<p><strong>Purpose: </strong>Previous work demonstrates a link between poor child sleep and increased caregiver mental health symptoms. In particular, children with NGS are known to experience severe and persistent sleep difficulties. Few studies have examined the association between child sleep disturbances and caregiver internalizing symptoms across families affected by neurogenic syndromes. More specifically, no study has examined how sleep disturbances in children diagnosed with NGS impact caregiver internalizing symptoms severity across development (from infancy to school-age children), using a longitudinal framework and multilevel analyses<em>. </em>Thus, the current study aims to test the effect of child sleep duration on caregiver mental health changes over the course of development (child age, from infancy to school-age children) in a mixed cohort of families affected by neurogenetic syndromes and a sub-group of neurotypical children. <strong>Method: </strong>A total of 193 caregivers were recruited, via web-based support groups, syndrome research registries, and social networks, as part of a broader longitudinal study, the Early Phenotype Study. To measure child sleep duration and caregiver internalizing symptoms, parents completed the Brief Infant Sleep Questionnaire and the Depression, Anxiety, and Stress Scale, respectively, at each time point yielding a total of 718 observations. Separate multilevel models were conducted for caregiver depression, anxiety, and stress in relation to child sleep duration at the between- and the within-person level with child age as a moderator. <strong>Results: </strong>Results of the present study revealed a between-person main effect of child sleep duration on caregiver symptoms of depression and a within-person effect of child sleep duration on stress symptoms in caregivers. The moderating effect of child age was not statistically significant across models. <strong>Conclusions: </strong>Overall, findings of the current study support previous literature and suggest child sleep duration may provide us with information on who may be at greater risk of exhibiting greater symptoms of depression, drawing the importance of focusing on improving child sleep duration as a way to reduce caregiver mental health challenges. </p>

<p>Early detection and characterization of autism spectrum disorder (ASD) may be improved by incorporating ecologically valid methods into ASD screening and assessment, capitalizing on prospective monitoring of high-risk populations, and targeting highly informative ASD features that emerge early in development. The present study aims to address these barriers by characterizing early vocal and pre-linguistic communication features present during naturalistic behavior samples of young children with neurogenetic syndromes (NGS). Participants were 39 children aged 5-30 months diagnosed with an NGS and 39 children aged 4-26 months at low risk for developmental delays. Participants completed a daylong audio recording of child vocalizations from which measures of early vocal features (child vocalization rate, canonical babbling ratio, and pitch variability) were obtained. Participants and their mothers also completed an unstructured play-based task during which pre-linguistic communicative features (communication complexity and function) were coded. We first used Bayesian analyses to compare the early vocal and pre-linguistic communication features of children with NGS to those of children at low risk for developmental delays. Children with NGS used less canonical babble, lower communication complexity overall and for behaviors for the purposes of joint attention. Next, we conducted a cluster analysis of early vocal and pre-linguistic communication features using the full sample of NGS and low-risk participants. The selected model identified 6 clusters that were primarily differentiated by canonical babbling and communicative function. These clusters differentiated participants beyond risk status, chronological age and adaptive age. Furthermore, certain clusters reflected differences in adaptive communication and socialization skills that may be relevant to early ASD profiles. These findings suggest that canonical babble and communicative function provide meaningful information about early developmental risk and may be useful to incorporate into the ASD screening and diagnostic processes.</p>

L’amusie congénitale est un trouble neurogénétique qui se caractérise par une inhabileté à acquérir des habiletés musicales de base, telles que la perception musicale et la reconnaissance musicale normales, malgré une audition, un développement du langage et une intelligence normaux (Ayotte, Peretz & Hyde, 2002). Récemment, une éude d’aggrégation familiale a démontré que 39% des membres de familles d’individus amusiques démontrent le trouble, comparativement à 3% des membres de familles d’individus normaux (Peretz et al., 2007). Cette conclusion est intéressante puisqu’elle démontre une prévalence de l’amusie congénitale dans la population normale. Kalmus et Fry (1980) ont évalué cette prévalence à 4%, en utilisant le Distorted Tunes Test (DTT). Par contre, ce test présente certaines lacunes méthodologiques et statistiques, telles un effet plafond important, ainsi que l’usage de mélodies folkloriques, désavantageant les amusiques puisque ceux-ci ne peuvent pas assimiler ces mélodies correctement. L’étude présente visait à réévaluer la prévalence de l’amusie congénitale en utilisant un test en ligne récemment validé par Peretz et ses collègues (2008). Mille cent participants, d’un échantillon homogène, ont complété le test en ligne. Les résultats démontrent une prévalence globale de 11.6%, ainsi que quatre profiles de performance distincts: pitch deafness (1.5%), pitch memory amusia (3.2%), pitch perception amusia (3.3%), et beat deafness (3.3%). La variabilité des résultats obtenus avec le test en ligne démontre l’existence de quatre types d’amusies avec chacune une prévalence individuelle, indiquant une hétérogénéité dans l’expression de l’amusie congénitale qui devra être explorée ultérieurement. / Congenital amusia is a heritable disorder in which subjects fail to acquire basic musical abilities, such as normal music perception and music-recognition abilities, despite normal hearing, normal language abilities, and normal intelligence (Ayotte, Peretz & Hyde, 2002). Recently, a family-aggregation study showed that 39% of first-degree relatives in amusic families express the disorder, compared to 3% in control families (Peretz et al., 2007). This latter finding is interesting in that it illustrates a prevalence of the disorder in non-amusic families. Kalmus and Fry (1980) evaluated the prevalence of congenital amusia at 4%, using the Distorted Tunes Test (DTT). However, this test presents some methodological and statistical problems, such as a strong ceiling effect, as well as the use of folkloric tunes, which disadvantages the amusic participants since they cannot assimilate these melodies correctly. The present study aimed at re-evaluating the presence of congenital amusia, using a recently validated online test by Peretz and colleagues (2008). One thousand one hundred participants, from a homogeneous sample, completed the online test. Results showed a global prevalence of 11.6%, with four distinct patterns of performance emerging: pitch deafness (1.5%), pitch memory amusia (3.2%), pitch perception amusia (3.3%), and beat deafness (3.3%). The variability in the results obtained with the online test brings evidence of at least four types of amusias with individual prevalences, indicating a heterogeneity in congenital amusia that needs to be further explored in later studies.

L’amusie congénitale est un trouble neurogénétique qui se caractérise par une inhabileté à acquérir des habiletés musicales de base, telles que la perception musicale et la reconnaissance musicale normales, malgré une audition, un développement du langage et une intelligence normaux (Ayotte, Peretz & Hyde, 2002). Récemment, une éude d’aggrégation familiale a démontré que 39% des membres de familles d’individus amusiques démontrent le trouble, comparativement à 3% des membres de familles d’individus normaux (Peretz et al., 2007). Cette conclusion est intéressante puisqu’elle démontre une prévalence de l’amusie congénitale dans la population normale. Kalmus et Fry (1980) ont évalué cette prévalence à 4%, en utilisant le Distorted Tunes Test (DTT). Par contre, ce test présente certaines lacunes méthodologiques et statistiques, telles un effet plafond important, ainsi que l’usage de mélodies folkloriques, désavantageant les amusiques puisque ceux-ci ne peuvent pas assimiler ces mélodies correctement. L’étude présente visait à réévaluer la prévalence de l’amusie congénitale en utilisant un test en ligne récemment validé par Peretz et ses collègues (2008). Mille cent participants, d’un échantillon homogène, ont complété le test en ligne. Les résultats démontrent une prévalence globale de 11.6%, ainsi que quatre profiles de performance distincts: pitch deafness (1.5%), pitch memory amusia (3.2%), pitch perception amusia (3.3%), et beat deafness (3.3%). La variabilité des résultats obtenus avec le test en ligne démontre l’existence de quatre types d’amusies avec chacune une prévalence individuelle, indiquant une hétérogénéité dans l’expression de l’amusie congénitale qui devra être explorée ultérieurement. / Congenital amusia is a heritable disorder in which subjects fail to acquire basic musical abilities, such as normal music perception and music-recognition abilities, despite normal hearing, normal language abilities, and normal intelligence (Ayotte, Peretz & Hyde, 2002). Recently, a family-aggregation study showed that 39% of first-degree relatives in amusic families express the disorder, compared to 3% in control families (Peretz et al., 2007). This latter finding is interesting in that it illustrates a prevalence of the disorder in non-amusic families. Kalmus and Fry (1980) evaluated the prevalence of congenital amusia at 4%, using the Distorted Tunes Test (DTT). However, this test presents some methodological and statistical problems, such as a strong ceiling effect, as well as the use of folkloric tunes, which disadvantages the amusic participants since they cannot assimilate these melodies correctly. The present study aimed at re-evaluating the presence of congenital amusia, using a recently validated online test by Peretz and colleagues (2008). One thousand one hundred participants, from a homogeneous sample, completed the online test. Results showed a global prevalence of 11.6%, with four distinct patterns of performance emerging: pitch deafness (1.5%), pitch memory amusia (3.2%), pitch perception amusia (3.3%), and beat deafness (3.3%). The variability in the results obtained with the online test brings evidence of at least four types of amusias with individual prevalences, indicating a heterogeneity in congenital amusia that needs to be further explored in later studies.

Le Syndrome d’Impatiences Musculaires de l’Éveil (SIME) est une maladie neurologique caractérisée par un besoin urgent de bouger les jambes. C’est également l’une des causes les plus fréquentes d’insomnie. C’est une maladie très répandue, avec une prévalence de presque 15 % dans la population générale. Les maladies multifactorielles comme le SIME sont souvent le résultat de l’évolution d’une composante génétique et d’une composante environnementale. Dans le cadre du SIME, les études d’association génomique ont permis l’identification de 4 variants à effet modéré ou faible. Cependant, ces quatre variants n’expliquent qu’une faible partie de la composante génétique de la maladie, ce qui confirme que plusieurs nouveaux variants sont encore à identifier. Le rôle des déséquilibres génomiques (Copy Number Variations ou CNVs) dans le mécanisme génétique du SIME est à ce jour inconnu. Cependant, les CNVs se sont récemment positionnés comme une source d’intérêt majeur de variation génétique potentiellement responsable des phénotypes. En collaboration avec une équipe de Munich, nous avons réalisé deux études CNVs à échelle génomique (biopuces à SNP et hybridation génomique comparée (CGH)) sur des patients SIME d’ascendance germanique. À l’aide d’une étude cas-contrôle, nous avons pu identifier des régions avec une occurrence de CNVs différentes pour les patients SIME, comparés à différents groupes contrôles. L’une de ces régions est particulièrement intéressante, car elle est concordante à la fois avec des précédentes études familiales ainsi qu’avec les récentes études d’associations génomiques. / Restless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.

Le Syndrome d’Impatiences Musculaires de l’Éveil (SIME) est une maladie neurologique caractérisée par un besoin urgent de bouger les jambes. C’est également l’une des causes les plus fréquentes d’insomnie. C’est une maladie très répandue, avec une prévalence de presque 15 % dans la population générale. Les maladies multifactorielles comme le SIME sont souvent le résultat de l’évolution d’une composante génétique et d’une composante environnementale. Dans le cadre du SIME, les études d’association génomique ont permis l’identification de 4 variants à effet modéré ou faible. Cependant, ces quatre variants n’expliquent qu’une faible partie de la composante génétique de la maladie, ce qui confirme que plusieurs nouveaux variants sont encore à identifier. Le rôle des déséquilibres génomiques (Copy Number Variations ou CNVs) dans le mécanisme génétique du SIME est à ce jour inconnu. Cependant, les CNVs se sont récemment positionnés comme une source d’intérêt majeur de variation génétique potentiellement responsable des phénotypes. En collaboration avec une équipe de Munich, nous avons réalisé deux études CNVs à échelle génomique (biopuces à SNP et hybridation génomique comparée (CGH)) sur des patients SIME d’ascendance germanique. À l’aide d’une étude cas-contrôle, nous avons pu identifier des régions avec une occurrence de CNVs différentes pour les patients SIME, comparés à différents groupes contrôles. L’une de ces régions est particulièrement intéressante, car elle est concordante à la fois avec des précédentes études familiales ainsi qu’avec les récentes études d’associations génomiques. / Restless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.

8 Summary The thesis "The elucidation of the causes of neurogenetic diseases by the MPS data analysis using advanced algorithms" is focused on processing the massively parallel sequencing (MPS) data from a gene panel, whole-exome sequencing (WES) and whole-genome sequencing (WGS). The aim of the study was to develop a suitable pipeline to evaluate at least 250 MPS gene panel data, 150 WES data and 20 WGS data in order to improve molecular genetic testing of rare neurogenetic disorders. Associated data management and database implementation is also described. Targeted gene panel sequencing A custom-designed gene panel consisting of ge- nes previously associated with the disease was used. In the Epileptic Encephalopathy (EE) panel, two prerequisites need to be met for inclusion into the panel: the gene has to have been published in at least two independent publications OR at least in one publication but in multiple independent families. In the case of the EE panel, 112 genes were included. The targeted gene panel sequencing was then performed on 257 patients with EE. Pathogenic or likely pathogenic (according to ACMG criteria) variants have been found in 28% of patients (72 out of 257). Further analysis of the pathogenic or likely pathogenic variants was performed (76 in total); the variants were grouped by...