Genetic counseling during COVID-19 pandemic: Tuscany experience

Background: COVID-19 outbreak prompted health centres to reorganize their clinical and surgical activity. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to pandemic. Methods: We stratified all our scheduled visits, from March 9th through April 30th, and assessed case-by-case which genetic consultations should be maintained as face-to-face visit, or postponed/switched to telemedicine. Results: Out of 288 scheduled appointments, 60 were prenatal consultations and 228 were postnatal visits. We performed most of prenatal consultations as face-to-face visits, as women would have been present in the hospital to perform other procedures in addition to our consult. As for postnatal care, we suspended all outpatient first visits and opted for telemedicine for selected follow-up consultations: interestingly, 75% of our patients’ parents revealed that they would have cancelled the appointment themselves for the fear to contract an infection. Conclusions: Spread of COVID-19 in Italy forced us to change our working habits. Given the necessity to optimize healthcare resources and minimize the risk of in-hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the <i>FMR1</i> Gene.

Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the &lt;i&gt;FMR1&lt;/i&gt; gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes

Estimation du sexe fœtal à partir de l’ilium

La détermination du sexe est une des problématiques les plus fréquemment rencontrées en anthropologie médico-légale. Chez l’adulte, cette détermination est essentiellement basée sur l’os iliaque et autorise un très fort taux de classification correcte, tandis que chez le fœtus, les études sont beaucoup moins nombreuses et conduisent à des résultats souvent contradictoires.Nous avons recherché sur 83 paires d’ilia fœtaux de la collection ostéologique hongroise de Fazekas et Kosa quels étaient les critères métriques qui décrivaient le mieux le dimorphisme sexuel, en évaluant les différentes méthodes proposées sur l’ilium fœtal et en adaptant certaines de celles proposées chez l’adulte. Nous avons pour cela établi et validé un protocole de prise de clichés photographiques et une méthode de mesure sur image numérisée à partir du logiciel Adobe Photoshop 6‚.Certains des paramètres retenus dans l’étude – principalement ceux qui ont été relevés sur l’échancrure ischiatique – présentant de fortes corrélations avec le sexe, nous avons établi une régression logistique estimant la probabilité d’appartenir à l’un ou l’autre des deux sexes. Le faible pourcentage de discrimination sexuelle obtenu avec cette formule nous a amené à tenir compte de l’âge : nous avons donc structuré notre échantillon en différents groupes d’âge et avons établi une formule permettant de déterminer correctement le sexe dans plus de 85 % des cas (sur l’échantillon qui a servi à l’établir) pour les fœtus dont l’âge est inférieur à 26 semaines d’aménorrhée.Sex estimation is one of the most frequently encountered issues in forensic medicine. While in the case of adults this determination is essentially based on iliac bones and provides a rather reliable classification, there are fewer studies conducted on fetuses and the results are often contradictory.Therefore, we examinated 83 pairs of fetal iliac bones in the Hungarian collection of Fazekas and Kosa and searched for metric criteria that can the best be applied for determining sexual dimorphism. During this research, we tested the different methods proposed for fetal iliac bones and adapted some others used particularly in the case of adults.For this reason, we set up and validated a protocol of taking photographs, as well as a measurement technique developed for numeric pictures with the help of a software program, Adobe Photoshop 6‚.During this study, we selected certain parameters, principally the ones taken on the great sciatic notch, which showed a strong correlation with sex, and we established a logistic regression for estimating the probability of belonging to one sex or the other.The weak percentage of sexual differentiation obtained by this formula led us to take into account age: we organised our sample in different age groups and established a formula that permits correct sex determination in more than 85% of cases (in our sample) for fetuses that are less than 24 gestational weeks old

Developing a policy for paediatric biobanks: Principles for good practice

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions

Judging in the Genomic era: judges’ genetic knowledge, confidence and need for training

Genetic information is increasingly used in many contexts, including health, insurance, policing and sentencing – with numerous potential benefits and risks. Protecting from the related risks requires updates to laws and procedures by justice systems. These updates depend to a large extent on what the key stakeholders – the judiciary – know and think about the use of genetic information. This study used a battery of 25 genetic knowledge items to collect data from 73 supreme court judges from the same country (Romania) on their knowledge of genetic information. Their responses were compared with those of two other groups: lawyers (but not judges; N = 94) and nonlawyers (N = 116) from the same country. The data were collected at approximately the same time from the three groups. The judges’ results were also compared to the results obtained from a general population data collection (N = 5310). The results showed that: 1) judges had overall better knowledge of genetics than the other groups, but their knowledge was uneven across different genetic concepts; 2) judges were overall more confident in their knowledge than the other two groups, but their confidence was quite low; and 3) the correlation between knowledge and confidence was moderate for judges, weak for lawyers and not significant for non-lawyers. Finally, 100% of the judges agreed that information on gene-environment processes should be included in judges’ training. Increasing genetic expertise of the justice stakeholders is an important step towards achieving adequate legal protection against genetic data misuse

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P &lt; .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (&gt;100) compared with the deletion group (P &lt; .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits

The phenotype of Floating-Harbor syndrome: Clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results. Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from