Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Prenatal diagnosis of Desbuquois dysplasia type 1 by whole exome sequencing before the occurrence of specific ultrasound signs

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Influence of ultrasonographers training on prenatal diagnosis of congenital heart diseases: a 12-year population-based study.

International audienceOBJECTIVE: Since 1998, French multidisciplinary prenatal diagnosis centers (CPDPN) offer a training opportunity to first-level screening sonographers. This study measures the impact of this training on prenatal detection rates of congenital heart diseases (CHDs). METHODS: We analyzed the sensitivity of screening sonographers by comparing CHD prenatal diagnoses and CHDs observed after birth in the area of Angers from 1994 to 2006. Two groups of sonographers were compared, those who attended the training (n=19) and those who did not (control group. n=21). The evolution of CHD detection rate was compared between two successive periods of 6 years each. RESULTS: Of 947 CHDs, 438 (46%) were detected prenatally. The control group sensitivity was 16 versus 37% for the sonographers who had attended the training course (p<0.001).Between the two study periods, detection rates for all CHDs and significant CHDs remained unchanged in the control group, whereas they improved significantly in the other group (respectively 54% vs 33% and 75% vs 38%, p<0.05). CONCLUSION: This study supports the hypothesis of a beneficial effect of CPDPN on prenatal diagnosis of CHDs. These centers not only fulfill their primary purpose but also operate as learning centers in which screening sonographers may improve their practice

Binder phenotype in mothers affected with auto-immune disorders.

International audienceAbstract Objective: To report four foetal cases of the Binder phenotype associated with maternal autoimmune disorders. Patients and Methods: In three mothers with autoimmune diseases, 2D and 3D ultrasonographic measurements were made on four foetuses with the Binder profile, and were compared with postnatal phenotypes. Results: The Binder phenotype can be detected in early pregnancy (14.5 WG). All foetuses had verticalized nasal bones and midfacial hypoplasia. Punctuate calcifications were found in almost all the cases. No specific maternal auto-antibody has been associated with foetal Binder phenotype. Conclusion: Since the Binder phenotype can be diagnosed at ultrasound examination during pregnancy, it is important to establish the underlying cause so as to assess the foetal prognosis. This study stresses the importance of systematic checks for maternal autoimmune disease in cases of prenatally diagnosed Binder phenotypes

Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia

Mutations in the oligophrenin 1 gene (OPHN1) have been identified in patients with X-linked intellectual disability (XLID) associated with cerebellar hypoplasia and ventriculomegaly, suggesting it could be a recognizable syndromic intellectual disability (ID). Affected individuals share additional clinical features including speech delay, seizures, strabismus, behavioral difficulties, and slight facial dysmorphism. OPHN1 is located in Xq12 and encodes a Rho-GTPase-activating protein involved in the regulation of the G-protein cycle. Rho protein members play an important role in dendritic growth and in plasticity of excitatory synapses. Here we report on 17 individuals from four unrelated families affected by mild to severe intellectual disability due to OPHN1 mutations without cerebellar anomaly on brain MRI. We describe clinical, genetic and neuroimaging data of affected patients. Among the identified OPHN1 mutations, we report for the first time a missense mutation occurring in a mosaic state. We discuss the intrafamilial clinical variability of the disease and compare our patients with those previously reported. We emphasize the power of next generation techniques (X-exome sequencing, whole-exome sequencing and targeted multi-gene panel) to expand the phenotypic and mutational spectrum of OPHN1-related ID

Run of homozygosity analysis reveals a novel nonsense variant of the CNGB1 gene involved in retinitis pigmentosa 45

International audienceBACKGROUND: Retinitis pigmentosa (RP) is a group of retinal disorders with clinical and genetic heterogeneity characterized by the progressive dysfunction of photoreceptors. Mutations in the CNGB1 gene are involved in a rare autosomal recessive form of RP (RP45). We report the case of a 51-year-old woman, born of consanguineous parents (f = 1/32) of French origin, affected with non-syndromic RP.MATERIALS AND METHODS: Homozygosity mapping was performed on this patient and her two unaffected brothers using oligonucleotide arrays containing 300,000 markers including 200,000 single nucleotide polymorphisms.RESULTS: The largest homozygous region not shared by the patient and her brothers was a 23Mb region containing the CNGB1 gene situated on chromosome 16q12.1q23. Subsequent Sanger sequencing of CNGB1 identified a nonsense variant (p.Trp313*) segregating with the disease.CONCLUSIONS: To date, only 13 pathogenic CNGB1 variants have been reported in studies of 12 families. Six unrelated index patients were homozygous for a missense variant, four were homozygous for a splice-site variant, and two were compound heterozygous for nonsense and frameshift variants. The patient we report here is the first to be found homozygous for a novel nonsense CNGB1 variant. Our finding underscores the clinical usefulness of a genotype-first approach in recessive R

Effects of OPA1 mutations on mitochondrial morphology and apoptosis: relevance to ADOA pathogenesis.: OPA1: mitochondrial morphology, apoptosis, and optic atrophy

To characterize the molecular links between type-1 autosomal dominant optic atrophy (ADOA) and OPA1 dysfunctions, the effects of pathogenic alleles of this dynamin on mitochondrial morphology and apoptosis were analyzed, either in fibroblasts from affected individuals, or in HeLa cells transfected with similar mutants. The alleles were missense substitutions in the GTPase domain (OPA1(G300E) and OPA1(R290Q)) or deletion of the GTPase effector domain (OPA1(Delta58)). Fragmentation of mitochondria and apoptosis increased in OPA1(R290Q) fibroblasts and in OPA1(G300E) transfected HeLa cells. OPA1(Delta58) did not influence mitochondrial morphology, but increased the sensitivity to staurosporine of fibroblasts. In these cells, the amount of OPA1 protein was half of that in control fibroblasts. We conclude that GTPase mutants exert a dominant negative effect by competing with wild-type alleles to integrate into fusion-competent complexes, whereas C-terminal truncated alleles act by haplo-insufficiency. We present a model where antagonistic fusion and fission forces maintain the mitochondrial network, within morphological limits that are compatible with cellular functions. In the retinal ganglion cells (RGCs) of patients suffering from type-1 ADOA, OPA1-driven fusion cannot adequately oppose fission, thereby rendering them more sensitive to apoptotic stimuli and eventually leading to optic nerve degeneration

Hereditary spastic paraplegia and prominent sensorial involvement: think MAG mutations!

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