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D'Angelo D.,Columbia University | Lebon S.,Columbia University | Chen Q.,Columbia University | Martin-Brevet S.,University of Lausanne | And 49 more authors.
JAMA Psychiatry | Year: 2016

IMPORTANCE The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (-40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0%in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0%and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits. Copyright 2016 American Medical Association. All rights reserved.


Depienne C.,French Institute of Health and Medical Research | Depienne C.,University Pierre and Marie Curie | Gourfinkel-An I.,Groupe Hospitalier Pitie Salpetriere | Saint-Martin C.,French Institute of Health and Medical Research | And 15 more authors.
Journal of Medical Genetics | Year: 2010

Background: Mutations in SCN1A can cause genetic epilepsy with febrile seizures plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation. Objectives and patients: 19 selected families with at least one DS patient were studied to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele specific assays. Results: Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04-85%. In the six remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture. Conclusion: The results indicate that mosaicism is found in at least 7% of families with DS. In the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.


Lopez-Gonzalez V.,Hospital Clinico Universitario Virgen Of La Arrixaca | Lopez-Gonzalez V.,Institute Salud Carlos III ISCIII | Domingo-Jimenez M.R.,Institute Salud Carlos III ISCIII | Domingo-Jimenez M.R.,Hospital Clinico Universitario Virgen Of La Arrixaca | And 8 more authors.
Anales de Pediatria | Year: 2014

Schinzel-Giedion syndrome (SGS) (#MIM 269150) is a rare genetic disorder charac-terized by very marked craniofacial dysmorphism, multiple congenital anomalies and severe disabilityintellectual disability. Most affected patients die in early childhood. SETBP1 was identified asthe causative gene, but a limited number of patients with molecular confirmation have beenreported to date.The case is reported of a 4 and a half year-old male patient, affected by SGS. SETBP1sequencing analysis revealed the presence of a non-previously described mutation: c.2608G>T(p.Gly870Cys). The clinical features and differential diagnosis of this rare condition are revie-wed.Dysmorphic features are strongly suggestive of SGS. Its clinical recognition is essential toenable an early diagnosis, a proper follow-up, and to provide the family with genetic counseling.To date, this is the seventeenth SGS patient published with SETBP1 mutation, and the first inSpain, helping to widen clinical and molecular knowledge of the disease. © 2013 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.


PubMed | Unite Fonctionnelle de Genetique Clinique, Hospital Clinico Universitario Virgen Of La Arrixaca, Charles III University of Madrid and Lille University Hospital Center
Type: Case Reports | Journal: Anales de pediatria (Barcelona, Spain : 2003) | Year: 2015

Schinzel-Giedion syndrome (SGS) (#MIM 269150) is a rare genetic disorder characterized by very marked craniofacial dysmorphism, multiple congenital anomalies and severe intellectual disability. Most affected patients die in early childhood. SETBP1 was identified as the causative gene, but a limited number of patients with molecular confirmation have been reported to date. The case is reported of a 4 and a half year-old male patient, affected by SGS. SETBP1 sequencing analysis revealed the presence of a non-previously described mutation: c.2608G>T (p.Gly870Cys). The clinical features and differential diagnosis of this rare condition are reviewed. Dysmorphic features are strongly suggestive of SGS. Its clinical recognition is essential to enable an early diagnosis, a proper follow-up, and to provide the family with genetic counseling. To date, this is the seventeenth SGS patient published with SETBP1 mutation, and the first in Spain, helping to widen clinical and molecular knowledge of the disease.


PubMed | Baylor College of Medicine, Unite fonctionnelle de Genetique Clinique, Childrens Hospital, Lille University Hospital Center and 21 more.
Type: Journal Article | Journal: JAMA psychiatry | Year: 2016

The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P<.001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (40) and higher than the mean (>100) compared with the deletion group (P<.001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies.The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.


El Chehadeh S.,University of Burgundy | Aral B.,University of Burgundy | Gigot N.,University of Burgundy | Thauvin-Robinet C.,University of Burgundy | And 27 more authors.
Journal of Medical Genetics | Year: 2010

Background: Cohen syndrome is a rare autosomal recessive inherited disorder that results from mutations of the VPS13B gene. Clinical features consist of a combination of mental retardation, facial dysmorphism, postnatal microcephaly, truncal obesity, slender extremities, joint hyperextensibility, myopia, progressive chorioretinal dystrophy, and intermittent neutropenia. Patients and methods: The aim of the study was to determine which of the above clinical features were the best indicators for the presence of VPS13B gene mutations in a series of 34 patients with suspected Cohen syndrome referred for molecular analysis of VPS13B. Results: 14 VPS13B gene mutations were identified in 12 patients, and no mutation was found in 22 patients. The presence of chorioretinal dystrophy (92% vs 32%, p=0.0023), intermittent neutropenia (92% vs 5%, p<0.001), and postnatal microcephaly (100% vs 48%, p=0.0045) was significantly higher in the group of patients with a VPS13B gene mutation compared to the group of patients without a mutation. All patients with VPS13B mutations had chorioretinal dystrophy and/or intermittent neutropenia. The Kolehmainen diagnostic criteria provided 100% sensibility and 77% specificity when applied to this series. Conclusion: From this study and a review of more than 160 genotyped cases from the literature, it is concluded that, given the large size of the gene, VPS13B screening is not indicated in the absence of chorioretinal dystrophy or neutropenia in patients aged over 5 years. The followup of young patients could be a satisfactory alternative unless there are some reproductive issues.


Sinico M.,Service dAnatomie Pathologique foetopathologie et Microscopie Electronique | Bassez G.,University Paris Est Creteil | Touboul C.,Service de Gynecologie Obstetrique | Cave H.,Unite de Genetique Moleculaire et Biochimie | And 11 more authors.
Pediatric and Developmental Pathology | Year: 2011

The neuromuscular spindle (NMS) is a proprioceptive myofibrillar component of skeletal muscles that is necessary to maintain normal muscle tone and coordination. Recently, an excess of NMS has been reported as a congenital neuromuscular syndrome with a Noonan phenotype, now linked to Costello syndrome (CS). The vast majority of patients with CS have a de novo heterozygous mutation in the HRAS gene involved in the Ras/mitogen-activated protein kinase (MAPK) pathway. CS has many features in common with Noonan and cardiofaciocutaneous syndromes, also linked to activating mutations (but in other genes) of the Ras/MAPK pathway. This makes the orientation of molecular screening difficult. The observation of excess NMS in a 26-weeks'-gestation stillborn prompted us to screen the HRAS gene for mutation. The identification of a HRAS mutation made it possible to establish a diagnosis of CS. We conclude that the excess of NMS is the most reliable sign for the diagnosis of CS. Our findings also show the instrumental role of histological study of the skeletal muscles in the context of polyhydramnios and fetal hydrops. © 2011 Society for Pediatric Pathology.


Dupont C.,University of Paris Descartes | Guimiot F.,Service de Biologie du Developpement APHP | Guimiot F.,University Paris Diderot | Perrin L.,Unite fonctionnelle de Genetique clinique | And 11 more authors.
Clinical Genetics | Year: 2012

ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome is a rare autosomal recessive disorder characterised by severe immunodeficiency, craniofacial anomalies and chromosome instability. Chromosome analyses from blood samples show a high frequency of decondensation of pericentromeric heterochromatin (PH) and rearrangements involving chromosomes 1 and 16. It is the first and, as far as we know, the only disease associated with a mutation in a DNA methyltransferase gene, DNMT3B, with significant hypomethylation of the classical satellite DNA, the major component of the juxtacentromeric heterochromatin. To better understand the complex links between the hypomethylation of the satellite DNA, the cytogenetic anomalies and the clinical features of ICF syndrome, we performed three-dimensional (3D) FISH on preserved cells from a patient with a suspected ICF phenotype. Analysis of DNMT3B did not reveal any mutation in our patient, making this case an ICF type 2. The results of 3D-FISH showed a statistically significant change in the intranuclear position of PH of chromosome 1 in cells of the patient as compared to normal cells. It is difficult to understand how a defect in the methylation pathway can be responsible for the various symptoms of this condition. From our observations we suggest a mechanistic link between the reorganisation of the nuclear architecture and the altered gene expression. © 2011 John Wiley & Sons A/S.

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