Programmpunkt

11:48–11:50

Titel: BRCA2-stress-paradigm: BRCA2 heterozygosity and additional stress factors predispose to neuropsychiatric abnormalities
ID: P-ClinG-048
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
ClinG 2

Referent: Malin Dewenter (Mainz/DE), Ann-Sophie Pabst (Mainz/DE)


Abstract - Text

Abstract-Text

DNA damage is the molecular basis of tumorigenesis. Besides the second hit hypothesis (Knudson, 1971), new evidence suggests that haploinsufficiency of BRCA2 without loss of the wild type allele is enough to cause increased levels of DNA damage in healthy BRCA2 carrier breast tissue (Karaayvaz-Yildirim et al., 2020). In addition to its involvement in tumorigenesis, there is scattered evidence implicating DNA damage and impaired DNA damage repair in (neuro-) psychiatric diseases and intellectual disability (Shiwaku & Okazawa, 2015, Raza et al., 2016). Association of a common BRCA2 variant with bipolar disorder (Tesli et al., 2010) and of two de novo missense mutations in the BRCA2 gene with autism spectrum disorder (Neale et al., 2012) support this.


Here we report on three unrelated carriers of BRCA2 loss of function (LoF) mutations who were identified by Next Generation Sequencing (NGS) in a cohort of 161 patients with neuropsychiatric disorders and/or intellectual disability. No other causative variants were identified. All three patients came from unfavorable social backgrounds including substantial stress exposure during pregnancy.


Causes of DNA damage are abundant – both by external (exogenous) and cell internal (endogenous) insults. Influenceable factors include smoking (Yamaguchi, 2019), alcohol abuse (Garaycoechea et al., 2018), chemical agents, irradiation (Mehta et al., 2014) as well as chronic stress (Flint & Bovbjerg, 2012). To repair these coincidental DNA damages, the cell relies on DNA repair mechanism such as homologous recombination involving BRCA2.


Our observations support the hypothesis that the combination of reduced DNA repair capabilities (due to a heterozygous BRCA2 mutation) and accumulation of DNA damage (by stressors) increases the risk for neuropsychiatric disorders (BRCA2-stress-paradigm). Larger studies will be required to confirm and quantify these results.