Treatment-resistant psychotic symptoms and the 15q11.2 BP1–BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature

Farrell, Martilias S.; Lichtenstein, Maya; Harner, Matthew K.; Crowley, James J.; Filmyer, Dawn M.; Lázaro‐Muñoz, Gabriel; Dietterich, Tyler E; Bruno, Lisa; Shaughnessy, Rita A.; Biondi, Tamara F; Burkholder, Stephan; Donmoyer, Jane; Berg, Jonathan S.; Szatkiewicz, Jin P.; Sullivan, Patrick F.; Josiassen, Richard C.

doi:10.1038/s41398-020-0725-x

Cited by 13 publications

(13 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, a meta-analysis estimated the overall effect size of the deletion to be a 4.3-point decrease in IQ and a slightly increased risk of schizophrenia and epilepsy [49]. However, there is considerable phenotype variability among 15q11.2 deletion carriers in the literature [50,51]. Multiple brain-expressed genes are located in this region of 15q11.2, most notably CYFIP1, which is thought to impact neuronal function and morphology [52][53][54].…”

Section: Discussionmentioning

confidence: 99%

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation

Chen

Naesström

Halvorsen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.

show abstract

Section: Discussionmentioning

confidence: 99%

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation

Chen

Naesström

Halvorsen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, it remains an open question as to whether testing is similarly justified for other psychiatric conditions based on considerations of potential harms and benefits 69 . As we have previously argued 70, 71 , there is a shortage of the type of detailed clinical data needed to investigate the impact that large-effect CNVs have on health comorbidities and treatment outcomes in adult psychiatric patients. This limited knowledgebase has made it impossible to assess areas in which specific genetic etiologies may provide guidance to patients’ treatment management and understanding of individual health risks 72 .…”

Section: Discussionmentioning

confidence: 99%

Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

Farrell

Dietterich²,

Harner³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundIt remains unknown why ∼30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations into treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we test whether schizophrenia-associated CNVs are more prevalent in patients with treatment-resistant psychotic symptoms compared to previously published schizophrenia cases not selected for treatment-resistance.MethodsCNVs were identified using chromosomal microarrays and exome sequencing in 509 patients with treatment-resistant psychosis (a lack of clinical response to ≥ 3 adequate antipsychotic medication trials over at least five years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared against a previous large schizophrenia cohort study.ResultsIn total, 47 cases (9.2%) carried at least one CNV with known or possible neuropsychiatric risk. The prevalence of schizophrenia-associated CNVs (n=21; 4.1%) was significantly increased compared to a previous schizophrenia cohort study (p = 0.005322; OR = 1.93). This increase in prevalence was primarily due to duplications at 15q11.2-q13.1 and 16p11.2, which were independently associated with treatment-resistance in pairwise loci-based analysis.ConclusionsThese findings suggest that rare schizophrenia-associated CNVs, particularly duplications of 15q11.2-q13.1 and 16p11.2, may serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.

show abstract

“…However, the sources of the 15q11.2 microdeletions of fetus 1, fetus 2, and fetus 4 are unknown, requiring further follow‐up studies. According to existing research reports, the most common clinical manifestations of the 15q11‐q13 microdeletion are mental delay, autism spectrum disorders, and other related behaviors (Butler, 2017; Farrell et al, 2020). The size of the lost region of fetus 6 and fetus 7 at 15q11‐q13 was approximately 4–5 MB and contained the 15q11‐q13 recurrence PWS/AS region (BP2‐BP3).…”

Section: Discussionmentioning

confidence: 99%

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

Huang

Chen

et al. 2021

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background The 15q11‐q13 region contains three breakpoints (BP1 to BP3), and copy number variations often occur in the region. Aims 15q11‐q13 microdeletion and microduplication are usually associated with Prader‐Willi and Angelman syndromes, respectively. It is not yet clear to what extent microdeletion and microduplication affect the physical health of the fetus and the child. In this study, we examined seven fetuses ranging in gestational age from 15 to 27 weeks. Materials & Methods Detailed prenatal screening and laboratory examinations were performed, while karyotype analysis and chromosomal microarray analysis (CMA) of the amniotic fluid and umbilical cord blood were applied for genetic analysis. Results CMA analysis showed that four fetuses harbored a microdeletion and one fetus showed a microduplication at 15q11.2 BP1‐BP2, two fetuses had a microdeletion at 15q11‐q13 BP2‐BP3, and one fetus had an additional microdeletion at 16p13.11. Discussion There is no clear standard for the clinical diagnosis of 15q11‐q13 microdeletion and microduplication, some of them have clinical phenotypes or are clinically affected. Conclusion Therefore, parents of such fetuses should be informed of the possibility of microdeletions or microduplications to mitigate the psychological burden, and medical consultation and assistance should be provided when communicating the results of the mid‐gestation screening.

show abstract

Treatment-resistant psychotic symptoms and the 15q11.2 BP1–BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature

Cited by 13 publications

References 45 publications

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: a preliminary investigation

Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

Contact Info

Product

Resources

About