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1.
J Med Genet ; 56(10): 701-710, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451536

RESUMO

BACKGROUND: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders. METHODS: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant. RESULTS: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias. CONCLUSIONS: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

2.
Am J Med Genet A ; 179(10): 2075-2082, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361404

RESUMO

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.

4.
Eur J Hum Genet ; 26(2): 287-292, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29255276

RESUMO

CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.

5.
Genet Med ; 20(7): 745-753, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29261186

RESUMO

PURPOSE: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. METHODS: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. RESULTS: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. CONCLUSION: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.

6.
Am J Med Genet C Semin Med Genet ; 175(4): 417-430, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29178447

RESUMO

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Estudos de Coortes , Nervos Cranianos/anormalidades , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , França , Testes Genéticos , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Adulto Jovem
7.
Am J Med Genet A ; 2017 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-28449304

RESUMO

DNMT3A-Overgrowth Syndrome (also known as Tatton-Brown-Rahman Syndrome) (MIM 615879) has recently been described in 13 individuals with de novo heterozygous mutations in DNMT3A gene. This autosomal dominant condition is characterized by overgrowth, dysmorphic facial features and moderate intellectual disability. Missense and truncating point mutations, a small in-frame deletion, as well as microdeletion 2p23 have been reported. Moreover, DNMT3A is commonly somatically mutated in acute myeloid leukemia. We herein report a family with two siblings and their father affected by the syndrome. The proband is a 12 year-old boy with tall stature, macrocephaly, facial dysmorphism, and intellectual disability. His 10-year-old sister also has learning difficulties, overgrowth and mild facial dysmorphism. Their father is a 49 year-old man with tall stature, macrocephaly, learning difficulties, and minor facial dysmorphism. He had a right occipital osteoma removed at 20 years of age. A heterozygous splice site mutation NM_022552.4 (DNMT3A): c.2323-2A > T was found in the proband by whole exome sequencing analysis and by targeted Sanger Sequencing for the proband's sister and father. This mutation has not been previously reported and is believed to be pathogenic. Indeed, this substitution involves a highly conserved canonical splice site and is predicted to cause exon skipping. This is the first report of a familial transmission of DNMT3A-Overgrowth Syndrome, supporting the autosomal dominant inheritance. The proband's phenotype is more severe than that of his two other affected family members, which illustrates variable expressivity in the syndrome.

8.
Hum Genet ; 136(4): 463-479, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283832

RESUMO

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Proteínas Repressoras/genética , Humanos
9.
J Hum Genet ; 61(8): 693-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27193221

RESUMO

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.


Assuntos
Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Fenótipo , Alelos , Substituição de Aminoácidos , Éxons , Facies , Feminino , Filaminas/genética , Humanos , Masculino , Linhagem , Análise de Sequência de DNA
10.
Hum Mutat ; 37(8): 786-93, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27120018

RESUMO

Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.


Assuntos
Mutação com Ganho de Função , Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Receptores do Ácido Retinoico/genética , Adolescente , Criança , Pré-Escolar , Distúrbios Distônicos , Feminino , Humanos , Recém-Nascido , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto , Conformação Proteica , Receptores do Ácido Retinoico/química , Ativação Transcricional
11.
Am J Med Genet A ; 170A(1): 116-29, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26420639

RESUMO

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.


Assuntos
Encefalopatias/genética , Cromossomos Humanos X/genética , Duplicação Gênica , Imagem por Ressonância Magnética/métodos , Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Encefalopatias/patologia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Retardo Mental Ligado ao Cromossomo X/patologia , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prognóstico , Adulto Jovem
12.
Eur J Hum Genet ; 24(6): 830-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26395556

RESUMO

The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.


Assuntos
Deleção Cromossômica , Anormalidades Craniofaciais/genética , Endoglina/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas com Homeodomínio LIM/genética , Proteínas Munc18/genética , Fatores de Transcrição/genética , Adolescente , Criança , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/diagnóstico , Epilepsia/diagnóstico , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome
13.
Orphanet J Rare Dis ; 10: 31, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25885655

RESUMO

BACKGROUND: Multiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care. METHODS: The phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient's molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models. RESULTS: The most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses. CONCLUSIONS: This detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype-phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment development.


Assuntos
Doença da Deficiência de Múltiplas Sulfatases/genética , Doença da Deficiência de Múltiplas Sulfatases/metabolismo , Sulfatases/metabolismo , Criança , Pré-Escolar , Feminino , Regulação Enzimológica da Expressão Gênica , Genótipo , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Mutagênese Sítio-Dirigida , Mutação , Fenótipo , Conformação Proteica , Sulfatases/genética
14.
Am J Hum Genet ; 96(4): 519-31, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25772936

RESUMO

The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.


Assuntos
Alopecia/genética , Disostose Mandibulofacial/genética , Receptor de Endotelina A/genética , Alopecia/patologia , Animais , Sequência de Bases , Endotelina-1/metabolismo , Exoma/genética , Humanos , Hibridização In Situ , Disostose Mandibulofacial/patologia , Dados de Sequência Molecular , Morfolinos/genética , Mutação de Sentido Incorreto/genética , Linhagem , RNA Mensageiro/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real , Receptor de Endotelina A/metabolismo , Análise de Sequência de DNA , Síndrome , Tomografia Computadorizada por Raios X , Peixe-Zebra , Zigoma/patologia
15.
Eur J Hum Genet ; 23(1): 92-102, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24736735

RESUMO

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.


Assuntos
Estudos de Associação Genética , Fatores de Transcrição Kruppel-Like/genética , Mutação , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Acrocefalossindactilia/diagnóstico , Acrocefalossindactilia/genética , Estudos de Coortes , Análise Mutacional de DNA , Família , Expressão Gênica , Rearranjo Gênico , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Fenótipo , Proteína Gli3 com Dedos de Zinco
16.
Arch Dis Child ; 100(3): 259-64, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25324567

RESUMO

OBJECTIVE: 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation. PATIENTS AND DESIGN: Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders. RESULTS: The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school. CONCLUSIONS: Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling.


Assuntos
Doenças do Sistema Nervoso Central/genética , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Transtornos Mentais/genética , Adolescente , Doenças do Sistema Nervoso Central/complicações , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/complicações , Feminino , França , Humanos , Hibridização in Situ Fluorescente , Lactente , Doenças Renais Císticas/complicações , Masculino , Fenótipo , Estudos Prospectivos
17.
J Med Genet ; 51(11): 724-36, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25167861

RESUMO

BACKGROUND: Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. METHODS: We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. RESULTS: We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. CONCLUSIONS: With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Técnicas de Diagnóstico Molecular/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Análise de Sequência de DNA/métodos , Adulto Jovem
18.
Hum Mutat ; 35(9): 1092-100, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24924640

RESUMO

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.


Assuntos
Anormalidades Múltiplas/genética , Elementos Alu , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Éxons , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Deleção de Sequência , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA , Facies , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Lactente , Masculino , Mutação , Fenótipo , RNA Mensageiro/genética , Displasia Septo-Óptica/diagnóstico , Adulto Jovem
19.
Am J Med Genet A ; 164A(8): 1965-75, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24782328

RESUMO

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).


Assuntos
Obesidade/diagnóstico , Obesidade/genética , Fenótipo , Locos de Características Quantitativas , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Lactente , Masculino , Síndrome
20.
Eur J Hum Genet ; 22(4): 471-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24129437

RESUMO

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.


Assuntos
Cromossomos Humanos Par 2/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Fatores de Transcrição/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Obesidade/complicações , Obesidade/diagnóstico , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Análise de Sequência de DNA
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