter (PM), via air pollution, is an environmental factor known to worsen the symptoms of asthma, but also, PM has been associated with increased risk of neuropsychiatric disorders. Despite the links between asthma and PM with neuropsychiatric disorders, there is a lack of laboratory models investigating combined prenatal exposure to asthma and PM on offspring neurodevelopment. Thus, we developed a novel mouse model that combines exposure to maternal allergic asthma (MAA) and ultrafine iron-soot (UIS), a common component of PM. In the current study, female BALB/c mice were sensitized for allergic asthma with ovalbumin (OVA) prior to pregnancy. Following mating and beginning on gestational day 2 (GD2), dams were exposed to either aerosolized OVA to induce allergic asthma or phosphate buffered saline (PBS) for 1 h. Following the 1-h exposure, pregnant females were then exposed to UIS with a size distribution of 55 to 169 nm at an average concentration of 176 ± 45 μg/m3) (SD), or clean air for 4 h, over 8 exposure sessions. Offspring brains were collected at postnatal days (P)15 and (P)35. Cortices and hippocampal regions were then isolated and assessed for changes in cytokines using a Luminex bead-based multiplex assay. Analyses identified changes in many cytokines across treatment groups at both timepoints in the cortex, including interleukin-1 beta (IL-1β), and IL-17, which remained elevated from P15 to P35 in all treatment conditions compared to controls. There was a suppressive effect of the combined MAA plus UIS on the anti-inflammatory cytokine IL-10. Potentially shifting the cytokine balance towards more neuroinflammation. In the hippocampus at P15, elevations in cytokines were also identified across the treatment groups, namely IL-7. The combination of MAA and UIS exposure (MAA–UIS) during pregnancy resulted in an increase in microglia density in the hippocampus of offspring, as identified by IBA-1 staining. Together, these data indicate that exposure to MAA, UIS, and MAA–UIS result in changes in the neuroimmune environment of offspring that persist into adulthood.

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Research models of neurodevelopmental disorders: The right model in the right place

Cited by 5 publications

References 261 publications

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Characterizing the neuroimmune environment of offspring in a novel model of maternal allergic asthma and particulate matter exposure

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