Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

21 Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy 22 caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase 23 enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with oedema, Hypsarrhythmia and Optic atrophy). The proband presented with 25 severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, 26 acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and 27 delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but 28 sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing 29 revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly 30 conserved amino acid and a frameshift variant with consequent degradation of the transcript 31 resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features 32 distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia 33 and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with 34 more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO 35 syndrome patients. The study highlights the challenges in clinical diagnosis of patients with 36 neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI 37 findings. 38 39 Keywords 40 Pontocerebellar hypoplasia type 6, RARS2, PEHO syndrome, progressive cerebellar and cerebral 41 atrophy 3 42 Introduction 43 Pontocerebellar hypoplasia (PCH) is a group of neurodegenerative disorders with autosomal 44 recessive inheritance. Up to date 11 different subtypes have been described, with 17 causative 45 genes identified (van Dijk et al., 2018). Most of the subtypes are characterized by prenatal or 46 neonatal onset, global developmental delay and intellectual disability, microcephaly, hypoplasia and variable atrophy of cerebellar cortex and/or brainstem. The specific neurological symptoms 48 and the severity of symptoms and brain loss vary between the subtypes (van Dijk et al., 2018).49 Pontocerebellar hypoplasia type 6 (PCH6; MIM 611523) is a rare form of PCH first described in 50 2007 in three patients of a consanguineous Sephardic Jewish family (Edvardson et al., 2007). Since 51 then, altogether 32 patients in 18 families have been reported in the literature (for a detailed 52 summary of the patients and phenotypes, see Supplementary Table;Edvardson et al., 2007;

Background Streptococcus dysgalactiae subspecies equisimilis is a human pathogen causing severe invasive infections. Detailed information on S. dysgalactiae subsp. equisimilis bacteremia and especially of predisposing factors are lacking. The purpose of the study is to investigate the risk factors of S. dysgalactiae subsp. equisimilis bacteremia compared to the general population in Finland. Methods We retrospectively reviewed all patients older than 18 years with S. dysgalactiae subsp. equisimilis bacteremia in the Pirkanmaa health district from August 2015 to July 2018. The risk factors for S. dysgalactiae subsp. equisimilis bacteremia were investigated with respect to the normal population in Finland using the Finhealth study data provided by the Finnish institute for health and welfare. The study group was matched with the Finhealth study by age and sex. Results Altogether 230 cases of S. dysgalactiae subsp. equisimilis bacteremia were detected. The medical records of 217 episodes of S. dysgalactiae subsp. equisimilis bacteremia (involving 211 patients) were available for analysis. Obesity was a statistically significant risk factor for S. dysgalactiae subsp. equisimilis bacteremia (Odds Ratio 2.96 [95% CI 2.22–3.96]). Diabetes and coronary artery disease were also associated with an increased risk of S. dysgalactiae subsp. equisimilis bacteremia (OR 4.82 [95% CI 3.62–6.42]) and (OR 3.03 [95% CI 2.18–4.19]). Conclusions We found obesity, diabetes, and coronary artery disease to be associated with an increased risk for S. dysgalactiae subsp. equisimilis bacteremia. These results provide an increased understanding of risk factors for S. dysgalactiae subsp. equisimilis bacteremia.

Streptococcus dysgalactiae subspecies equisimilis (SDSE) is a human pathogen causing severe invasive infections. Population-based studies on SDSE bacteremia are limited. The purpose of this study was to investigate the incidence, seasonal pattern, clinical manifestations, and recurrence of SDSE bacteraemia. Records regarding patients aged ≥ 18 years with SDSE bacteremia in the Pirkanmaa health district in August 2015 to July 2018 were retrospectively reviewed. A total of 230 SDSE bacteremia episodes were identified, with 217 episodes (involving 211 patients) available for analysis. The mean annual incidence rate of SDSE bacteremia was 16.9/100 000 inhabitants. Most episodes (33%) were detected in the summer (June to August) (p = 0.058). Episodes with bacteremic cellulitis were statistically significantly more common during the summer compared with other seasons (p = 0.008). Cellulitis was the most common presenting clinical manifestation of SDSE bacteremia (68% of all episodes). Risk factors of recurring bacteremia were chronic eczema and/or skin erosion (OR 3.96 [95% CI 1.11–14.1]), heart disease (OR 3.56 [95% CI 1.22–10.4]), diabetes (OR 3.77 [95% CI 1.35–10.5]) and a history of cellulitis. We found a remarkably high incidence of SDSE bacteraemia in the Pirkanmaa health district. Bacteraemic cellulitis, which was the predominant clinical manifestation is more often occurred in the summer. Risk factors of recurring SDSE bacteremia were a history of cellulitis, chronic eczema or skin erosion, diabetes, and heart disease.