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PURPOSE: The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome. METHODS: Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants. RESULTS: The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS). CONCLUSION: The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.

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.

One of the main factors influencing the clinical utility of genetic tests for cancer predisposition is the ability to provide actionable classifications (ie pathogenic or benign). However, a large fraction of the variants identified in cancer predisposing genes (CPGs) are of uncertain significance (VUS), and cannot be used for clinical purposes either to identify individuals at risk or to drive treatment. Here we analyze the current status of VUS identification in a subset of 24 CPGs included by the American College of Medical Genetics/Association for Molecular Pathology in the list of genes that should be considered for the return of incidental findings. To this purpose we retrieved published literature using different search strings according to the frequency of the condition and we extracted corresponding data from ClinVar. The total number of VUS has not decreased with time, due to widespread multigene panel testing, and the relative yield of VUS compared to pathogenic variants is higher in more recent studies, which tend to involve series not selected for the presence of specific high risk criteria. In addition, only few studies adopt gene specific interpretation criteria when these are available. Despite the large yield of VUS associated with multigene testing, the data obtained from such studies can be very useful for variant classification, especially for those variants that are more likely to be benign, since these are expected to be detected more frequently in a population that does not show gene specific manifestations. In addition, wider use of gene specific interpretation criteria should be promoted in order to optimize the interpretation process.

The development of innovative technologies and the advances in the genetics and genomics, have offered new opportunities for personalized treatment in oncology. Although the selection of the patient based on the molecular characteristics of the neoplasm has the potential to revolutionize the therapeutic scenario of oncology, this approach is extremely challenging. The access, homogeneity, and economic sustainability of the required genomic tests should be warranted in the clinical practice, as well as the specific scientific and clinical expertise for the choice of medical therapies. All these elements make essential the collaboration of different specialists within the Molecular Tumor Boards (MTBs). In this position paper, based on experts' opinion, the AIOM-SIAPEC/IAP-SIBioC-SIC-SIF-SIGU-SIRM Italian Scientific Societies critically discuss the available molecular profiling technologies, the proposed criteria for the selection of patients candidate for evaluation by the MTB, the criteria for the selection and analysis of biological samples, and the regulatory and pharmaco-economic issues.

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM–AIRO–AISP–ANISC–AURO–Fondazione AIOM–SIAPEC/IAP–SIBioC–SICO–SIF–SIGE–SIGU–SIU–SIURO–UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

The implementation of cancer molecular characterization in clinical practice has improved prognostic re-definition, extending the eligibility to a continuously increasing number of targeted treatments. Broad molecular profiling technologies better than organ-based approaches are believed to serve such dynamic purposes. We here present the workflow our institution adopted to run a comprehensive cancer genome profiling in clinical practice. This article describes the workflow designed to make a comprehensive cancer genome profiling program feasible and sustainable in a large-volume referral hospital. Keywords: bioinformatics; cancer; comprehensive cancer genome profiling; genomics; target therapy.

Background: The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date. Materials and methods: From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors. Results: The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together. Conclusions: Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas. Keywords: CDKN2A; gene panel; germline; melanoma; predictors; susceptibility.

Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts’ consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR de

Background Spinal muscular atrophy (SMA) is due to the homozygous absence of SMN1 in around 97% of patients, independent of the severity (classically ranked into types I-III). The high genetic homogeneity, coupled with the excellent results of presymptomatic treatments of patients with each of the three disease-modifying therapies available, makes SMA one of the golden candidates to genetic newborn screening (NBS) (SMA-NBS). The implementation of SMA in NBS national programmes occurring in some countries is an arising new issue that the scientific community has to address. We report here the results of the first Italian SMA-NBS project and provide some proposals for updating the current molecular diagnostic scenario. Methods The screening test was performed by an in-house-developed qPCR assay, amplifying SMN1 and SMN2. Molecular prognosis was assessed on fresh blood samples. Results We found 15 patients/90885 newborns (incidence 1:6059) having the following SMN2 genotypes: 1 (one patient), 2 (eight patients), 2+c.859G>C variant (one patient), 3 (three patients), 4 (one patient) or 6 copies (one patient). Six patients (40%) showed signs suggestive of SMA at birth. We also discuss some unusual cases we found. Conclusion The molecular diagnosis of SMA needs to adapt to the new era of the disease with specific guidelines and standard operating procedures. In detail, SMA diagnosis should be felt as a true medical urgency due to therapeutic implications; SMN2 copy assessment needs to be standardised; commercially available tests need to be improved for higher SMN2 copies determination; and the SMN2 splicing-modifier variants should be routinely tested in SMA-NBS.

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

No abstract available

Atopic dermatitis (AD) has a big impact on quality of life. The usefulness of health-related quality of life questionnaires for children with AD in general practice, and the relationship of quality of life to disease severity, as assessed by parents and by investigators, however, is not known. This study used the Infants' Dermatitis Quality of Life Index (IDQoL) to assess quality of life in children with AD selected from general practice. Severity of AD was determined by investigators and parents using the objective SCORAD (SCORing Atopic Dermatitis), the TIS (three-item severity scale), or by an additional question on the IDQoL. A total of 66 patients (41% boys, mean age 31 months) were included. Correlations between disease severity assessed by parents and by investigators were low (R-s 0.29-0.51). Correlations between IDQoL and severity assessed by investigators were also low (R-s 0.08-0.36). However, correlations between IDQoL and severity according to parents were high (R-s 0.67-0.73). In conclusion, disease severity and disease-related quality of life are different aspects of AD and must be taken into consideration when evaluating treatment or investigating new dermatological therapies in trials.

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.

Purpose: EEG anomalies and epilepsy are a not so rare clinical manifestation in patients with Phosphatase and tensin homolog (PTEN) variants. The main aim of this study is to analyze the characteristics of EEG traces, neuroimaging findings and epilepsy to better define the neurological aspects in a set of patients with PTEN variants collected in four Italian Centres. As a secondary aim, we describe the neurodevelopmental profile and the psychiatric comorbidities of this cohort. Methods: Patients with PTEN variants, identified by Sanger sequencing or target resequencing, were enrolled. For each subjects, clinical data were retrospectively extracted from medical charts, with a focus on epilepsy and neuroimaging data. Results: 54 patients with PTEN variants were enrolled, with a mean age of 18.8 years. 72.2% have at least one psychiatric diagnosis, being Autism Spectrum Disorder and Intellectual Disability the most frequent diagnosis (29 and 25 cases, respectively). 22 subjects show an abnormal EEG and 8 received a diagnosis of epilepsy, mainly focal epilepsy (7/8), with a mean age at seizure onset of 3.8 years. 3/8 subjects have a drug resistant epilepsy, independently from the underlying neuroimaging pattern. The finding of a Focal cortical dysplasia is significantly associated with both an abnormal EEG (p = 0.02) and the occurrence of seizures (p = 0.002). Conclusion: EEG should be taken into consideration in the first-line diagnostic flowchart of subjects with PTEN variants. The onset of a focal epilepsy, independently from its response to antiepileptic drugs, highly recommends to carry out a neuroimaging exam. Keywords: Autism; EEG anomalies; Epilepsy; Focal cortical dysplasia; Intellectual disability; PTEN.

Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR de

The PTEN hamartoma tumor syndrome (PHTS) is a heterogeneous set of multisystem disorders caused by germline pathogenic variants in the PTEN tumor suppressor gene. Manifestations include developmental anomalies and proliferative lesions. Evidence of involvement of the GI tract has accrued over time, leading to the incorporation of GI manifestations (multiple hamartomas, glycogenic acanthosis and colorectal cancer) into the diagnostic criteria. Polyps of the upper and lower GI tract are found in most adult patients and in a significant fraction of children. Polyps tend to be of mixed histology, with a predominance of hamartomas and ganglioneuromas. PHTS patients are also at increased risk of colorectal cancer, and surveillance by colonoscopy is advised starting at the age of 35–40 years. A number of additional manifestations, including eosinophilic gastrointestinal disorders, have been observed in few or single cases, and their association with PHTS has yet to be determined.

Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants. Keywords: Genetic association studies; Genetic variation; Human genetics; Medical oncology; Phenotype.

Background: Despite increasing use of next-generation sequencing (NGS), data concerning the gain in germline pathogenic variants (PVs) remain scanty, especially with respect to uncanonical ones. We aimed to verify the impact of different cancer predisposition genes (CPGs) on colorectal cancer (CRC) in patients referred for genetic evaluation. Materials and methods: We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history. Results: Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P = 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases: 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH). Conclusion: Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype. Keywords: DNA microsatellite instability; colorectal cancer; colorectal cancer genes; gene testing; inherited cancers.

Background: Spinal muscular atrophy (SMA) is due to the homozygous absence of SMN1 in around 97% of patients, independent of the severity (classically ranked into types I-III). The high genetic homogeneity, coupled with the excellent results of presymptomatic treatments of patients with each of the three disease-modifying therapies available, makes SMA one of the golden candidates to genetic newborn screening (NBS) (SMA-NBS). The implementation of SMA in NBS national programmes occurring in some countries is an arising new issue that the scientific community has to address. We report here the results of the first Italian SMA-NBS project and provide some proposals for updating the current molecular diagnostic scenario. Methods: The screening test was performed by an in-house-developed qPCR assay, amplifying SMN1 and SMN2. Molecular prognosis was assessed on fresh blood samples. Results: We found 15 patients/90885 newborns (incidence 1:6059) having the following SMN2 genotypes: 1 (one patient), 2 (eight patients), 2+c.859G>C variant (one patient), 3 (three patients), 4 (one patient) or 6 copies (one patient). Six patients (40%) showed signs suggestive of SMA at birth. We also discuss some unusual cases we found. Conclusion: The molecular diagnosis of SMA needs to adapt to the new era of the disease with specific guidelines and standard operating procedures. In detail, SMA diagnosis should be felt as a true medical urgency due to therapeutic implications; SMN2 copy assessment needs to be standardised; commercially available tests need to be improved for higher SMN2 copies determination; and the SMN2 splicing-modifier variants should be routinely tested in SMA-NBS. Keywords: Genetic Testing; Genetics, Population; Neonatal Screening; Neuromuscular Diseases.

Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.g., syndactyly is typical of Apert and rare in Pfeiffer syndrome. Their inheritance is autosomal dominant with incomplete penetrance and one of the main genes responsible for these syndromes is FGFR2, mapped on chromosome 10, encoding fibroblast growth factor receptor 2. We report an FGFR2 gene variant in a mother and daughter who present with different clinical features of Crouzon syndrome. The daughter is more severely affected than her mother, as also verified by a careful study of the face and oral cavity. The c.1032G>A transition in exon 8, already reported as a synonymous p.Ala344 = variant in Crouzon patients, also activates a new donor splice site leading to the loss of 51 nucleotides and the in-frame removal of 17 amino acids. We observed lower FGFR2 transcriptional and translational levels in the daughter compared to the mother and healthy controls. A preliminary functional assay and a molecular modeling added further details to explain the discordant phenotype of the two patients.

Costello syndrome (CS) is a rare disorder affecting development and growth characterized by cancer predisposition and caused by mutations in HRAS proto-oncogene. Somatic HRAS mutations drive bladder carcinogenesis. The aim of this study was to analyze prevalence and histological characterization of bladder cancer (BC) in a cohort of patients with CS to help clinicians plan effective management strategies. This study included 13 patients above 10 years of age with molecular diagnosis of CS. Screening cystoscopies (31 total procedures) were performed to exclude BC. Any lesion was analyzed through cold-cup biopsy or trans-urethral resection of the bladder. According to histology, patients were followed-up with urinalysis and abdominal ultrasound yearly, and cystoscopies every 12–24 months. During study enrollment, bladder lesions (often multifocal) were detected in 11/13 patients. Histological analysis documented premalignant lesions in 90% of cystoscopies performed, epithelial dysplasia in 71%, and papillary urothelial neoplasm of low-malignant potential in 19%. BC G1/low grade (Ta) were removed in 10%. Overall, 76% of patients showed a bladder lesion at first cystoscopy. The present findings document that individuals with CS aged 10 years and older have high prevalence of bladder lesions (premalignant/malignant), highlighting the importance of personalized screening protocols.

Since the approval of the first poly adenosine diphosphate (ADP) ribose polymerase inhibitor (PARPi), olaparib for platinum-sensitive relapsed high grade ovarian cancer, with either germline or somatic BRCA1/2 deleterious variants, the strategies for BRCA1/2 testing are dynamically changing. In fact, along with germline assay, patients are now tested for tumor BRCA1/2 also above all for treatment decisions. In fact, it is reported as by tumor BRCA analysis we can identify 3–9% more mutated women which can therefore benefit from PARPi therapy. Although this new type of approach looks like challenging, in particular due to the technical and analytical difficulties regarding low quality DNA deriving from formalin-fixed paraffin-embedded specimens, the new CE-IVD on NGS-based pipelines, can overcome these issues, allowing specialized molecular laboratories to ensure high quality results and perform the best test settings. Nevertheless, each new NGS pipeline (CE-IVD or in house) should be validated using peculiar samples along with commercially available reference and certified materials, before being introduced in routine settings. The validation set should be appropriately chosen in order to provide unequivocal data regarding robustness of each NGS tBRCA pipeline. Therefore, in order to harmonize the patient and laboratory path, a group of Italian Scientific Societies [Italian Society of Clinical Chemistry (SIBioC), Italian Association of Medical Oncology (AIOM), Italian Association of Clinical Pathology (SIAPEC), Italian Society of Human Genetics (SIGU)] provided the present recommendations which are aimed to guide all professionals (oncologists, gynaecologists, clinical and laboratory geneticists, clinical molecular biologists and pathologists). The intersociety group is confident that the present paper can offer all ovarian cancer women a well-organized pathway of diagnosis and treatment.

Background: Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European "Care for CMMRD" (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods: Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results: Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1-40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19-45) and 22% (95% CI: 12-37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions: Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches. Keywords: MMR biallelic germline mutation; brain tumor; café-au-lait spot; childhood cancer; constitutional mismatch repair deficiency; high-grade glioma; predisp

PIK3CA-related overgrowth spectrum (PROS) are overgrowth diseases involving mesenchymal tissues caused by postzygotic variants in the PIK3CA gene. Fibro-Adipose hyperplasia or Overgrowth (FAO) belongs to PROS. We reported the beneficial effect of oral low-dose sirolimus therapy in a child affected by progressive FAO in term of stabilization of the disease, good tolerability, and easy management.

Medical knowledge is a powerful instrument that is meant for individual and collective good. Since the time of Hippocrates, we have known it should never be abused, even if serious misuses have occurred in modern history. Among the most recent examples of harm is the compulsory collection of DNA samples from ordinary people being carried out by the Chinese authorities in Xinjiang province as part of a programme of surveillance and control [1]. As members of ESHG, professionals working in genetics and genomics, we feel that we must point out the damage that such a collection may cause: first to those directly affected, but also to the reputation of academic and healthcare institutions (including ethics committees), companies and publishers, and the image of genetics in the wider world. Such abuses of genetic tests and DNA collection may damage the trust citizens put into genetics and the promise of personalised medicine, and thus could impair the future of genetic research and healthcare overall. The recent announcement by Springer Nature of the retraction of a 2019 paper [2] on Y-chromosome profiling of ethnic minorities in China and of another on InDel profiling [3], and the placing under scrutiny of more than two dozen others for similar concerns, is an important step in the right direction. However, it still appears that almost half of over a thousand articles describing forensic genetics studies in Chinese populations have at least one co-author from the Chinese police, judiciary or related institutions. It is impossible to carry out forensic population genetics research in China independently from the Chinese authorities. All this literature is thus potentially ethically tainted. Publishers correctly require that the studies described in submitted manuscripts have ethical approvals. However, they may fail to recognise that some ethics committees may not function or abide by expected ethical standards. For example, multiple studies have been approved by ethics c

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the FMR1 gene. The co-occurrence of FXS with other genetic disorders has only been occasionally reported. Here, we describe three independent cases of FXS co-segregation with three different genetic conditions, consisting of Duchenne muscular dystrophy (DMD), PPP2R5D–related neurodevelopmental disorder, and 2p25.3 deletion. The co-occurrence of DMD and FXS has been reported only once in a young boy, while in an independent family two affected boys were described, the elder diagnosed with FXS and the younger with DMD. This represents the second case in which both conditions coexist in a 5-year-old boy, inherited from his heterozygous mother. The next double diagnosis had never been reported before: through exome sequencing, a girl with FXS who was of 7 years of age with macrocephaly and severe psychomotor delay was found to carry a de novo variant in the PPP2R5D gene. Finally, a maternally inherited 2p25.3 deletion associated with a decreased level of the MYT1L transcript, only in the patient, was observed in a 33-year-old FXS male with severe seizures compared to his mother and two sex-and age-matched controls. All of these patients represent very rare instances of genetic conditions with clinical features that can be modified by FXS and vice versa.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the FMR1 gene. The co-occurrence of FXS with other genetic disorders has only been occasionally reported. Here, we describe three independent cases of FXS co-segregation with three different genetic conditions, consisting of Duchenne muscular dystrophy (DMD), PPP2R5D–related neurodevelopmental disorder, and 2p25.3 deletion. The co-occurrence of DMD and FXS has been reported only once in a young boy, while in an independent family two affected boys were described, the elder diagnosed with FXS and the younger with DMD. This represents the second case in which both conditions coexist in a 5-year-old boy, inherited from his heterozygous mother. The next double diagnosis had never been reported before: through exome sequencing, a girl with FXS who was of 7 years of age with macrocephaly and severe psychomotor delay was found to carry a de novo variant in the PPP2R5D gene. Finally, a maternally inherited 2p25.3 deletion associated with a decreased level of the MYT1L transcript, only in the patient, was observed in a 33-year-old FXS male with severe seizures compared to his mother and two sex-and age-matched controls. All of these patients represent very rare instances of genetic conditions with clinical features that can be modified by FXS and vice versa.

No abstract available