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Stress exposure during pregnancy is critically linked with maternal mental health and child development. The effects might involve altered patterns of DNA methylation in specific stress-related genes (i.e., glucocorticoid receptor gene, NR3C1, and serotonin transporter gene, SLC6A4) and might be moderated by the gestational timing of stress exposure. In this study, we report on NR3C1 and SLC6A4 methylation status in Italian mothers and infants who were exposed to the COVID-19 pandemic lockdown during different trimesters of pregnancy. From May 2020 to February 2021, 283 mother–infant dyads were enrolled at delivery. Within 24 h from delivery, buccal cells were collected to assess NR3C1 (44 CpG sites) and SLC6A4 (13 CpG sites) methylation status. Principal component (PC) analyses were used to reduce methylation data dimension to one PC per maternal and infant gene methylation. Mother–infant dyads were split into three groups based on the pregnancy trimester (first, second, third), during which they were exposed to the COVID-19 lockdown. Mothers and infants who were exposed to the lockdown during the first trimester of pregnancy had lower NR3C1 and SLC6A4 methylation when compared to counterparts exposed during the second or third trimesters. The effect remained significant after controlling for confounders. Women who were pregnant during the pandemic and their infants might present altered epigenetic biomarkers of stress-related genes. As these epigenetic marks have been previously linked with a heightened risk of maternal psychiatric problems and less-than-optimal child development, mothers and infants should be adequately monitored for psychological health during and after the pandemic.

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients’ phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663–1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663–1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant. © 2019 Wiley Periodicals, Inc.

We have investigated the feasibility of using lyophilization as a method of preserving whole blood samples for HLA class II molecular typing. Genomic DNA extracted from lyophilized blood appears similar in size to that extracted from fresh or frozen blood and is suitable for both PCR amplification and Southern blot analysis.

Background Two different polymorphisms (TPH2 G-703T and 5-HTTLPR) involved in the serotonergic pathway have been reported to play a role, both alone and in interaction with the environment, in early and adult emotion regulation. As most of these studies are cross-sectional, we know little about the impact of these polymorphisms over time, particularly during adolescence. Methods Because we were interested in the effects of these polymorphisms and environment (i.e., family structure) at different time-points on the emotional dysregulation profile, we performed a path analysis model in a general adolescent population sample of a five-year follow-up study. Results We found a high stability of Dysregulation Profile problems independently from the examined allelic variants. We also found that early family structure directly influences the levels of dysregulation problems in early adolescence, both alone and in interaction with TPH2, suggesting the presence of a gene-environment interaction effect. Furthermore, we found that in adolescents homozygous for the TPH2 G allele, the effect of the early family structure remains active during late adolescence, albeit mediated by earlier emotional problems. Limitations The high attrition rate, the use of only one source on behavioral problems of adolescents, and the focus on a single polymorphism in the investigated genes could limit the generalizability of the present results. Conclusions These results suggest that early family structure could play a significant role in the development and maintenance of emotional and behavioral problems not only in early adolescence but also in late-adolescence, although this effect was mediated and moderated by behavioral and genetic variables.

Aims.Many studies of various stress reactive phenotypes suggest that 5-HTTLPR short allele carriers (S-carriers) are characterised by the stable trait of negative affectivity that is converted to psychopathology only under conditions of stress. In this study, we examined the moderating role of the 5-HTTLPR on the relationship between two objective chronic risk factors, i.e. socioeconomic status (SES) and family structure, and internalising symptoms across adolescence.Methods.A multigroup path analysis was employed in a general adolescent population sample of a 5-year follow-up study.Results.Internalising problems were significantly more stable in theS-carriers. The focus on the main dimensions of internalising problems, i.e. anxiety and depression, revealed two different developmental patterns. In theS-carriers Anxiety problems seemed to be more stable and to predict a possible evolution towards the development of Depressive problems. In the long allele homozygotes (LL-subjects) the anxiety trait was significantly less stable, and, in late-adolescence, seemed to be significantly predicted by SES, suggesting a possible gene–environment interaction (G × E). Family structure seemed to play a role in a G × E perspective only until early-adolescence, while during late-adolescence SES seemed to play a pivotal role in interaction with 5-HTTLPR, with the S-allele playing a protective role.Conclusions.Future models of the developmental link between environmental adversities and internalising behaviour therefore need to consider that the effect of G × E interaction, may be associated with internalising behaviour via different mechanisms during different time frames and that shifts in the strength of this effect should be expected across development.

BackgroundThe COVID-19 pandemic is a collective trauma that may expose susceptible individuals to high levels of stress. Pregnant women represent a high-risk population, considering that pregnancy is a period of heightened neuroplasticity and susceptibility to stress through epigenetic mechanisms. Previous studies showed that the methylation status of the BDNF gene is linked with prenatal stress exposure. The goals of this study were (a) to assess the association between pandemic-related stress and postnatal anxiety and (b) to investigate the potential role of maternal BDNF methylation as a significant mediator of this association.MethodsIn the present study, we report data on the association among pandemic-related stress during pregnancy, maternal BDNF methylation, and postnatal anxiety symptoms. Pandemic-related stress and postnatal anxiety were assessed through self-report instruments. BDNF methylation was estimated in 11 CpG sites in DNA from mothers’ buccal cells. Complete data were available from 108 mothers.ResultsResults showed that pandemic-related stress was associated with an increased risk of postnatal anxiety, r = 0.20, p < 0.05. CpG-specific BDNF methylation was significantly associated with both prenatal pandemic-related stress, r = 0.21, p < 0.05, and postnatal maternal anxious symptoms, r = 0.25, p = 0.01. Moreover, a complete mediation by the BDNF CpG6 methylation emerged between pandemic-related stress during pregnancy and postnatal maternal anxiety, ACME = 0.66, p < 0.05.ConclusionThese findings suggest that BDNF epigenetic regulation by pandemic-related stress might contribute to increase the risk of anxiety in mothers. Policymakers should prioritize the promotion of health and wellbeing in pregnant women and mothers during the present healthcare emergency.

Background: Sex-specific differences in DNA methylation of the oxytocin receptor gene (OXTR) have been shown in adults and are related to several mental disorders. Negative affectivity early in life is a trans-diagnostic risk marker of later psychopathology and is partly under genetic control. However, sex-specific variations in OXTR methylation (OXTRm) in infants and their associations with negative affectivity are still unknown. Aims: Here, we explored sex differences in the association between infant OXTRm at birth and negative affectivity at 3 months of age. Methods: Infants and their mothers (N = 224) were recruited at delivery. Infants’ methylation status was assessed in 13 CpG sites within the OXTR gene intron 1 region (chr3: 8810654–8810919) in buccal cells at birth while 3-month-old infants’ negative affectivity was assessed by mothers using a well-validated temperament questionnaire. Results: OXTRm at 12 CpG sites was higher in females than in males. Moreover, higher infants’ OXTRm at 6 specific CpG sites was associated with greater negative affectivity in males, but not in females. Conclusions: These results provide new insights into the role of sex-dependent epigenetic mechanisms linking OXTRm with early infants’ emotional development. Understanding the degree to which epigenetic processes relate to early temperamental variations may help inform the etiology of later childhood psychopathological outcomes.

The COVID-19 pandemic is a collective trauma that is threatening citizens' mental health resulting in increased emotional stress, reduced social support, and heightened risk for affective symptoms. The present study aimed to investigate the effects of antenatal pandemic-related emotional stress and perceived social support on the symptoms of depression and anxiety of mothers who were pregnant during the initial COVID-19 outbreak in northern Italy. A sample of 281 mothers was enrolled at eight maternity units in the first hotspot region of the COVID-19 outbreak in northern Italy. Participants filled out online questionnaires assessing the direct or indirect exposure to the SARS-CoV-2 virus, pandemic-related stress, perceived social support, as well as symptoms of depression and anxiety. Depressive and anxious symptomatology was above clinical concern, respectively, in 26 and 32% of the respondents. Mothers who reported no exposure to SARS-CoV-2 during pregnancy and those who reported at least one direct or indirect exposure did not differ in terms of affective symptoms. Continuous scores and risk for severe depression and anxiety were positively associated with prenatal pandemic-related emotional stress and negatively linked with perceived social support during pregnancy. Women who become mothers during the COVID-19 emergency may be at high risk for affective problems. Dedicated preventive programs are needed to provide adequate preventive support and care for maternal mental health during and after the COVID-19 pandemic.

The COVID-19 pandemic is a global traumatic experience for citizens, especially during sensitive time windows of heightened plasticity such as pregnancy and neonatal life. Pandemic-related stress experienced by mothers during pregnancy may act as an early risk factor for infants’ regulatory capacity development by altering maternal psychosocial well-being (e.g., increased anxiety, reduced social support) and caregiving environment (e.g., greater parenting stress, impaired mother–infant bonding). The aim of the present longitudinal study was to assess the consequences of pandemic-related prenatal stress on infants’ regulatory capacity. A sample of 163 mother–infant dyads was enrolled at eight maternity units in northern Italy. They provided complete data about prenatal stress, perceived social support, postnatal anxiety symptoms, parenting stress, mother–infant bonding, and infants’ regulatory capacity at 3 months of age. Women who experienced emotional stress and received partial social support during pregnancy reported higher anxious symptoms. Moreover, maternal postnatal anxiety was indirectly linked to the infants’ regulatory capacity at 3 months, mediated by parenting stress and mother–infant bonding. Dedicated preventive interventions should be delivered to mothers and should be focused on protecting the mother–infant dyad from the detrimental effects of pandemic-related stress during the COVID-19 healthcare emergency.

Background Copy number variants in coding and noncoding genomic regions have been implicated as risk factor for schizophrenia (SCZ). Rare duplications of the RB1CC1 gene were found enriched in SCZ patients. Considering that the effect of such duplications on RB1CC1 expression has never been evaluated and partial gene duplications of RB1CC1 have also been reported in SCZ patients, it is unclear whether the pathogenesis is mediated by haploinsufficiency rather than genuine overexpression of the gene. Methods and Results We studied a patient with schizophrenia, suicidality, and obesity, who carried a de novo RB1CC1 complete duplication, as assessed by high‐resolution array‐CGH. Molecular breakpoint cloning allowed to identify nonhomologous end joining (NHEJ) as driving mechanism in this rearrangement. On the contrary, trio‐based whole‐exome sequencing excluded other potential causative variants related to the phenotype. Functional assays showed significant overexpression of RB1CC1 in the peripheral blood lymphocytes of the proband compared to control subjects, suggesting overdosage as leading mechanism in SCZ pathophysiology. Conclusion We hypothesized a pathogenetic model that might explain the correlation between RB1CC1 overexpression and schizophrenia by altering different cell signaling pathways, including autophagy, a promising therapeutic target for schizophrenic patients., It is unproven whether the RB1CC1 pathogenesis in schizophrenia is mediated by haploinsufficiency rather than genuine overexpression of the gene. We identified a de novo RB1CC1 complete duplication in a SCZ patient showing significant overexpression of RB1CC1. We hypothesized a pathogenetic model that might explain the correlation between RB1CC1 overexpression and schizophrenia by altering different cell signaling pathways, including autophagy, a promising therapeutic target for schizophrenic patients.

The COVID-19 pandemic represents a collective trauma that may have enduring stress effects during sensitive periods, such as pregnancy. Prenatal stress may result in epigenetic signatures of stress-related genes (e.g., the serotonin transporter gene, SLC6A4) that may in turn influence infants’ behavioral development. In April 2020, we launched a longitudinal cohort study to assess the behavioral and epigenetic vestiges of COVID-19-related prenatal stress exposure in mothers and infants. COVID-19-related prenatal stress was retrospectively assessed at birth. SLC6A4 methylation was assessed in thirteen CpG sites in mothers and infants’ buccal cells. Infants’ temperament was assessed at 3-month-age. Complete data were available from 108 mother-infant dyads. Greater COVID-19-related prenatal stress was significantly associated with higher infants’ SLC6A4 methylation in seven CpG sites. SLC6A4 methylation at these sites predicted infants’ temperament at 3 months.

Background: The coronavirus disease of 2019 (Covid-19) represents an unprecedented threat for human health worldwide that may have profound stress effects Pregnancy is a sensitive period for adverse parenting effects on infants’ development and epigenetic mechanisms (DNA methylation) may play a pivotal role Here we present the study protocol of the MOM-COPE project Methods: Mothers and infants will be enrolled in twelve neonatal units in Northern Italy, a dramatic hotspot for Covid-19 contagion in Europe Maternal covid-related stress will be assessed with an ad-hoc questionnaire At birth, newborns and mothers’ salivary samples will be obtained to estimate target genes’ methylation (BDNF, FKBP5, NR3C1, SLC6A4, and OXTR) Post-natal bonding and infants’ temperament will be assessed through maternal reports at 3, 6 and 12 months Maternal sensitivity and infants’ emotional regulation will be assessed during remote videotaped mother-infant interaction at 12 months Results: The study has obtained approval of the Ethics Committee and is going to start by May 15th Hypotheses and anticipated results will be discussed according to the available behavioral epigenetic literature on parenting, pregnancy and large-scale disasters Discussion: This multi-centric study will provide evidence about the effect of pandemic-related prenatal stress exposure on the health and well-being of mothers and infants from birth to 12 months of age Moreover, the longitudinal nature of the study will allow to assess the relative role of epigenetic regulation of specific target genes in mediating the effect of this precocious adverse exposure on short- and long-term outcomes

IntroductionCOVID-19 is a highly infectious respiratory disease that rapidly emerged as an unprecedented epidemic in Europe, with a primary hotspot in Northern Italy during the first months of 2020. Its high infection rate and rapid spread contribute to set the risk for relevant psychological stress in citizens. In this context, mother–infant health is at risk not only because of potential direct exposure to the virus but also due to high levels of stress experienced by mothers from conception to delivery. Prenatal stress exposure associates with less-than-optimal child developmental outcomes, and specific epigenetic mechanisms (eg, DNA methylation) may play a critical role in mediating this programming association.Methods and analysisWe present the methodological protocol for a longitudinal, multicentric study on the behavioural and epigenetic effects of COVID-19-related prenatal stress in a cohort of mother–infant dyads in Northern Italy. The dyads will be enrolled at 10 facilities in Northern Italy. Saliva samples will be collected at birth to assess the methylation status of specific genes linked with stress regulation in mothers and newborns. Mothers will provide retrospective data on COVID-19-related stress during pregnancy. At 3, 6 and 12 months, mothers will provide data on child behavioural and socioemotional outcomes, their own psychological status (stress, depressive and anxious symptoms) and coping strategies. At 12 months, infants and mothers will be videotaped during semistructured interaction to assess maternal sensitivity and infant’s relational functioning.Ethics and disseminationThis study was approved by the Ethics Committee (Pavia). Results will be published in peer-reviewed journals and presented at national and international scientific conferences.Trial registration numberNCT04540029; Pre-results.

Background The COVID-19 pandemic represents a collective trauma that may have enduring stress effects during sensitive periods, such as pregnancy. Prenatal stress may result in epigenetic signatures of stress-related genes (e.g., the serotonin transporter gene, SLC6A4) that may in turn influence infants’ behavioral development. Methods In April 2020, we launched a longitudinal cohort study to assess the behavioral and epigenetic vestiges of COVID-19-related prenatal stress exposure in mothers and infants. COVID-19-related prenatal stress was retrospectively assessed at birth. SLC6A4 methylation was assessed in infants’ buccal cells. Infants’ temperament was assessed at 3-month-age. Results Complete data were available from 108 mother-infant dyads. Greater COVID-19-related prenatal stress was significantly associated with higher infants’ SLC6A4 methylation (RR =.07, p =.007, B =.16 [.05;.29]). SLC6A4 methylation at these sites predicted infants’ temperament at 3 months (RR =.05, p =.027, B = -.45 [-.92;-.06]). Conclusion Indirect effects of the pandemic may alter the trajectories of behavioral development infants. Appropriate prevention and care acts need to be adopted by healthcare systems.

Aim: Recent findings show that DNA methylation is susceptible to very preterm (VPT) birth and to the experience of the early stay in the neonatal intensive care unit. The aim of the study was to compare PLAGL1 methylation between VPT and full-term (FT) infants at birth as well as between VPT infants at discharge and FT infants at birth. Methods: DNA was collected from cord blood of 56 VPT and 27 FT infants at birth and from peripheral blood in VPT infants at neonatal intensive care unit discharge. Sociodemographic and neonatal variables were considered. Results: PLAGL1 methylation at birth and at discharge were highly correlated in VPT infants. Lower methylation emerged in VPT infants at birth and discharge compared to FT counterparts. Conclusion: PLAGL1 hypomethylation emerged as a potential epigenetic mark of VPT birth. Future research is warranted to assess the functional consequences of PLAGL1 diminished methylation in VPT infants’ development.

Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain.

INTRODUCTION: The DCDC2 gene is involved in neuronal migration. Heterotopias have been found within the white matter of DCDC2-knockdown rats. A deletion in DCDC2/intron 2 (DCDC2d), which encompasses a regulatory region named 'regulatory element associated with dyslexia 1' (READ1), increases the risk for dyslexia. We hypothesized that DCDC2d can be associated to alterations of the white matter structure in general and in dyslexic brains. METHODS: Based on a full-factorial analysis of covariance (ANCOVA) model, we investigated voxel-based diffusion tensor imaging (VB-DTI) data of four groups of subjects: dyslexia with/without DCDC2d, and normal readers with/without DCDC2d. We also tested DCDC2d effects upon correlation patterns between fractional anisotropy (FA) and reading scores. RESULTS: We found that FA was reduced in the left arcuate fasciculus and splenium of the corpus callosum in subjects with versus without DCDC2d, irrespective of dyslexia. Subjects with dyslexia and DCDC2d showed reduced FA, mainly in the left hemisphere and in the corpus callosum; their counterpart without DCDC2d showed similar FA alterations. Noteworthy, a conjunction analysis in impaired readers revealed common regions with lower FA mainly in the left hemisphere. When we compared subjects with dyslexia with versus without DCDC2d, we found lower FA in the inferior longitudinal fasciculus and genu of the corpus callosum, bilaterally. Normal readers with versus without DCDC2d had FA increases and decreases in both the right and left hemisphere. DISCUSSION: The major contribution of our study was to provide evidence relating genes, brain and behaviour. Overall, our findings support the hypothesis that DCDC2d is associated with altered FA. In normal readers, DCDC2-related anatomical patterns may mark some developmental cognitive vulnerability to learning disabilities. In subjects with dyslexia, DCDC2d accounted for both common - mainly located in the left hemisphere - and unique - a more severe and extended pattern - alterations of white matter fibre tracts. Copyright © 2014 Elsevier Ltd. All rights reserved.

In a pilot study of 120 children with reading disabilities, we assessed the presence of linkage and association between the DRD2/Taql and the DRD4/48bp-repeat polymorphisms and quantitative measures of behavioral problems derived from parental rated Child Behavior Checklist (CBCL) [Achenbach, T. M. (1991). TM Manual for the CBCL 14-18. Burlington, VT: University of Vermont]. Analyses included measures of between-family association, and a test of the presence of linkage and association by a logistic regression-based extension of the Transmission Disequilibrium Test (i.e., the logistic regression quantitative TDT). In between-family association analyses the "Social Problem" scale was weakly associated with the number of risk alleles of DRD2 and DRD4, while the "Withdrawn" scale was related to the number of risk alleles of DRD4 (the 7-repeat and the A1 allele respectively were considered the risk alleles). Logistic regression quantitative TDTs yielded statistically significant evidence in favor of linkage and association between DRD2 and "Social Problems" (Wald chi2 = 4.13, df = 1, p = 0.042, odds ratio = 1.97). A statistical trend in favor of linkage and association was found for "Withdrawn" and DRD4 (Wald chi2 = 2.65, df = 1, p = 0.104, odds ratio =1.44). Although preliminary, these findings are consistent with previous data that suggest a role of the same polymorphism in influencing individual sensitivity to reward and response to social cues and reinforcements in man and animal.

While the genetic and environmental contributions to developmental dyslexia (DD) have been studied extensively, the effects of identified genetic risk susceptibility and of specified environmental hazardous factors have usually been investigated separately. We assessed potential gene-by-environment (GxE) interactions on DD-related reading, spelling and memory phenotypes. The presence of GxE effects were investigated for the DYX1C1, DCDC2, KIAA0319 and ROBO1 genes, and for seven specified environmental moderators in 165 nuclear families in which at least one member had DD, by implementing a general test for GxE interaction in sib-pair-based association analysis of quantitative traits. Our results support a diathesis-stress model for both reading and memory composites: GxE effects were found between some specified environmental moderators (i.e. maternal smoke during pregnancy, birth weight and socio-economic status) and the DYX1C1-1259C/G marker. We have provided initial evidence that the joint analysis of identified genetic risk susceptibility and measured putative risk factors can be exploited in the study of the etiology of DD and reading-related neuropsychological phenotypes, and may assist in identifying/preventing the occurrence of DD.

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.

By array-CGH, we identified a cryptic deletion of about 3.4 Mb involving the chromosomal region 11q13.2q13.4 in a child with speech and developmental delay. Highly homologous segmental duplications related to the well-known olfactory receptor (OR)-containing clusters at 8p and 4p are located at the breakpoints of the imbalance and may be involved in its occurrence. Although these structural features are known to promote recurrent chromosomal rearrangements and previous studies had included the 11q13.2q13.4 deletion region among those considered potentially more unstable, neither deletions nor duplications of this region had been reported until now. Among the deleted genes, SHANK2 might play a role in the phenotype of the patient since it encodes a postsynaptic scaffolding protein similar to SHANK3, whose haploinsufficiency is a well-known cause of severe speech delay and autistic-like behavior, and recently deletions and mutations of SHANK2 have been described in patients with an autistic spectrum disorder or mental retardation.

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes 9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21 deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous 9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands. Electronic supplementary material The online version of this article (doi:10.1007/s00439-009-0689-7) contains supplementary material, which is available to authorized users.

The molecular characterization of balanced chromosomal rearrangements has often been a powerful tool for the positional identification of genes associated with specific diseases. In some instances, these rearrangements may be associated with a variety of different phenotypes, and thus establishing a genotype-phenotype correlation may be a complex process. However, molecular characterization of the rearrangement remains a useful tool for diagnoses or prognoses, or for identifying new genes and establishing a gene-to-function relationship. In this work we describe the characterization of a de novo balanced translocation t(2;6)(q24.3;q22.31) found in a patient with a complex phenotype. The major clinical finding was a severe neurological involvement. Thanks to the molecular characterization of this translocation we found that the rearrangement led to the truncation of the TCBA1 gene on chromosome 6q. We found that the gene is transcribed in different splice variants and is highly specific for the central nervous system. TCBA1 does not show any similarity with other known genes, and no information is available about its function. However, the gene appears to be well conserved among species, and we were able to infer the sequence of a putative mouse homolog of TCBA1. This allowed us to perform a more detailed expression study in mice, thus confirming its specificity for the nervous system. This finding is of particular interest because it suggests that TCBA1 may be correlated with the neurological phenotype of our patient, and possibly mutated in genetic diseases with a neurological phenotype. Hum Mutat 26(5), 426-436, 2005. (c) 2005 Wiley-Liss, Inc.

Dopamine genes are candidate genes for dyslexia in the light of the well-known comorbidity between dyslexia and ADHD. Within-family association and linkage disequilibrium were tested between four genetic markers at DRD4, DRD3, DRD2, and DAT loci, and dyslexia, in a sample of 130 Italian dyslexic children, 16.9% of whom had comorbid ADHD. No evidence of either association or linkage disequilibrium was found, neither in the total sample nor in the comorbid subgroup. Negative results do not support a common genetic basis between these two disorders for these markers.

Background Childhood shyness can predate social anxiety disorder and may be associated with biased discrimination of facial expressions of emotions. Objective To determine whether childhood shyness, or the serotonin transporter promoter polymorphism genotype, can predict participants’ visual event-related potentials in response to expressions of children of similar ages. Design Study group drawn from an inception cohort of 149 subjects characterized 1 year before the present study by their degree of shyness. Setting Third- and fourth-grade schoolchildren. Participants Forty-nine of the inception cohort children, randomly selected. Main Outcome Measures Latencies and amplitudes of the N400 waveform in response to happy, neutral, and angry expressions. Results Shyness predicted significantly smaller N400 amplitudes in response to anger (at Pz: P ≤.04) and to a neutral expression (at Pz: P ≤.047). Shyness was significantly different across the 3 genotypes, the SS genotype being associated with higher shyness levels (analysis of variance: F 2,42 = 4.47, P ≤.02; Tukey honestly significant difference, SS vs LL , P ≤.01). An analysis of covariance showed that neither the type of expression nor the genotype per se influenced the N400 amplitudes, but a significant expression×genotype interaction was found (F 4,72 = 3.57, P ≤.01), sustained by the difference in amplitude of the SS and S carrier subjects compared with the LL subjects when exposed to the anger expression (Tukey honestly significant difference, P ≤.02). Conclusion Children who manifest higher levels of shyness or have 1 or 2 copies of the short allele of the serotonin transporter promoter gene appear to have a different pattern of processing affective stimuli of interpersonal hostility.

Objective To investigate possible associations between serotonin transporter (5-HTT) promoter genotypic variants ( I/I, I/s , and s/s ) and differential regulation of platelet 5-HTT functionality parameters in a group of drug-naive depressed children and adolescents and healthy controls. Method Children and adolescents with major depression ( n = 18) defined by DSM-III-R criteria and normal controls ( n = 21) were assessed both for platelet serotonin functionality and for genotypic variants on 5-HTT promoter region. Four parameters were considered: (1) serotonin uptake rate (V max ); (2) serotonin dissociation constant (K m ); (3) paroxetine binding and density of site (B max ); and (4) paroxetine dissociation constant (K d ). Results Depressed children had lower V max and K m. Control subjects with I/I genotype had significantly higher V max than control subjects with I/s and s/s genotype. Control subjects with I/I genotype also had significantly higher V max than their depressed homologs. In contrast, V max was not significantly different between depressed and nondepressed subjects who carried the other 2 genotypes. The 5-HTT promoter genotype, diagnoses, or their interaction had no effect on the other serotonin parameters. Conclusions While showing a significant decrease of V max and K m in a group of drug-naive depressed children and adolescents, these data suggest that I/I genotype has a substantial effect on the decrease of V max during a depressive episode.