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Polygenic risk score analyses on embryos (PGT-P) are being marketed by some private testing companies to parents using in vitro fertilisation as being useful in selecting the embryos that carry the least risk of disease in later life. It appears that at least one child has been born after such a procedure. But the utility of a PRS in this respect is severely limited, and to date, no clinical research has been performed to assess its diagnostic effectiveness in embryos. Patients need to be properly informed on the limitations of this use of PRSs, and a societal debate, focused on what would be considered acceptable with regard to the selection of individual traits, should take place before any further implementation of the technique in this population.

PFAPA is an autoinflammatory syndrome characterized by periodic fever, aphthous stomatitis, sterile pharingitis, and adenitis, with an onset usually before the age of five. While the condition is most commonly sporadic, a few cases are familial and are usually compatible with an autosomal dominant (AD) transmission pattern, with reduced penetrance in some pedigrees. We performed exome analysis in a family where PFAPA was present in three relatives in two generations showing apparent AD segregation, identifying several rare and/or novel heterozygous variants in genes involved in the autoinflammatory pathway. Following segregation analysis of candidate variants, only one, c. 2770T>C p.(S924P) in the ALPK1 gene, was found to be consistently present in affected family members. ALPK1 is broadly expressed in different tissues and its protein is the intracellular kinase activated by the bacterial ADP-heptose bisphosphate that phosphorylates and activates TRAF-Interacting protein with Forkhead-Associated domain (TIFA) and triggers the immediate response to Gram-negative bacterial invasion. Sequencing analysis of 13 additional sporadic cases and 10 familial PFAPA cases identified two additional heterozygous missense variants c.1024G>C p.(D342H) and c.710C>T p.(T237M) in two sporadic patients, suggesting that rare variants in ALPK1 may represent a predisposing factor for recurrent periodic fever in a pediatric population.

A Correction to this paper has been published: https://doi.org/10.1038/s41431-021-00814-z

Purpose Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A . We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. Methods We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. Results We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4 : 58%, BMPR1A : 88%) and the stomach (overall: 21%; SMAD4 : 27%, BMPR1A : 0%). Conclusion This comprehensive retrospective study on genotype–phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

Background Genetic testing has led to a considerable enhancement in the ability to identify individuals at risk of Hereditary Breast and Ovarian Cancer syndrome related to BRCA1/2 pathogenic variants, thus necessitating personalised prevention programs. However, barriers related to intrafamilial communication, privacy regulations, and genetic information dissemination hinder preventive care, particularly in Italy, where legal constraints limit the disclosure of genetic risks to at-risk relatives. This study examines the relationship between BRCA1/2 carriers’ communication challenges and three factors: cancer status, comprehension of genetic information, and the genetic counseling pathway accessed (Traditional Genetic Counseling, TGC vs. Mainstream Cancer Genetics, MCG). Methods This multicenter, prospective, observational study included 277 BRCA1/2 carriers (probands and relatives) aged 18–80 from various Italian centers. Participants completed a sociodemographic form, a self-administered survey, and psychological assessments (Impact of Event Scale, IES and Distress Thermometer, DT). Categorical variables were compared using Pearson’s Chi-squared test or Fisher’s exact test based on sample size and expected frequencies, whereas continuous variables were analyzed using the Wilcoxon rank-sum test because of non-normal data distribution. Results Among the 277 carriers (115 probands, 162 relatives), 79.4% received TGC and 20.6% MCG. The cancer prevalence was higher in probands (83%) than in relatives (22%). The probands exhibited greater psychological distress (higher IES and DT scores), and cancer-affected relatives had higher distress levels than healthy relatives (p = 0.008). While no severe psychological distress or PTSD was found, distress was more associated with cancer diagnosis than genetic status. Genetic comprehension was significantly higher in relatives (p = 0.007) and in those who underwent TGC compared to MCG (p < 0.001). TGC carriers also better understood genetic risks and management strategies (p < 0.001). Conclusions Psychological distress and genetic comprehension significantly influenced the communication. TGC enhances understanding more effectively than MCG, highlighting the need for tailored support for both carriers and healthcare professionals to improve cascade counseling and testing rates, and cancer prevention. As we look into the future, we need to critically approach MCG, and determine how to address carriers understanding and prevention needs and reincorporate a more comprehensive genetic risk assessment into the MCG model.

Genomic testing expansion is accompanied by an increasing need for genetic counselling and intrafamilial communication. Genetic counselling can play an important role in facilitating intrafamilial communication and relationships. We conducted a cross-sectional, multicenter study including 252 Italian women, using a questionnaire divided in two sections, the first one to be filled after the pre-test counselling and the second after receiving BRCA test results. We assessed the factors influencing intrafamilial disclosure of genetic information for hereditary breast and ovarian cancer, family members with whom probands are more prone to share genetic information, and the perceived understanding of information received by counselees during genetic counselling. Women were accompanied to the counselling more often by their husband/partner. Among those with a positive BRCA test result, 49% intended to communicate it to their offspring and 27% to their husband/partner. Younger women, those living with their husband/partner, and those who described family communication as open/profound and spontaneous/sincere had a higher probability of being accompanied during genetic counselling and discuss about it with relatives. Spontaneous/sincere or open/profound family communication and joyful/happy familial relationships were associated with the decision to undergo genetic testing as a responsibility towards relatives. Women had a good understanding of counselling contents (mean score 9.27 in a scale 1–10). Genetic counselling providers should consider that genetic information disclosure does not depend only on the clarity of the information provided, but also on pre-existing intrafamilial communication and relationships, family structure and marital status, indicating the need for a personalised approach accounting for these factors.

Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5′ UTR of the FMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to FMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of FMR1-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clarifying how UFM cells differ from CTRL and FXS cells, a comparative proteomic approach was undertaken, from which emerged an overexpression of SOD2 in UFM cells, also confirmed in PM but not in FXS. The SOD2-mRNA bound to FMRP in UFM more than in the other cell types. The high SOD2 levels in UFM and PM cells correlated with lower levels of superoxide and reactive oxygen species (ROS), and with morphological anomalies and depolarization of the mitochondrial membrane detected through confocal microscopy. The same effect was observed in CTRL and FXS after treatment with MC2791, causing SOD2 overexpression. These mitochondrial phenotypes reverted after knock-down with siRNA against SOD2-mRNA and FMR1-mRNA in UFM and PM. Overall, these data suggest that in PM and UFM carriers, which have high levels of FMR1 transcription and may develop FXTAS, SOD2 overexpression helps to maintain low levels of both superoxide and ROS with signs of mitochondrial degradation.

Fragile X syndrome (FXS) is a very frequent cause of inherited intellectual disability (ID) and autism. Most FXS patients have an expansion over 200 repeats of (CGG)n sequence (“full mutation” (FM)) located in the 5′UTR of the FMR1 gene, resulting in local DNA methylation (methylated “full mutation” (MFM)) and epigenetic silencing. The absence of the FMRP protein is responsible for the clinical phenotype of FXS. FM arises from a smaller maternal allele with 56–200 CGG repeats (“premutation” (PM)) during maternal meiosis. Carriers of PM alleles, which are typically unmethylated, can manifest other clinical features (primary ovarian insufficiency (POI) or FXS-associated tremor-ataxia syndrome (FXTAS)), known as fragile X-related disorders. In FXS families, rare males who have inherited an unmethylated “full mutation” (UFM) have been described. These individuals produce enough FMRP to allow normal intellectual functioning. Here we report the rare case of three sisters with a completely methylated PM of around 140 CGGs and detail their neuropsychological function. X inactivation analysis confirmed that the three sisters have a random inactivation of the X chromosome, suggesting that the PM allele is always methylated also when residing on the active X. We propose that in exceptional cases, just as the FM may be unmethylated, also a PM allele may be fully methylated. To our knowledge, females with a methylated PM allele and a mild impairment have reported only once. The study of these atypical individuals demonstrates that the size of the CGG expansion is not as tightly coupled to methylation as previously thought.

Lynch syndrome (LS) is an autosomal dominant condition caused by pathogenic variants in mismatch repair (MMR) genes that predispose individuals to different malignancies, such as colorectal cancer (CRC) and endometrial cancer. Current guidelines recommended testing for LS in individuals with newly diagnosed CRC to reduce cancer morbidity and mortality in relatives. Economic evaluations in support of such approach, however, are not available in Italy. We developed a decision-analytic model to analyze the cost-effectiveness of LS screening from the perspective of the Italian National Health System. Three testing strategies: the sequencing of all MMR genes without prior tumor analysis (Strategy 1), a sequential IHC and MS-MLPA analysis (Strategy 2), and an age-targeted strategy with a revised Bethesda criteria assessment before IHC and methylation-specific MLPA for patients [greater than or equal to] than 70 years old (Strategy 3) were analyzed and compared to the \"no testing\" strategy. Quality Adjusted Life Years (QALYs) in relatives after colonoscopy, aspirin prophylaxis and an intensive gynecological surveillance were estimated through a Markov model. Assuming a CRC incidence rate of 0.09% and a share of patients affected by LS equal to 2.81%, the number of detected pathogenic variants among CRC cases ranges, in a given year, between 910 and 1167 depending on the testing strategy employed. The testing strategies investigated, provided one-time to the entire eligible population (CRC patients), were associated with an overall cost ranging between [euro]1,753,059.93-[euro]10,388,000.00. The incremental cost-effectiveness ratios of the Markov model ranged from [euro]941.24 /QALY to [euro]1,681.93 /QALY, thus supporting that \"universal testing\" versus \"no testing\" is cost-effective, but not necessarily in comparison with age-targeted strategies. This is the first economic evaluation on different testing strategies for LS in Italy. The results might support the introduction of cost-effective recommendations for LS screening in Italy.