Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae

Publisher Copyright: © 2022 The AuthorsNuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants. In contrast to previous reports, the clinical penetrance was not complete even with advancing age and the prevalence of CVID/hypogammaglobulinemia was significantly lower, whereas (auto)inflammatory manifestations were more common (42% of the total cohort). At current stage of knowledge, routine genetic screening of asymptomatic individuals is not recommended, but counseling of potential adult carriers seems necessary.Peer reviewe

Radiographic oral findings and death risk in the elderly

Abstract Radiographic oral and maxillofacial findings were recorded in a cohort of 293 home living elderly, in Helsinki, Finland, derived from a random sample of 8035 subjects, , born in 1904, 1909, and 1912, who participated in the Helsinki Ageing Study. They were 76, 81, and 86 years old at the commencement of the radiographic study. The relationships of potentially infectious findings with increased all-cause mortality over four years were studied. During the four-year follow-up, 18.5% of the subjects died. Of the 124 edentulous subjects, 17% had condylar findings, 13% radiopaque intraosseous findings, 9% retained roots, 6% maxillary sinus findings, 4% impacted teeth and 3% radiolucent findings. Edentulous women had more arthrotic condylar findings than men. The mean number of teeth in the 169 dentate subjects was 13.9, 15.5 in men and 13.2 in women. Carious teeth were found in 75%, radiolucent findings in 41%, teeth with vertical infrabony pockets in 51%, furcation lesions in 28%, calculus in 40%, and condylar findings in 25%. Periodontal attachment loss was slight in 18%, moderate in 31%, and advanced in 46%. 21% of the teeth had been endodontically treated. Periapical lesions were found in 17% of these teeth, and in 4% of the other teeth. 75% of the rootfillings were inadequate, exhibiting periapical lesions twice as often as the adequate ones. Men had more carious teeth, periapical lesions and furcation lesions than women, indicating better oral hygiene and/or utilisation of dental services in women. Compared with the previous studies carried out in Finland, slightly more teeth and less tooth-associated pathology were found in the present subjects. In contemporary Scandinavian studies, only a slightly better oral health status in the elderly has been reported. During the four-year follow-up, mortality was higher in the subjects with moderate to advanced infrabony pockets, OR 2.2, 1.0-4.7. In the previous studies, similar associations have been found in larger study cohorts including younger subjects. Our results indicate that oral foci may be more dangerous for the elderly than it has been previously thought, as the subjects who died had poorer dental health than those who survived

Radiographic periodontal findings in an elderly Finnish population

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Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition

Abstract CHEK2 is a well-established breast cancer susceptibility gene. The most frequent pathogenic CHEK2 variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is CHEK2 c.1312 G > T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of CHEK2 p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen CHEK2 p.(Asp438Tyr) carriers were identified (14/2284, 0.6%, P = 0.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2/281, 0.7%, P = 1.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12/2003, 0.6%, P = 0.66). This frequency did not differ from the frequency in the general population (10/1299, 0.8%). No CHEK2 p.(Asp438Tyr) homozygotes were identified. Our results indicate that CHEK2 p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the CHEK2 p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer

Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae

Publisher Copyright: © 2022 The AuthorsNuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants. In contrast to previous reports, the clinical penetrance was not complete even with advancing age and the prevalence of CVID/hypogammaglobulinemia was significantly lower, whereas (auto)inflammatory manifestations were more common (42% of the total cohort). At current stage of knowledge, routine genetic screening of asymptomatic individuals is not recommended, but counseling of potential adult carriers seems necessary.Peer reviewe