Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller’s dementia infantilis, a rare subtype of autism spectrum disorder

International audienceAbstractBackgroundDeletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD).Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.Case presentationHere, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3.The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.ConclusionOur present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years

Proceedings of the 13th annual conference of INEBRIA

CITATION: Watson, R., et al. 2016. Proceedings of the 13th annual conference of INEBRIA. Addiction Science & Clinical Practice, 11:13, doi:10.1186/s13722-016-0062-9.The original publication is available at https://ascpjournal.biomedcentral.comENGLISH SUMMARY : Meeting abstracts.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-016-0062-9Publisher's versio

Apport des nouveaux outils de cytogénétique moléculaire à la définition clinique et moléculaire de nouveaux syndromes

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Women’s Attitudes Toward Invasive and Noninvasive Testing When Facing a High Risk of Fetal Down Syndrome

International audienceImportance: Noninvasive prenatal testing (NIPT) using cell-free DNA in maternal blood is increasingly common compared with invasive testing (IT) in routine antenatal detection of Down syndrome (DS).Objective: To assess attitudes and decision making in pregnant women facing a risk of fetal DS greater than 1 in 250 as established by combined first trimester screening at 11 to 14 weeks of gestation.Design, Setting, and Participants: Survey study in which data were collected from pregnant women at high risk of fetal DS participating in a randomized clinical trial. Data were collected from April 8, 2014, to April 7, 2016, in 57 prenatal diagnosis centers in France. Data were analyzed in 2018.Interventions Data on attitudes were collected prior to offering randomization between NIPT and IT, whereas data on decision making and test results were collected as part of the clinical trial.Main Outcome and Measures: The primary outcome related to attitudes. A hierarchical cluster analysis was conducted to identify clusters with contrasting attitudes. Logistic regression analyses were used to identify factors associated with attitudes.Results: All 2436 consecutive women to whom the study was proposed (mean [SD] age, 36.3 [5.0] years) answered the questionnaire: 515 (21.1%) expressed preference toward IT with complete karyotyping, whereas 1843 (75.7%) favored NIPT with almost certain but limited information. Hierarchical cluster analysis yielded 4 different clusters that mainly differed in attitudes toward risk taking and extent of information seeking. Factors likely associated with attitudes driven by risk aversion were mostly age and religious beliefs (adjusted odds ratio [aOR], 1.03; 95% CI, 1.00-1.05; P = .03 and aOR, 1.62; 95% CI, 1.29-2.04; P < .001, respectively), whereas higher nuchal translucency measurements by ultrasonography were associated with attitudes driven by ambiguity aversion (aOR, 1.67; 95% CI, 1.27-2.20; P < .001). For attitudes involving both risk and ambiguity aversion at different extents, lower education was associated with highly valuing all possibilities of getting information on pregnancy, whereas higher education was associated with highly valuing information on fetal DS as a primary concern (aOR, 0.54; 95% CI, 0.44-0.67; P < .001 and aOR, 1.44; 95% CI, 1.20-1.74; P < .001, respectively). In all, decision making was in line with attitudes.Conclusions and Relevance: Aversion to risk of fetal loss related to IT and aversion to ambiguity generated by incomplete information from NIPT played a major role in shaping attitudes and decision making. Informed decision making should require pregnant women at high risk of DS to receive extensive information on targeted abnormalities by both tests

Xq25 duplications encompassing GRIA3 and STAG2 genes in two families convey recognizable X-linked intellectual disability with distinctive facial appearance.

International audienceWe report here on two patients with Xq25 duplication encompassing GRIA3 gene, encoding glutamate receptor, ionotropic, AMPA subunit 3. The first case of Xq25 duplication was identified using genome-wide array comparative genomic hybridization (array-CGH) in a 24-year-old patient with syndromic intellectual disability. Based on similar facial features, we clinically suspected a second case of Xq25 duplication in a 4-year-old boy with intellectual disabilty. This duplication was confirmed by multiplex ligation-dependent probe amplification (MLPA) of the GRIA3 gene, as well as by fluorescence in situ hybridization (FISH) and further refined by array-CGH. We suggest that Xq25 duplication is responsible for a novel clinically recognizable X-linked intellectual disability. Finally, the review of so far published Xq25 duplications support, in addition to the role of GRIA3 gene, a potential contribution of the duplication of STAG2 (Stromal Antigen 2) gene coding for the subunit SA1 of the cohesin complex in the clinical phenotype

Mutations in SETD2 cause a novel overgrowth condition

International audienceBACKGROUND: Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers catalyse two specific post-translational modifications of histones: methylation of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or EZH2 abnormalities. METHODS: We analysed the coding sequences of 14 H3K27 methylation-related genes and eight H3K36 methylation-related genes using a targeted next-generation sequencing approach in three Sotos, 11 'Sotos-like' and two Weaver syndrome patients. RESULTS: We identified two heterozygous mutations in the SETD2 gene in two patients with 'Sotos-like' syndrome: one missense p.Leu1815Trp de novo mutation in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is non-redundantly responsible for H3K36 trimethylation. The two probands shared similar clinical features, including postnatal overgrowth, macrocephaly, obesity, speech delay and advanced carpal ossification. CONCLUSIONS: Our results illustrate the power of targeted next-generation sequencing to identify rare disease-causing variants. We provide a compelling argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by loss-of-function mutations of epigenetic writers of the H3K36 histone mark

Foveal hypoplasia grading in 95 cases of congenital aniridia: correlation to phenotype and PAX6 genotype

International audiencePurpose: To correlate the degree of foveal hypoplasia in congenital aniridia with visual acuity, iris phenotype, and PAX6 mutations.Design: Retrospective case series.Methods: 95 consecutive patients with high quality Spectral-domain optical coherence tomography (SD-OCT) records and available genotype were included in a single referral center. Iris hypoplasia was classified as complete, presence of iris root or remnants and mild atypical aniridia. SD-OCT images were assessed to classify foveal hypoplasia as Grade 1 to 4 and to determine mean thicknesses for retinal layers. For statistical analysis one eye for each patient have been used and one member of the same family has been included (n=76 eyes).Results: Most eyes (93.5%) showed variable degree of foveal hypoplasia. PAX6-positive patients presented higher degree of foveal hypoplasia than patients negative for PAX6 (p<0.0001). PAX6 deletions, PAX6 variants subjected to nonsense-mediated decay and C-terminal extension variants were mostly associated with grade 3 or 4 foveal hypoplasia. Deletions restricted to the 3' flanking regulatory regions of PAX6 were associated with grade 1 or 2 foveal hypoplasia (p<0.0001). BCVA was higher and foveal outer retinal layers were thicker in patients with deletions in the 3' regulatory region of PAX6 (p= 0.001 and p< 0.0001). Patients with missense mutations presented with variable degree of foveal hypoplasia. The degree of foveal hypoplasia was most frequently correlated with the severity of iris defects, with 95% of eyes with complete aniridia presenting foveal hypoplasia of grade 3 or 4 (p=0.005). However, among eyes with mild iris phenotype, 70% showed severe foveal hypoplasia.Conclusions: All types of PAX6 variants, even those associated to mild iris defects, may be at risk for severe foveal hypoplasia with poor visual prognosis, except for deletions restricted to the 3' regulatory PAX6 regions

Whole-exome sequence analysis highlights the role of unmasked recessive mutations in copy number variants with incomplete penetrance.

International audienceSeveral hypotheses have been proposed to explain the phenotypic variability between parent and offspring carrying the same genomic imbalance, including unmasking of a recessive variant by a chromosomal deletion. Here, 19 patients with neurodevelopmental disorders harboring a rare deletion inherited from a healthy parent were investigated by whole-exome sequencing to search for SNV on the contralateral segment. This strategy allowed us to identify a candidate variant in two patients in the NUP214 and NCOR1 genes. This result demonstrates that the analysis of the genes included in non-deleted contralateral allele is a key point in the etiological investigation of patients harboring a deletion inherited from a parent. Finally, this strategy is also an interesting approach to identify new recessive intellectual disability genes