Survey of Italian Pediatricians on awareness, experiences and beliefs regarding direct-to-consumer genetic testing in minors

Background: Our study wanted to assess Italian pediatricians’ awareness, experience and beliefs regarding directto-consumer (DTC) genetic tests (GT) in minors, with a focus on those for predisposition to complex disease, lyfestyle, athletic ability and other inborn talents. Methods: A 28-item questionnaire was administered through the SurveyMonkey® web platform to the 9,086 members of the Italian Society of Pediatrics for which a valid email address was available. The survey was opened from April through November 2017. Statistical analyses were performed using the Graphpad software package. Results: 36.2% of the 442 respondents were aware of DTC-GT, but only 23.1% of them felt adequately prepared to meet families’ information needs. The first three sources of knowledge were the Internet (20.98%), magazines/ newspapers (16.78%) and TV/Radio (14.33%), while companies’ direct marketing activity influenced knowledge only in 2.45% of the cases. Only 16.4% of the aware respondents had been already approached for advice. More than 95% of the pediatricians who were aware would not advise DTC-GT for lifestyle, athletic performance or other inborn skills. 69.2% was unfavourable to susceptibility tests for complex diseases. Most of them expressed an interest in learning more and indicated as preferred sources of information public policies issued by professional societies. Conclusion: The low awareness and experience and the vendors’ tiny contribution to knowledge suggest a still limited penetration of DTC-GT companies in Italy. A great interest in learning more was found. Scientific societies are best positioned to support health professionals in this educational goal thanks to their role of trusted sources of information and guidance.&nbsp

Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype

A "Down Syndrome critical region" (DSCR) sufficient to induce the most constant phenotypes of Down syndrome (DS) had been identified by studying partial (segmental) trisomy 21 (PT21) as an interval of 0.6-8.3 Mb within human chromosome 21 (Hsa21), although its existence was later questioned. We propose an innovative, systematic reanalysis of all described PT21 cases (from 1973 to 2015). In particular, we built an integrated, comparative map from 125 cases with or without DS fulfilling stringent cytogenetic and clinical criteria. The map allowed to define or exclude as candidates for DS fine Hsa21 sequence intervals, also integrating duplication copy number variants (CNVs) data. A highly restricted DSCR (HR-DSCR) of only 34 kb on distal 21q22.13 has been identified as the minimal region whose duplication is shared by all DS subjects and is absent in all non-DS subjects. Also being spared by any duplication CNV in healthy subjects, HR-DSCR is proposed as a candidate for the typical DS features, the intellectual disability and some facial phenotypes. HR-DSCR contains no known gene and has relevant homology only to the chimpanzee genome. Searching for HR-DSCR functional loci might become a priority for understanding the fundamental genotype-phenotype relationships in DS

Emilia-Romagna Study on Pregnancy and Exposure to Antiepileptic drugs (ESPEA): a population-based study on prescription patterns, pregnancy outcomes and fetal health

Objectives To assess the prevalence of antiepileptic drug (AED) exposure in pregnant women and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirths, major birth defects (MBDs), neonatal distress and small for gestational age (SGA) infants following intrauterine AED exposure in the Emilia Romagna region, Italy (4 459 246 inhabitants on 31 December 2011). Methods We identified all deliveries and hospitalised abortions in Emilia Romagna in the period 2009-2011 from the certificate of delivery assistance registry (Certificato di Assistenza al Parto -CedAP) and the hospital discharge card registry, exposure to AEDs from the reimbursed drug prescription registries, MBDs from the regional registry of congenital malformations, and Apgar scores and cases of SGA from the CedAP. Records from different registries were linked. Results We identified 145 243 pregnancies: 111 284 deliveries, 16 408 spontaneous abortions and 17 551 TOPs. Six hundred and eleven pregnancies (0.42%; 95% Cl 0.39 to 0.46) were exposed to AEDs. In the AED-exposed group 21% of pregnancies ended in TOPs vs 12% in the non-exposed women (OR: 2.24; 95% CI 1.41 to 3.56). Rates of spontaneous abortions, stillbirths, neonatal distress and SGA were comparable. Three hundred and fifty-three babies (0.31%; 95% CI 0.28 to 0.35) were exposed to AEDs during the first trimester. MBD rates were 2.3% in the exposed vs 2.0% in the non-exposed pregnancies (OR: 1.12, 95% CI 0.55 to 2.55). Conclusion The Emilia Romagna prevalence of AED exposure in pregnancy was 0.42%, comparable with previous European studies. Rates of spontaneous abortions, stillbirths, neonatal distress, SGA and MBDs following AED exposure were not significantly increased. The rate of TOPs was significantly higher in the AED-exposed women

Partial trisomy 21 with or without highly restricted Down syndrome critical region (HR-DSCR): report of two new cases and reanalysis of the genotype-phenotype association

Background: Down syndrome (DS) is caused by the presence of an extra copy of full or partial human chromosome 21 (Hsa21). Partial (segmental) trisomy 21 (PT21) is the duplication of only a delimited region of Hsa21 and can be associated or not to DS: the study of PT21 cases is an invaluable model for addressing genotype-phenotype correlation in DS. Previous works reported systematic reanalyses of 132 subjects with PT21 and allowed the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. Methods: We report clinical data and cytogenetic analysis of two children with PT21, one with DS and the other without DS. Moreover, we performed a systematic bibliographic search for any new PT21 report. Results: Clinical and cytogenetic analyses of the two PT21 children have been reported: in Case 1 the duplication involves the whole long arm of Hsa21, except for the last 2.7 Mb, which are deleted as a consequence of an isodicentric 21: the HR-DSCR is within the duplicated regions and the child is diagnosed with DS. In Case 2 the duplication involves 7.1 Mb of distal 21q22, with a deletion of 2.1 Mb of proximal 20p, as a consequence of an unbalanced translocation: the HR-DSCR is not duplicated and the child presents with psychomotor development delay but no clinical signs of DS. Furthermore, two PT21 reports recently published (named Case 3 and 4) have been discussed: Case 3 has DS diagnosis, nearly full trisomy for Hsa21 and a monosomy for the 21q22.3 region. Case 4 is a baby without DS and a 0.56-Mb duplication of 21q22.3. Genotype-phenotype correlation confirmed the presence of three copies of the HR-DSCR in all DS subjects and two copies in all non-DS individuals. Conclusions: The results presented here are fully consistent with the hypothesis that the HR-DSCR is critically associated with DS diagnosis. No exception to this pathogenetic model was found. Further studies are needed to detect genetic determinants likely located in the HR-DSCR and possibly responsible for core DS features, in particular intellectual disability

One-carbon pathway metabolites are altered in the plasma of subjects with Down syndrome: Relation to chromosomal dosage

Introduction: Down syndrome (DS) is the most common chromosomal disorder and it is caused by trisomy of chromosome 21 (Hsa21). Subjects with DS show a large heterogeneity of phenotypes and the most constant clinical features present are typical facies and intellectual disability (ID). Several studies demonstrated that trisomy 21 causes an alteration in the metabolic profile, involving among all the one-carbon cycle. Methods: We performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 5 different intermediates of the one-carbon cycle in plasma samples obtained from a total of 164 subjects with DS compared to 54 euploid subjects. We investigated: tetrahydrofolate (THF; DS n = 108, control n = 41), 5-methyltetrahydrofolate (5-methyl-THF; DS n = 140, control n = 34), 5-formyltetrahydrofolate (5-formyl-THF; DS n = 80, control n = 21), S-adenosyl-homocysteine (SAH; DS n = 94, control n = 20) and S-adenosyl-methionine (SAM; DS n = 24, control n = 15). Results: Results highlight specific alterations of THF with a median concentration ratio DS/control of 2:3, a decrease of a necessary molecule perfectly consistent with a chromosomal dosage effect. Moreover, SAM and SAH show a ratio DS/control of 1.82:1 and 3.6:1, respectively. Discussion: The relevance of these results for the biology of intelligence and its impairment in trisomy 21 is discussed, leading to the final proposal of 5-methyl-THF as the best candidate for a clinical trial aimed at restoring the dysregulation of one-carbon cycle in trisomy 21, possibly improving cognitive skills of subjects with DS

Prevalence of hypospadias in Italy according to severity, gestational age and birthweight: an epidemiological study

<p>Abstract</p> <p>Background</p> <p>Hypospadias is a congenital displacement of the urethral meatus in male newborns, being either an isolated defect at birth or a sign of sexual development disorders. The aim of this study was to assess the prevalence rate of hypospadias in different Districts of Italy, in order to make a comparison with other countries all over the world.</p> <p>Methods</p> <p>We reviewed all the newborns file records (years 2001–2004) in 15 Italian Hospitals.</p> <p>Results</p> <p>We found an overall hypospadias prevalence rate of 3.066 ± 0.99 per 1000 live births (82.48% mild hypospadias, 17.52% moderate-severe). In newborns Small for Gestational Age (birthweight < 10^thpercentile) of any gestational age the prevalence rate of hypospadias was 6.25 per 1000 live births. Performing multivariate logistic regression analysis for different degrees of hypospadias according to severity, being born SGA remained the only risk factor for moderate-severe hypospadias (p = 0.00898) but not for mild forms (p > 0.1).</p> <p>Conclusion</p> <p>In our sample the prevalence of hypospadias results as high as reported in previous European and American studies (3–4 per 1000 live births). Pathogenesis of isolated hypospadias is multifactorial (genetic, endocrine and environmental factors): however, the prevalence rate of hypospadias is higher in infants born small for gestational age than in newborns with normal birth weight.</p

Clinical and molecular characterization of patients affected by Beckwith-Wiedemann spectrum conceived through assisted reproduction techniques

The prevalence of Beckwith-Wiedemann spectrum (BWSp) is tenfold increased in children conceived through assisted reproductive techniques (ART). More than 90% of ART-BWSp patients reported so far display imprinting center 2 loss-of-methylations (IC2-LoM), versus 50% of naturally conceived BWSp patients. We describe a cohort of 74 ART-BWSp patients comparing their features with a cohort of naturally conceived BWSp patients, with the ART-BWSp patients previously described in literature, and with the general population of children born from ART. We found that the distribution of UPD(11)pat was not significantly different in ART and naturally conceived patients. We observed 68.9% of IC2-LoM and 16.2% of mosaic UPD(11)pat in our ART cohort, that strongly differ from the figure reported in other cohorts so far. Since UPD(11)pat likely results from post-fertilization recombination events, our findings allows to hypothesize that more complex molecular mechanisms, besides methylation disturbances, may underlie BWSp increased risk in ART pregnancies. Moreover, comparing the clinical features of ART and non-ART BWSp patients, we found that ART-BWSp patients might have a milder phenotype. Finally, our data show a progressive increase in the prevalence of BWSp over time, paralleling that of ART usage in the last decades