Variable Penetrance of the 15q11.2 BP1-BP2 Microduplication in a Family with Cognitive and Language Impairment

Benítez‐Burraco, Antonio; Barcos-Martínez, Montserrat; Espejo-Portero, Isabel; Jiménez-Romero, Ma Salud

doi:10.1159/000468192

Cited by 9 publications

(8 citation statements)

References 21 publications

(10 reference statements)

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“…We did detect more subtle behavioral phenotypes such as learning and memory deficits and increased fear conditioning. This is consistent with large clinical databases which find that lone CYFIP1 duplication is present in 0.5–1% of subjects, most of whom are neurotypical, and suggests that it is some combination of the 3 other genes, NIPA1 , NIPA2 , and TUBGCP5 , in the duplication region or even unidentified genetic mutations outside the region that contribute to the severe, but variable, ASD-related phenotypes observed in humans with BP1-2 dup [12, 63–66].…”

Section: Discussionsupporting

confidence: 86%

“…Our mouse behavioral phenotypes are echoed in research describing patients with BP1-2 duplications (which include the CYFIP1 gene), noting that while half of BP1-2 duplication carries have developmental delay or speech delay [63], the phenotypes are highly variable, signifying that additional, unknown genetic modifiers may be necessary to cause ASD-associated deficits [12, 64]. Perhaps the most remarkable behavioral phenotype found in this study is the overt increase in conditioned fear.…”

Section: Discussionmentioning

confidence: 55%

“…While duplication of the BP2-3 region within 15q11-13 is sufficient to cause Dup15q, the severity of this disorder is worsened by the additional duplication of the BP1-2 region, resulting in more cognitive and behavioral problems, lower language ability, and a higher propensity to develop ASD [10, 11]. At the same time, microduplication of the BP1-2 region is associated with highly variable penetrant phenotypes ranging from neurotypical to high levels of impairment and including autistic features, language, and cognitive dysfunction [12]. Thus, analysis of genes in the BP1-2 region is of increasing interest.…”

Section: Introductionmentioning

confidence: 99%

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CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes

et al. 2019

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Background CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood. Methods We developed and validated a mouse model of human CYFIP1 overexpression ( CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala. Results Extensive behavioral testing in CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes, and myelination. We also identified GABA-A subunit composition changes in basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit. Conclusion Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1. Electronic supplementary material The online version of this article (10.1186/s13229-019-0278-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

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CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes

et al. 2019

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“…Indeed, other modulatory pathways were not excluded and some of these may be similar to 15q11.2 and 16p11.2 duplications, for example, dosage-sensitive pathways, the presence of a protective allele, sequence changes, and the impact of duplicated noncoding genes (Benítez-Burraco et al, 2017;Jing et al, 2014;Lee et al, 2015;Ulfarsson et al, 2017;Zwaag et al, 2009). We emphasize the importance of future analyses, particularly messenger ribonucleic acid/protein expression studies and more detailed methods for revealing the start and end of duplications of 9p24.3 and other loci.…”

Section: Discussionmentioning

confidence: 99%

Duplication of 9p24.3 in three unrelated patients and their phenotypes, considering affected genes, and similar recurrent variants

Capkova

Srovnal

et al. 2021

Molec Gen & Gen Med

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Background Recent studies suggest that duplication of the 9p24.3 chromosomal locus, which includes the DOCK8 and KANK1 genes, is associated with autism spectrum disorders (ASD), intellectual disability/developmental delay (ID/DD), learning problems, language disorders, hyperactivity, and epilepsy. Correlation between this duplication and the carrier phenotype needs further discussion. Methods In this study, three unrelated patients with ID/DD and ASD underwent SNP aCGH and MLPA testing. Similarities in the phenotypes of patients with 9p24.3, 15q11.2, and 16p11.2 duplications were also observed. Results All patients with ID/DD and ASD carried the 9p24.3 duplication and showed intragenic duplication of DOCK8. Additionally, two patients had ADHD, one was hearing impaired and obese, and one had macrocephaly. Inheritance of the 9p24.3 duplication was confirmed in one patient and his sibling. In one patient KANK1 was duplicated along with DOCK8. Carriers of 9p24.3, 15q11.2, and 16p11.2 duplications showed several phenotypic similarities, with ID/DD more strongly associated with duplication of 9p24.3 than of 15q11.2 and 16p11.2. Conclusion We concluded that 9p24.3 is a likely cause of ASD and ID/DD, especially in cases of DOCK8 intragenic duplication. DOCK8 is a likely causative gene, and KANK1 aberrations a modulator, of the clinical phenotype observed. Other modulators were not excluded.

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“…Paternal duplications of the PWACR may have less deleterious effect on development, but are associated with variable phenotypes, such as parasomnia or ASD (Finucane et al, 1993) (Urraca et al, 2013). Compared to microdeletion of BP1-BP2, microduplication of BP1-BP2 may have milder phenotypes including cognitive impairment, speech delay and developmental delay (Benitez-Burraco et al, 2017;Burnside et al, 2011;Menten et al, 2006), as well as high inter-individual variability of neurodevelopmental disorders (Picinelli et al, 2016).…”

Section: Duplications Involving 15q112mentioning

confidence: 99%

Microduplications at the 15q11.2 BP1–BP2 locus are enriched in patients with anorexia nervosa

Chang

Liu

et al. 2019

Journal of Psychiatric Research

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Microduplication at 15q11.2 have been reported in genetic association studies of schizophrenia and autism. Given the potential overlap in psychiatric symptoms of schizophrenia and autism with anorexia nervosa (AN), we were inspired to test the association of this CNV locus with the genetic susceptibility of AN using ParseCNV, a highly quality controlled CNV pipeline developed by our group. The CNV analysis was performed in 1,017 AN cases and 7,250 controls using the Illumina HumanHap610 SNP arrays data. We uncovered association of the 15q11.2 microduplication with AN with P=0.00023, while no genetic association between the microdeletion of this region and AN was identified. Among four genes in this region that are not imprinted, NIPA1 has the highest expression in brain and encodes a magnesium transporter protein on early endosomes and the cell surface in neurons. Targeting at Mg 2+ uptake mediated by NIPA1 presents an interesting research topic for the explorations of novel therapy for AN and other neurobehavioral diseases, such as schizophrenia and autism.

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Variable Penetrance of the 15q11.2 BP1-BP2 Microduplication in a Family with Cognitive and Language Impairment

Cited by 9 publications

References 21 publications

CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes

CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes

Duplication of 9p24.3 in three unrelated patients and their phenotypes, considering affected genes, and similar recurrent variants

Microduplications at the 15q11.2 BP1–BP2 locus are enriched in patients with anorexia nervosa

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