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Repetto, Gabriela

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Repetto

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Gabriela

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2023 - 20242
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Author: Angkustsiri, Kathleen ×

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    Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS
    (2023) Repetto, Gabriela; Zhao, Yingjie; Wang, Yujue; Shi, Lijie; McDonald, Donna; Crowley, Blaine; McGinn, Daniel; Tran, Oanh; Miller, Daniella; Lin, Jhih-Rong; Zacka, Elaine; Johnston, Richard; Chow, Eva; Vorstman, Jacob; Vingerhoets, Claudia; Van Amelsvoort, Therese; Gothelf, Doron; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris; Eliez, Stephan; Schneider, Maude; Van den Bree, Marianne; Owen, Michael; Kates, Wendy; Shashi, Vandana; Schoch, Kelly; Bearden, Carrie; Digili, M. Cristina; Unolt, Marta; Putotto, Carolina; Marino, Bruno; Pontillo, Maria; Armando, Marco; Vicar, Stefano; Angkustsiri, Kathleen; Campbell, Linda; Busa, Tiffany; Heine, Damian; Murphy, Kieran; Murphy, Declan
    Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD
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    Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome
    (2024) Repetto, Gabriela; Ge, Ruiyang; Ching, Christopher; Bassett, Anne; Kushan, Leila; Antshe, Kevin; Van Amelsvoort, Therese; Bakker, Geor; Butcher, Nancy; Campbell, Linda; Chow, Eva; Craig, Michael; Crossley, Nicolas; Cunningham, Adam; Daly, Eileen; Doherty, Joanne; Durdle, Courtney; Emanuel, Beverly; Fiksinski, Ania; Forsyth, Jennifer; Fremont, Wanda; Goodrich-Hunsaker, Naomi; Gudbrandsen, Maria; Gur, Raquel; Jalbrzikowski, Maria; Kates, Wendy; Lin, Amy; Linden, David; McCabe, Kathryn; McDonald, Donna; Moss, Hayley; Murphy, Declan; Murphy, Kieran; Owen, Michael; Villalon, Julio; Roalf, David; Ruparel, Kosha; Schmitt, J. Eric; Schuite, Sanne; Angkustsiri, Kathleen
    22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

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