Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers

Until recently, no prediction models for Lynch syndrome (LS) had been validated for PMS2 mutation carriers. We aimed to evaluate MMRpredict and PREMM5 in a clinical cohort and for PMS2 mutation carriers specifically. In a retrospective, clinic-based cohort we calculated predictions for LS according to MMRpredict and PREMM5. The area under the operator receiving characteristic curve (AU

Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers

Analysis and support of clinical decision makin

A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects

Background Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects. Methods In th

SNP association study in PMS2-associated Lynch syndrome

Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2–3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5–4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.Genetics of disease, diagnosis and treatmen

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders (vol 108, pg 1692, 2021)

Neurolog

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.Hereditary cancer genetic

PMS2-associated Lynch syndrome : the odd one out

Colorectal cancer is one of the most frequently diagnosed cancers in the Western world. Both hereditary and genetic factors play a role in its etiology. In approximately 3% of colorectal cancer cases the underlying cause is a hereditary cancer predisposition syndrome called Lynch syndrome. This thesis focuses on an important subset of Lynch syndrome patients, namely those carrying a mutation in the mismatch repair gene PMS2. Relatively little was known about PMS2-associated Lynch syndrome compared to Lynch syndrome caused by other genes. We provide evidence that PMS2 carriers should be considered a separate entity among Lynch patients. First off, PMS2 carriers have a lower penetrance for colorectal and endometrial cancer. Moreover, they are not at increased risk of other Lynch-associated cancers, such as ovarian cancer. The reason for relatively low colorectal cancer penetrance was investigated by analyzing the somatic mutation spectrum of these tumors. This indicated that PMS2 carriers may not develop cancer from so-called mismatch repair deficient crypts. Lastly the effect of lifestyle and single-nucleotide-polymorphisms (SNPs) was investigated which revealed no significant influence on colorectal cancer risk. The results of the studies described in this thesis have resulted in reconsideration of surveillance guidelines of PMS2-associated Lynch syndrome patients. </p

PMS2-associated Lynch syndrome : the odd one out

Colorectal cancer is one of the most frequently diagnosed cancers in the Western world. Both hereditary and genetic factors play a role in its etiology. In approximately 3% of colorectal cancer cases the underlying cause is a hereditary cancer predisposition syndrome called Lynch syndrome. This thesis focuses on an important subset of Lynch syndrome patients, namely those carrying a mutation in the mismatch repair gene PMS2. Relatively little was known about PMS2-associated Lynch syndrome compared to Lynch syndrome caused by other genes. We provide evidence that PMS2 carriers should be considered a separate entity among Lynch patients. First off, PMS2 carriers have a lower penetrance for colorectal and endometrial cancer. Moreover, they are not at increased risk of other Lynch-associated cancers, such as ovarian cancer. The reason for relatively low colorectal cancer penetrance was investigated by analyzing the somatic mutation spectrum of these tumors. This indicated that PMS2 carriers may not develop cancer from so-called mismatch repair deficient crypts. Lastly the effect of lifestyle and single-nucleotide-polymorphisms (SNPs) was investigated which revealed no significant influence on colorectal cancer risk. The results of the studies described in this thesis have resulted in reconsideration of surveillance guidelines of PMS2-associated Lynch syndrome patients. Publication of this thesis was financially supported by the Dutch Society for Gastroenterology.LUMC / Geneeskund

A PMS2-specific colorectal surveillance guideline

Hereditary cancer genetic