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Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS
(2023)
Yingjie Zhao
;
Yujue Wang
;
Lijie Shi
;
Donna M. McDonald-McGinn
;
T. Blaine Crowley
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>TBX1</jats:italic>, 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 <jats:italic>TBX1</jats:italic> 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 <jats:italic>EP400</jats:italic>, <jats:italic>KAT6A</jats:italic>, <jats:italic>KMT2C</jats:italic>, <jats:italic>KMT2D</jats:italic>, <jats:italic>NSD1, CHD7</jats:italic> and <jats:italic>PHF21A</jats:italic>. 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 <jats:italic>TBX1</jats:italic>, suggesting that they may be in the same genetic network. The genes <jats:italic>KAT6A</jats:italic>, <jats:italic>KMT2C</jats:italic>, <jats:italic>CHD7</jats:italic> and <jats:italic>EZH2</jats:italic>, have been previously shown to genetically interact with <jats:italic>TBX1</jats:italic> in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the <jats:italic>TBX1</jats:italic> gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the <jats:italic>TBX1</jats:italic> gene network in the etiology of CHD.</jats:p>
Scopus© Citations 4 3
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Abnormal nodal and global network organization in resting state functional MRI from subjects with the 22q11 deletion syndrome
(2021)
Teuntje A. D. Pelgrim
;
Matthijs G. Bossong
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Analía Cuiza
;
Luz María Alliende
;
Carlos Mena
<jats:title>Abstract</jats:title><jats:p>The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis.</jats:p>
Scopus© Citations 2 1
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Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome
(2023)
Sólveig Óskarsdóttir
;
Erik Boot
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Terrence Blaine Crowley
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Joanne C.Y. Loo
;
Jill M. Arganbright
Scopus© Citations 50 2
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Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion
(2020)
Isabelle Cleynen
;
Worrawat Engchuan
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Matthew S. Hestand
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Tracy Heung
;
Aaron M. Holleman
Scopus© Citations 98 2
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Analysis of REM sleep without atonia in 22q11.2 deletion syndrome determined by domiciliary polysomnography: a cross sectional study
(2021)
Jorge Mauro
;
Mario Diaz
;
Teresa Córdova
;
Katiuska Villanueva
;
Tania Cáceres
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Study Objectives</jats:title> <jats:p>Our aim is to evaluate the presence of REM sleep without atonia (RWA), the objective hallmark of REM sleep Behaviour Disorder (RBD), as prodromal marker of Parkinson’s disease (PD), in an adult cohort of 22q11.2 deletion syndrome (22qDS).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Sleep quality was assessed by means of Pittsburgh quality scale index (PSQI), and RBD symptoms by means of RBD questionnaire-Hong-Kong (RBDQ-HK). Attended domiciliary video-Polysomnography (v-PSG) were performed in 26 adults (18–51 years, 14 females) 22qDS patients. Electromyogram during REM sleep was analyzed by means of SINBAR procedure at 3-second time resolution (miniepochs).</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>An overall poor sleep quality was observed in the cohort and high RBDQ-HK score in 7 of the 26 patients, two additional patients with positive dream enactment reported by close relatives had low score of RBDQ-HK. Nevertheless, SINBAR RWA scores were lower than cut-off threshold for RWA (mean 5.5%, range 0–12.2%). TST and the percentage of light sleep (N1) were increased, with preserved proportions of N2 and N3. Participants reported poor quality of sleep (mean PSQI &gt; 5), with prolonged sleep latency in the v-PSG. No subjects exhibit evident dream enactment episodes during recording sessions.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>RWA was absent in the studied cohort of 22qDS adult volunteers according to validated polysomnographic criteria. High RBDQ-HK scores do not correlate with v-PSG results among 22qDS individuals.</jats:p> </jats:sec>
Scopus© Citations 5 2
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Functional Dysconnectivity in Ventral Striatocortical Systems in 22q11.2 Deletion Syndrome
(2021)
Ángeles Tepper
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Analía Cuiza
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Luz María Alliende
;
Carlos Mena
;
Juan Pablo Ramirez-Mahaluf
<jats:title>Abstract</jats:title> <jats:p>22q11.2 deletion syndrome (22q11.2DS) is a genetic neurodevelopmental disorder that represents one of the greatest known risk factors for psychosis. Previous studies in psychotic subjects without the deletion have identified a dopaminergic dysfunction in striatal regions, and dysconnectivity of striatocortical systems, as an important mechanism in the emergence of psychosis. Here, we used resting-state functional MRI to examine striatocortical functional connectivity in 22q11.2DS patients. We used a 2 × 2 factorial design including 125 subjects (55 healthy controls, 28 22q11.2DS patients without a history of psychosis, 10 22q11.2DS patients with a history of psychosis, and 32 subjects with a history of psychosis without the deletion), allowing us to identify network effects related to the deletion and to the presence of psychosis. In line with previous results from psychotic patients without 22q11.2DS, we found that there was a dorsal to ventral gradient of hypo- to hyperstriatocortical connectivity related to psychosis across both patient groups. The 22q11.2DS was additionally associated with abnormal functional connectivity in ventral striatocortical networks, with no significant differences identified in the dorsal system. Abnormalities in the ventral striatocortical system observed in these individuals with high genetic risk to psychosis may thus reflect a marker of illness risk.</jats:p>
1Scopus© Citations 6
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The COVID‐19 pandemic's impact on worry and medical disruptions reported by individuals with chromosome 22q11.2 copy number variants and their caregivers
(2022)
L. K. White
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T. B. Crowley
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B. Finucane
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S. Garcia‐Minaur
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G. M. Repetto
Scopus© Citations 2 1
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A normative chart for cognitive development in a genetically selected population
(2021)
Ania M. Fiksinski
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Carrie E. Bearden
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Anne S. Bassett
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René S. Kahn
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Janneke R. Zinkstok
15Scopus© Citations 19
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Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from the<scp>ENIGMA</scp>working groups on<scp>CNVs</scp>
(2021)
Ida E. Sønderby
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Christopher R. K. Ching
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Sophia I. Thomopoulos
;
Dennis Meer
;
Daqiang Sun
3Scopus© Citations 46
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Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness
(2020)
Christopher R.K. Ching
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Boris A. Gutman
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Daqiang Sun
;
Julio Villalon Reina
;
Anjanibhargavi Ragothaman
Scopus© Citations 44 8

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