Age and gender variations of sleep in subjects without sleep disorders.

OBJECTIVE: Although sleep is a biomarker for general health and pathological conditions, its changes across age and gender are poorly understood. METHODS: Subjective evaluation of sleep was assessed by questionnaires in 5,064 subjects, and 2,966 were considered without sleep disorders. Objective evaluation was performed by polysomnography in 2,160 subjects, and 1,147 were considered without sleep disorders. Only subjects without sleep disorders were included (aged 40-80 years). RESULTS: Aging was strongly associated with morning preference. Older subjects, especially women, complained less about sleepiness, and pathological sleepiness was significantly lower than in younger subjects. Self-reported sleep quality and daytime functioning improved with aging. Sleep latency increased with age in women, while sleep efficiency decreased with age in both genders. Deep slow-wave sleep decreased with age, but men were more affected. Spectral power densities within slow waves (< 5 Hz) and fast spindles (14-14.75 Hz) decreased, while theta-alpha (5-1 Hz) and beta (16.75-25 Hz) power in non-rapid eye movement sleep increased with aging. In REM sleep, aging was associated with a progressive decrease in delta (1.25-4.5 Hz) and increase in higher frequencies. CONCLUSIONS: Our findings indicate that sleep complaints should not be viewed as part of normal aging but should prompt the identification of underlying causes.

The 16p11.2 rearrangments genetic paradigms for obesity and neurodevelopmental disorders.

Recent discoveries of recurrent and reciprocal Copy Number Variants (CNVs) using genome- wide studies have led to a new understanding of the etiology of neuropsychiatric disorders. CNVs represent loss (deletion) or gain (duplication) of genomic material. This thesis work is focused on CNVs at the 16p11.2 BP4-BP5 locus, which are among the most frequent etiologies of neurodevelopmental disorders and have been associated with Autism Spectrum Disorders (ASD), schizophrenia, cognitive impairment, alterations of brain size as well as obesity and underweight. Because deletion and duplication of the 16p11.2 locus occur frequently and recurrently (with the same breakpoints), CNVs at this locus represent a powerful paradigm to understand how a genomic region may modulate cognitive and behavioral traits as well as the relationship and shared mechanisms between distinct psychiatric diagnoses such as ASD and schizophrenia. The present dissertation includes three studies: 1) The first project aims at identifying structural brain-imaging endophenotypes in 16p11.2 CNVs carriers at risk for ASD and schizophrenia. The results show that gene dosage at the 16p11.2 locus modulates global brain volumes and neural circuitry, including the reward system, language and social cognition circuits. 2) The second investigates the neuropsychological profile in 16p11.2 deletion and duplication carriers. While deletion carriers show specific deficits in language and inhibition, the profile of duplication carriers is devoid of specific weaknesses and presents enhanced performance in a verbal memory task. 3) The third study on food-related behaviors in 16p11.2 deletion and duplication carriers shows that alterations of the reponse to satiety are present in CNV carriers before the onset of obesity, pointing toward a potential mechanism driving the Body Mass Index increase in deletion carriers. Dysfunctions in the reward system and dopaminergic circuitries could represent a common mechanism playing a role in the phenotype and could be investigated in future studies. Our data strongly suggest that complex cognitive traits correlate to gene dosage in humans. Larger studies including expression data would allow elucidating the contribution of specific genes to these different gene dosage effects. In conclusion, a systematic and careful investigation of cognitive, behavioral and intermediate phenotypes using a gene dosage paradigm has allowed us to advance our understanding of the 16p11.2 BP4-BP5 locus and its effects on neurodevelopment. -- La récente découverte de variations du nombre de copies (CNVs pour 'copy number variants') dans le génome humain a amélioré nos connaissances sur l'étiologie des troubles neuropsychiatriques. Un CNV représente une perte (délétion) ou un gain (duplication) de matériel génétique sur un segment chromosomique. Ce travail de thèse est focalisé sur les CNVs réciproques (délétion et duplication) dans la région 16p11.2 BP4-BP5. Ces CNVs sont une cause fréquente de troubles neurodéveloppementaux et ont été associés à des phénotypes « en miroir » tels que obésité/sous-poids ou macro/microcéphalie mais aussi aux troubles du spectre autistique (TSA), à la schizophrénie et au retard de développement/déficience intellectuelle. La fréquence et la récurrence de la délétion et de la duplication aux mêmes points de cassure font de ces CNVs un paradigme unique pour étudier la relation entre dosage génique et les traits cognitifs et comportementaux, ainsi que les mécanismes partagés par des troubles psychiatriques apparemment distincts tels que les TSA et la schizophrénie. Ce travail de thèse comporte trois études distinctes : 1) l'étude en neuroimagerie structurelle identifie les endophénotypes chez les porteurs de la délétion ou de la duplication. Les résultats montrent une influence du dosage génique sur le volume cérébral total et certaines structures dans les systèmes de récompense, du langage et de la cognition sociale. 2) L'étude des profils neuropsychologiques chez les porteurs de la délétion ou de la duplication montre que la délétion est associée à des troubles spécifiques du langage et de l'inhibition alors que les porteurs de la duplication ne montrent pas de faiblesse spécifique mais des performances mnésiques verbales supérieures à leur niveau cognitif global. 3) L'étude sur les comportements alimentaires met en évidence une altération de la réponse à la satiété qui est présente avant l'apparition de l'obésité. Un dysfonctionnement dans le système de récompense et les circuits dopaminergiques pourrait représenter un mécanisme commun aux différents phénotypes observés chez ces individus porteurs de CNVs au locus 16p11.2. En conclusion, l'utilisation du dosage génique comme outil d'investigation des phénotypes cliniques et endophénotypes nous a permis de mieux comprendre le rôle de la région 16p11.2 BP4-BP5 dans le neurodéveloppement.

Single centre experience of the application of self navigated 3D whole heart cardiovascular magnetic resonance for the assessment of cardiac anatomy in congenital heart disease.

BACKGROUND: For free-breathing cardiovascular magnetic resonance (CMR), the self-navigation technique recently emerged, which is expected to deliver high-quality data with a high success rate. The purpose of this study was to test the hypothesis that self-navigated 3D-CMR enables the reliable assessment of cardiovascular anatomy in patients with congenital heart disease (CHD) and to define factors that affect image quality. METHODS: CHD patients ≥2 years-old and referred for CMR for initial assessment or for a follow-up study were included to undergo a free-breathing self-navigated 3D CMR at 1.5T. Performance criteria were: correct description of cardiac segmental anatomy, overall image quality, coronary artery visibility, and reproducibility of great vessels diameter measurements. Factors associated with insufficient image quality were identified using multivariate logistic regression. RESULTS: Self-navigated CMR was performed in 105 patients (55% male, 23 ± 12y). Correct segmental description was achieved in 93% and 96% for observer 1 and 2, respectively. Diagnostic quality was obtained in 90% of examinations, and it increased to 94% if contrast-enhanced. Left anterior descending, circumflex, and right coronary arteries were visualized in 93%, 87% and 98%, respectively. Younger age, higher heart rate, lower ejection fraction, and lack of contrast medium were independently associated with reduced image quality. However, a similar rate of diagnostic image quality was obtained in children and adults. CONCLUSION: In patients with CHD, self-navigated free-breathing CMR provides high-resolution 3D visualization of the heart and great vessels with excellent robustness.

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.Genet Med 17 8, 651-659.

The specificity of the familial aggregation of early-onset bipolar disorder: A controlled 10-year follow-up study of offspring of parents with mood disorders.

BACKGROUND: Two major sources of heterogeneity of mood disorders that have been demonstrated in clinical, family and genetic studies are the mood disorder subtype (i.e. bipolar (BPD) and major depressive disorder (MDD)) and age of onset of mood episodes. Using a prospective high-risk study design, our aims were to test the specificity of the parent-child transmission of BPD and MDD and to establish the risk of psychopathology in offspring in function of the age of onset of the parental disorder. METHODS: Clinical information was collected on 208 probands (n=81 with BPD, n=64 with MDD, n=63 medical controls) as well as their 202 spouses and 372 children aged 6-17 years at study entry. Parents and children were directly interviewed every 3 years (mean duration of follow-up=10.6 years). Parental age of onset was dichotomized at age 21. RESULTS: Offspring of parents with early onset BPD entailed a higher risk of BPD HR=7.9(1.8-34.6) and substance use disorders HR=5.0(1.1-21.9) than those with later onset and controls. Depressive disorders were not significantly increased in offspring regardless of parental mood disorder subtype or age of onset. LIMITATIONS: Limited sample size, age of onset in probands was obtained retrospectively, age of onset in co-parents was not adequately documented, and a quarter of the children had no direct interview. CONCLUSIONS: Our results provide support for the independence of familial aggregation of BPD from MDD and the heterogeneity of BPD based on patterns of onset. Future studies should further investigate correlates of early versus later onset BPD.

Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

Posttraumatic stress avoidance symptoms as mediators in the development of alcohol use disorders after exposure to childhood sexual abuse in a Swiss community sample.

This study examined the role of posttraumatic stress disorder (PTSD) symptoms of re-experience, avoidance, and hyperarousal in the relationship between different types of trauma and alcohol use disorders (AUD). We used data from 731 trauma-exposed individuals who participated in the first wave of the PsyCoLaus-study. Trauma characteristics were assessed relatively to the occurrence of lifetime PTSD symptoms and AUD. The results suggest that lifetime and childhood sexual abuse as well as overall childhood trauma were directly linked to AUD and PTSD symptoms, in particular to avoidance symptoms. From single symptom clusters PTSD avoidance was found to specifically mediate the trauma-AUD pathway. Both childhood and sexual trauma strongly contribute to the comorbidity of PTSD and AUD and avoidance-type symptoms appear to play a central role in maintaining this association. Hence, the alleviation of avoidance symptoms might be an important target for therapeutic intervention among victims of sexual abuse before specific addiction treatment is initiated.

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.

t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders.

Through a combined approach integrating RNA-Seq, SNP-array, FISH and PCR techniques, we identified two novel t(15;21) translocations leading to the inactivation of RUNX1 and its partners SIN3A and TCF12. One is a complex t(15;21)(q24;q22), with both breakpoints mapped at the nucleotide level, joining RUNX1 to SIN3A and UBL7-AS1 in a patient with myelodysplasia. The other is a recurrent t(15;21)(q21;q22), juxtaposing RUNX1 and TCF12, with an opposite transcriptional orientation, in three myeloid leukemia cases. Since our transcriptome analysis indicated a significant number of differentially expressed genes associated with both translocations, we speculate an important pathogenetic role for these alterations involving RUNX1.

Congenital anomalies associated with trisomy 18 or trisomy 13: A registry-based study in 16 european countries, 2000-2011.

The aim of this study was to examine the prevalence of trisomies 18 and 13 in Europe and the prevalence of associated anomalies. Twenty-five population-based registries in 16 European countries provided data from 2000-2011. Cases included live births, fetal deaths (20+ weeks' gestation), and terminations of pregnancy for fetal anomaly (TOPFAs). The prevalence of associated anomalies was reported in live births. The prevalence of trisomy 18 and trisomy 13 were 4.8 (95%CI: 4.7-5.0) and 1.9 (95%CI: 1.8-2.0) per 10,000 total births. Seventy three percent of cases with trisomy 18 or trisomy 13 resulted in a TOPFA. Amongst 468 live born babies with trisomy 18, 80% (76-83%) had a cardiac anomaly, 21% (17-25%) had a nervous system anomaly, 8% (6-11%) had esophageal atresia and 10% (8-13%) had an orofacial cleft. Amongst 240 Live born babies with trisomy 13, 57% (51-64%) had a cardiac anomaly, 39% (33-46%) had a nervous system anomaly, 30% (24-36%) had an eye anomaly, 44% (37-50%) had polydactyly and 45% (39-52%) had an orofacial cleft. For babies with trisomy 18 boys were less likely to have a cardiac anomaly compared with girls (OR = 0.48 (0.30-0.77) and with trisomy 13 were less likely to have a nervous system anomaly [OR = 0.46 (0.27-0.77)]. Babies with trisomy 18 or trisomy 13 do have a high proportion of associated anomalies with the distribution of anomalies being different in boys and girls. © 2015 Wiley Periodicals, Inc.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study.

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95 % CI 1.07-1.86, fluoxetine adjOR 1.43 95 % CI 0.85-2.40, paroxetine adjOR 1.53, 95 % CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95 % CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95 % CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95 % CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95 % CI 1.06-5.68), gastroschisis (adjOR 2.42, 95 % CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95 % CI 1.61-5.61), and clubfoot (adjOR 2.41, 95 % CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.