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OBJECTIVE: the aim of our study was to assess the contribution of quantitative fluorescent polymerase chain reaction (QF-PCR) and pathology studies in the diagnosis of diandric triploidies/partial hydatidiform moles. METHODS: this study included all fet al triploidies diagnosed by QF-PCR in chorionic villi or amniotic fluid in the 2 centers of BCNatal in which a maternal saliva sample was used to establish its parental origin. Pathology studies were performed in products of conception and concordance between a partial hydatidiform mole diagnosis and the finding of a diandric triploidy was assessed. RESULTS: among 46 fetal triploidies, found in 13 ongoing pregnancies and in 33 miscarriages, there were 26 (56%) diandric triploidies. Concordant molecular (diandric triploidy) and pathology results (partial mole) were achieved in 14 cases (54%), while in 6 cases (23%) pathology studies were normal, and in the remaining 6 cases (23%) pathology studies could not be performed because miscarriage was managed medically. CONCLUSIONS: diandric triploidy is associated with partial hydatidiform mole and its diagnosis is crucial to prevent the development of persistent trophoblastic disease. QF-PCR analysis in chorionic villi or amniotic fluid provides a more accurate diagnosis of the parental origin of triploidy than the classical pathology studies.

Objective: To explore the use of a new molecular work-up based on the stepwise use of Quantitative Fluorescence PCR (QF-PCR) extended to eight chromosomes and single nucleotide polymorphism array (SNP-array) in chorionic villi obtained by chorionic villi sampling (CVS) offered to women experiencing an early pregnancy loss. Methods: During a 3-year period (January 2016-December 2018), CVS was offered to women experiencing an early pregnancy loss before the evacuation of the products of conception (POC) to retrieve chorionic villi, irrespective of the number of previous losses. A new molecular work-up was prospectively assayed encompassing a first QF-PCR round (with the 21, 18, 13, 7, X, and Y chromosomes), a second QF-PCR round (with the 15, 16, and 22 chromosomes), and a high resolution SNP-array in those cases with normal QF-PCR results. A control group in which POC were collected after surgical uterine evacuation was used to be compared with the intervention group. Results: Around 459 women were enrolled in the intervention group (CVS) and 185 in the control group (POC after uterine evacuation). The QF-PCR testing success rates were significantly higher in the intervention group (98.5%: 452/459) as compared to the control group (74%: 109/147; p < 0.001), while the chromosomal anomaly rate at the two QF-PCR rounds was similar between the two groups: 52% (234/452) in the intervention and 42% (46/109) in the control group (p = 0.073). The SNP-array was performed in 202 QF-PCR normal samples of the intervention group and revealed 67 (33%) atypical chromosomal anomalies (>10 Mb), 5 (2.5%) submicroscopic pathogenic copy number variants, and 2 (1%) variant of uncertain significance (VOUS). Conclusion: Eighty-two percent of women experiencing an early pregnancy loss opted for a CVS. The testing success rates were higher in the intervention group (CVS; 98%) as compared to the control group (POC; 74%). The overall yields were 52% by QF-PCR (including three complete hydatiform moles), and 16% by SNP-array, including 15% atypical chromosomal anomalies and 1.1% submicroscopic pathogenic copy number variants.

OBJECTIVE: To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99(th) centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies. METHODS: This was a retrospective cohort study of 226 fetuses with NT > 99(th) centile at 11-14 weeks' gestation, between January 2013 and December 2017, in a clinical setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples. We assessed the theoretical yield of two cfDNA testing models, targeted cfDNA (chromosomes 21, 18 and 13) and extended cfDNA (chromosomes 21, 18, 13 and sex chromosomes), and compared it with that of cytogenetic testing and ultrasound assessment in the first and second or third trimesters. RESULTS: In the 226 fetuses analyzed, cytogenetic testing revealed 84 (37%) anomalies, including 68 typical aneuploidies (involving chromosomes 13, 18 or 21), six sex chromosome aneuploidies (four cases of monosomy X and two of trisomy X), three clinically relevant atypical chromosomal anomalies (one trisomy 22, one trisomy 21 mosaicism and one unbalanced translocation), five submicroscopic pathogenic variants and two cases with Noonan syndrome. Targeted and extended cfDNA testing would miss at least 12% (10/84) and 19% (16/84), respectively, of genetic anomalies, accounting for 4.4% and 7.1% of the fetuses with an increased NT, respectively. Finally, of the 142 fetuses with no identified genetic anomaly, a major fetal malformation was observed in 15 (10.6%) fetuses at the early anomaly scan, and in 19 (13.4%) in the second or third trimester. CONCLUSIONS: cfDNA does not appear to be the appropriate genetic test in fetuses with NT > 99(th) centile, given that it would miss 12-19% of genetic anomalies in this group. Additionally, first-trimester ultrasound will identify a major structural abnormality in 11% of the fetuses with NT > 99(th) centile and no genetic anomaly. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Chromosomal microarray analysis (CMA) has now replaced karyotyping in the analysis of prenatal cases with a fetal structural anomaly, whereas in those pregnancies undergoing invasive prenatal diagnosis with a normal fetal ultrasound, conventional karyotyping is still performed. The aims of this study were to establish the diagnostic yield of CMA in prenatal diagnosis, and to provide new data that might contribute to reconsider current practices. We reviewed 2905 prenatal samples with a normal rapid aneuploidy detection test referred for evaluation by CMA testing. Our study revealed pathogenic and reported susceptibility copy number variants associated with syndromic disorders in 4.8% (n = 138/2905) of cases, being 2.8% (n = 81/2905) the estimated added diagnostic value of CMA over karyotyping. Clinically significant CMA abnormality was detected in 5.4% (107/1975) of the fetuses with ultrasound anomalies and in 1.4% (5/345) of those considered as low-risk pregnancies. Our series shows that in prenatal samples, CMA increases 2-fold the diagnostic yield achieved by conventional karyotyping.

To date, the genes involved in familial non-medullary thyroid cancer (FNMTC) remain poorly understood, with the exception of syndromic cases of FNMTC. It has been proposed that germline mutations in telomere-related genes, such as POT1, described in familial melanoma might also predispose individuals to thyroid cancer, requiring further research. We aimed to identify germline mutations in POT1 in selected FNMTC families (with at least three affected members) without a history of other cancers or other features, and to describe the clinical characteristics of these families. Sequencing of the 5 ' UTR and coding regions of POT1 was performed in seven affected people (index cases) from seven families with FNMTC. In addition, we performed whole-exome sequencing (WES) of DNA from 10 affected individuals belonging to four of these families. We did not find germline variants of interest in POT1 by Sanger sequencing or WES. We neither found putative causative mutations in genes previously described as candidate genes for FNMTC in the 4 families studied by WES. In our study, no germline potentially pathogenic mutations were detected in POT1, minimizing the possibilities that this gene could be substantially involved in non-syndromic FNMTC.

Background: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02–2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06–3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05–2·44; p=0·04) and Asp294His (2·15, 1·05–4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. Funding: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831. © 2019 Elsevier Ltd