Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder

Background: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment. Methods: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR. Results: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3. Conclusions: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and consequently which of the three major SOX5 protein isoforms are affected. One intragenic deletion involving only untranslated exons was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene

Diagnostic d'anomalies cryptiques chromosomiques impliquées dans le retard mental (apport de la cytogénétique moléculaire)

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Anomalies chromosomiques et reproduction humaine (influence sur la qualité du conceptus)

Ce mémoire de thèse regroupe une série de travaux ayant trait, d'une part, à l'existence et à la fréquence des anomalies chromosomiques dans les gamètes humains et, d'autre part, à la responsabilité de ces anomalies dans les troubles du développement à travers la survenue de fausses couches ou l'apparition d'un retard mental dans la descendance. Les chromosomes 21 et X ont été évalués par FISH sur les ovocytes non fécondés. En dehors d'anomalies chromosomiques somatiques, chez l'homme, nous avons recherché si certains paramètres comme la tératospermie ou l'âge paternel, pouvaient jouer un rôle dans la genèse d'anomalies chromosomiques gamétiques. La responsabilité des anomalies chromosomiques dans l'apparition d'une infertilité masculine ou féminine a ensuite été abordée par la description de cas cliniques et par une enquête collaborative dans les populations ciblées. En dehors de l'infertilité, les anomalies chromosomiques sont responsables de FCS. Celles-ci peuvent être dues à la transmission déséquilibrée de remaniements chromosomiques parentaux. Nous avons recherché des anomalies cryptiques par des techniques de cytogénétique moléculaire récentes (FISH sur télomères) chez les couples concernés. Le déséquilibre chromosomique de ces conceptus peut être compatible avec une survie "in utero", aboutissant à la naissance d'un enfant atteint. La mise en évidence de ces anomalies chromosomiques nécessite également des techniques de cytogénétique moléculaire illustrées par la description de deux cas cliniques. Les remaniements chromosomiques déséquilibrés cryptiques, impliquant les télomères, apparaissent comme une cause fréquente de retard mental. Nous avons mesuré l'incidence des anomalies chromosomiques cryptiques chez des enfants présentant un retard mental idiopathique associé à une dysmorphie. Ce travail a révélé une fréquence de 9,2 % d'anomalies télomériques. En conclusion, nous apportons des données nouvelles sur le rôle et la fréquence des anomalies chromosomiques dans la formation des gamètes et le développement des produits de conception. Les limites de l'analyse cytogénétique classique sont dépassées par les techniques moléculaires, notamment la FISH télomérique.In humans, chromosomal abnormalities in embryos are particularly frequent and constitue one of the major causes of reproductive failure. Nowadays, new cytogenetic techniques allow the analysis of male and female germ cell karyotypes. This manuscript contains several publications dealing with the frequency of chromosomal abnormalities in human somatic cells and gametes as well as their consequences in offspring through the occurence of developing troubles such as miscarriages, fetal malformations or mental retardation. Numerical and structural abnormalities of chromosomes 21 and X have been investigated by fluorescence in situ hybridization (FISH) on unfertilized oocytes. In man, the relationships between structural rearrangements of chromosomes in gametes and factors like paternal age or teratozoospermia have been studied. The incidence of chromosomal abnormalities, both in male and female partner of couples candidate for ICSI (Intracytoplasmic spermatozoa injection) has also been evaluated by a French collaborative study. (...)PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Caractérisation par puces SNP d'anomalies chromosomiques équilibrées ou déséquilibrées impliquées dans l'autisme et le retard mental

L'autisme et le retard mental sont des pathologies neurodéveloppementales complexes ayant une grande hétérogénéité génétique. Les pathologies chromosomiques et les variations du nombre de copies (CNV) représentent jusqu'à 20 % des causes identifiées, elles sont variées et souvent non récurrentes. Leur identification est d'une importance majeure dans la connaissance de la physiopathologie de ces pathologies. L'objectif de notre travail est de montrer, en utilisant des micropuces SNP (Single Nucleotide Polymorphism), l'importance de la caractérisation moléculaire d'anomalies chromosomiques déséquilibrées ou apparemment équilibrées chez des patients présentant un autisme et/ou un retard mental. Nous montrons que la caractérisation moléculaire d'une duplication 6q24.2q25.3 chez une patiente atteinte de retard mental et d'arthrogrypose nous a permis d'une part d'impliquer ce locus dans le retard mental et d'autre part de suggérer l'implication du gène UTRN dans l'arthrogrypose. Par ailleurs, nous rapportons l'étude d'une famille multiplex où trois enfants sont atteints d'autisme. Deux jumeaux portent une duplication 16pll.2pl2, un frère a hérité d'une microdélétion 16pl 1.2 du père sain. Nous détaillons les anomalies chromosomiques et proposons que la microdélétion 16pl 1.2 du père ait pu favoriser la duplication chez ses enfants. L'exploration de réarrangements apparemment équilibrés chez 23 patients atteints d'autisme ou de retard mental nous conduit à faire un diagnostic étiologique dans 6 cas. Nous discutons les gènes impliqués et les mécanismes de survenue des anomalies chromosomiques identifiées. Nous évaluons l'intérêt et les limites des technologies utilisées.Autism and mental retardation are complex and highly heterogeneous neurodevelopmental disorders. Microscopically visible chromosomal rearrangements, submicroscopic deletions and duplications called copy number variations (CNV) represent up to 20% of genetic etiology. Their identification is of major importance in order to better determine the physiopathology of these disorders In our study using SNP (Single Nucleotide Polymorphism)-microarray, we defined molecularly two chromosomal imbalances and further explored apparently balanced chromosomal rearrangements (ABCR) in 23 patients presented with autism and/or mental retardation. We described first a 6q24.2q25.3 duplication in a girl who presented mental retardation and arthrogryposis in order to better defined the genotype-phenotype correlation. We also suggest that the UTRN gene could be a candidate for arthrogryposis. In a second report we described a complex multiplex family with three boys affected with autism, two monozygotic twins carried a de novo 16plI2pl2 duplication, their brother carried a 16pll.2 deletion inherited from his healthy father. We discuss the clinical and genetic implications of chromosomal rearrangements and suggest that the deletion in the father predispose to the duplication in his children Among 23 patients presented with autism and/or mental retardation, we identified causal CNVs in six patients We discuss potential candidate genes and regions for autism and mental retardation. We evaluate the interest and limits of SNP-array in the investigation of ABCR in patients with autism and intellectual disability.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Spontaneous conception after autologous hematopoietic stem cell transplantation: a case report

International audienc

Obesity leads to higher risk of sperm DNA damage in infertile patients

There has been a growing interest over the past few years in the impact of male nutrition on fertility. Infertility has been linked to male overweight or obesity, and conventional semen parameter values seem to be altered in case of high body mass index (BMI). A few studies assessing the impact of BMI on sperm DNA integrity have been published, but they did not lead to a strong consensus. Our objective was to explore further the relationship between sperm DNA integrity and BMI, through a 3-year multicentre study. Three hundred and thirty male partners in subfertile couples were included. Using the terminal uridine nick-end labelling (TUNEL) assay, we observed an increased rate of sperm DNA damage in obese men (odds ratio (95% confidence interval): 2.5 (1.2-5.1))