Dataset Information

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

ABSTRACT:

Background

Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.

Methods

Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.

Results

For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.

Conclusions

We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

SUBMITTER: Boen R

PROVIDER: S-EPMC7615370 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

Boen Rune R Kaufmann Tobias T van der Meer Dennis D Frei Oleksandr O Agartz Ingrid I Ames David D Andersson Micael M Armstrong Nicola J NJ Artiges Eric E Atkins Joshua R JR Bauer Jochen J Benedetti Francesco F Boomsma Dorret I DI Brodaty Henry H Brosch Katharina K Buckner Randy L RL Cairns Murray J MJ Calhoun Vince V Caspers Svenja S Cichon Sven S Corvin Aiden P AP Crespo-Facorro Benedicto B Dannlowski Udo U David Friederike S FS de Geus Eco J C EJC de Zubicaray Greig I GI Desrivières Sylvane S Doherty Joanne L JL Donohoe Gary G Ehrlich Stefan S Eising Else E Espeseth Thomas T Fisher Simon E SE Forstner Andreas J AJ Fortaner-Uyà Lidia L Frouin Vincent V Fukunaga Masaki M Ge Tian T Glahn David C DC Goltermann Janik J Grabe Hans J HJ Green Melissa J MJ Groenewold Nynke A NA Grotegerd Dominik D Grøntvedt Gøril Rolfseng GR Hahn Tim T Hashimoto Ryota R Hehir-Kwa Jayne Y JY Henskens Frans A FA Holmes Avram J AJ Håberg Asta K AK Haavik Jan J Jacquemont Sebastien S Jansen Andreas A Jockwitz Christiane C Jönsson Erik G EG Kikuchi Masataka M Kircher Tilo T Kumar Kuldeep K Le Hellard Stephanie S Leu Costin C Linden David E DE Liu Jingyu J Loughnan Robert R Mather Karen A KA McMahon Katie L KL McRae Allan F AF Medland Sarah E SE Meinert Susanne S Moreau Clara A CA Morris Derek W DW Mowry Bryan J BJ Mühleisen Thomas W TW Nenadić Igor I Nöthen Markus M MM Nyberg Lars L Ophoff Roel A RA Owen Michael J MJ Pantelis Christos C Paolini Marco M Paus Tomas T Pausova Zdenka Z Persson Karin K Quidé Yann Y Marques Tiago Reis TR Sachdev Perminder S PS Sando Sigrid B SB Schall Ulrich U Scott Rodney J RJ Selbæk Geir G Shumskaya Elena E Silva Ana I AI Sisodiya Sanjay M SM Stein Frederike F Stein Dan J DJ Straube Benjamin B Streit Fabian F Strike Lachlan T LT Teumer Alexander A Teutenberg Lea L Thalamuthu Anbupalam A Tooney Paul A PA Tordesillas-Gutierrez Diana D Trollor Julian N JN van 't Ent Dennis D van den Bree Marianne B M MBM van Haren Neeltje E M NEM Vázquez-Bourgon Javier J Völzke Henry H Wen Wei W Wittfeld Katharina K Ching Christopher R K CRK Westlye Lars T LT Thompson Paul M PM Bearden Carrie E CE Selmer Kaja K KK Alnæs Dag D Andreassen Ole A OA Sønderby Ida E IE

Biological psychiatry 20230903 2

<h4>Background</h4>Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.<h4>Methods</h4>Magnetic resonance imaging data were used to obtain regional brain values ...[more]

PMID: 37661008

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Project description:The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

Project description:BackgroundSeveral copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1-BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population-based sample of children.MethodsTwins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs).ResultsWe identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self-reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs.ConclusionsOur results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children.

Dataset Information

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

Background

Methods

Results

Conclusions

Publications

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

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