A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management

Territorial behaviour and population dynamics in red grouse Lagopus lagopus scoticus. I. Population experiments

&lt;p&gt;1: According to the ‘territorial behaviour’ hypothesis, population cycles of red grouse are caused by delayed density-dependent changes in the aggressiveness of territorial cocks. We report here on a replicated population experiment testing assumptions of this hypothesis.&lt;/p&gt; &lt;p&gt;2: We used testosterone implants to increase aggressiveness of cocks for 3 months during autumn, when recruitment and territory establishment take place. On two moors located in northern England, and on two 1-km2 areas within each moor, we implanted adult cocks with testosterone on an experimental area and with sham implants on a control area.&lt;/p&gt; &lt;p&gt;3: During the first autumn, the testosterone treatment prevented recruitment of young cocks into the territorial populations. This reduced breeding density and altered the age ratio among territorial cocks, and possibly levels of kinship. If so, the ‘kinship’ hypothesis predicted that density and recruitment should continue to differ between testosterone-treated and control areas.&lt;/p&gt; &lt;p&gt;4: Grouse density remained significantly lower on the experimental than on the control areas for two consecutive breeding seasons. This confirmed a strong spatial structuring within grouse populations, which prevented immigration from neighbouring higher-density areas. In the second autumn, testosterone was not implanted but the recruitment rate remained significantly lower and cock density continued to decline more on the experimental than on the control areas.&lt;/p&gt; &lt;p&gt;5: The results suggest that cocks continued to be aggressive and to maintain large territories for at least a year after aggressiveness was increased experimentally, and therefore that autumn aggressiveness is influenced by previous territorial contests.&lt;/p&gt; &lt;p&gt;6: The experiment validates key assumptions of the ‘territorial behaviour’ hypothesis for red grouse cycles. Population models in a subsequent paper demonstrate how changes in aggressiveness can cause population cycles.&lt;/p&gt