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1.
Eur J Hum Genet ; 27(4): 525-534, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30622331

RESUMO

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

2.
J Med Genet ; 55(6): 359-371, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29618507

RESUMO

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.

3.
J Med Genet ; 55(6): 422-429, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29459493

RESUMO

BACKGROUND: Segmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV. PATIENTS AND METHODS: We used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (DLL3, MESP2, LFNG, HES7 and TBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients. RESULTS: Ten diagnoses, including four biallelic variants in TBX6, two biallelic variants in LFNG and DLL3, and one in MESP2 and HES7, were made with the gene panel, and two diagnoses, including biallelic variants in FLNB and one variant in MEOX1, were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%). CONCLUSION: After negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.

4.
Am J Med Genet A ; 173(8): 2081-2087, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28573701

RESUMO

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/genética , Pré-Escolar , Cromossomos Humanos Par 2/genética , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Carioferinas/genética , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Proteínas Nucleares/genética , Fenótipo , Receptores Citoplasmáticos e Nucleares/genética , Proteases Específicas de Ubiquitina/genética
5.
J Med Genet ; 54(6): 371-380, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28289185

RESUMO

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.


Assuntos
Face/anormalidades , Síndromes Orofaciodigitais/genética , Anormalidades Múltiplas/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação/genética , Doenças Renais Policísticas/genética , Proteínas/genética , Retinite Pigmentosa
6.
Eur J Hum Genet ; 25(1): 52-58, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-27759030

RESUMO

The ubiquitin-proteasome pathway is involved in the pathogenesis of several neurogenetic diseases. We describe a Mauritanian patient harboring a homozygous deletion restricted to two contiguous genes HERC2 and OCA2 and presenting with severe developmental abnormalities. The deletion causes the complete loss of HERC2 protein function, an E3-ubiquitin ligase. HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation. We showed that loss of HERC2 function leads to the accumulation of XPA and BRCA1 in the patient's fibroblasts and generates decreased sensitivity to apoptosis and increased level of DNA repair. Our data describe for the first time the phenotypic consequences, both at the clinical and cellular levels, of a complete loss of HERC2 function in a patient. They strongly suggest that profound ubiquitin ligase - associated dysfunction is responsible for the severe phenotype in this patient, and that dysfunction of this pathway may be involved in other patients with similar neurodevelopmental diseases.


Assuntos
Proteína BRCA1/genética , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Transtornos do Neurodesenvolvimento/genética , Proteína de Xeroderma Pigmentoso Grupo A/genética , Ciclo Celular/genética , Hibridização Genômica Comparativa , Reparo do DNA/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Deleção de Genes , Homozigoto , Humanos , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo
7.
Hum Mutat ; 37(12): 1329-1339, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27363716

RESUMO

Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Holoprosencefalia/genética , Mutação , Feminino , Predisposição Genética para Doença , Proteínas Hedgehog/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Análise de Sequência de DNA/métodos , Transdução de Sinais
8.
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
9.
Eur J Hum Genet ; 24(8): 1124-31, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26757980

RESUMO

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.


Assuntos
Leucemia Mielomonocítica Juvenil/genética , Mutação , Síndrome de Noonan/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas ras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Síndrome de Noonan/patologia , Linhagem , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
10.
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
11.
Am J Med Genet A ; 170A(2): 441-445, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26494162

RESUMO

Our study was designed to analyze prenatal manifestations in patients affected with cardio-facio-cutaneous syndrome (CFCS), in order to define indications of DNA testing in utero. Prenatal features were extracted from a national database and additional data were collected from 16 families contacted through the French association of CFC-Costello syndrome. We collected results of ultrasound scan (USS) biometrics, presence of congenital birth defects, and polyhydramnios. From the database, increased nuchal translucency was present in 13% of pregnancies, polyhydramnios in 52%, macrosomia and/or macrocephaly in 16%. Of the 16 pregnancies, 81% were complicated by abnormal USS findings. Polyhydramnios was reported in 67%. Head circumference, biparietal diameter, and abdominal circumference were above the 90th centile in 72%, 83% and, 81% of fetuses, respectively. Contrasting with macrosomia, femur length was below the 10th centile in 38%. Urinary tract abnormalities were found in 47% of fetuses. Most CFCS fetuses showed a combination of macrocephaly, macrosomia, and polyhydramnios, contrasting with relatively short femora. This growth pattern is also seen in Costello syndrome. We suggest that screening for CFCS and Costello gene mutations could be proposed in pregnancies showing this unusual pattern of growth parameters.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Cardiopatias Congênitas/diagnóstico , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Anormalidades da Pele/diagnóstico , Anormalidades Múltiplas/patologia , Feminino , Feto/anormalidades , Feto/metabolismo , Feto/patologia , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Masculino , Fenótipo , Gravidez , Prognóstico , Anormalidades da Pele/genética
12.
Hum Mol Genet ; 25(3): 571-83, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26647307

RESUMO

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin γ-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Colo/anormalidades , Mucosa Intestinal/metabolismo , Pseudo-Obstrução Intestinal/genética , Contração Muscular/genética , Músculo Liso/metabolismo , Mutação de Sentido Incorreto , Bexiga Urinária/anormalidades , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Actinas/química , Actinas/metabolismo , Colo/metabolismo , Colo/patologia , Evolução Fatal , Feminino , Expressão Gênica , Heterozigoto , Humanos , Recém-Nascido , Pseudo-Obstrução Intestinal/metabolismo , Pseudo-Obstrução Intestinal/patologia , Intestinos/patologia , Masculino , Simulação de Dinâmica Molecular , Músculo Liso/patologia , Linhagem , Multimerização Proteica , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Adulto Jovem
13.
Hum Mutat ; 36(9): 894-902, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26077438

RESUMO

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Estudos de Associação Genética , Impressão Genômica , Fenótipo , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Alinhamento de Sequência
14.
Eur J Hum Genet ; 23(11): 1482-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25920557

RESUMO

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.


Assuntos
Síndrome de Down/genética , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Adolescente , Adulto , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 21/genética , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/fisiopatologia , Mutação , Fenótipo
15.
Am J Med Genet A ; 167A(5): 1008-17, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25728055

RESUMO

Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Estudos de Associação Genética , Deficiência Intelectual/genética , Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Deficiência Intelectual/classificação , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo
16.
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
17.
Eur J Hum Genet ; 23(8): 1010-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25351778

RESUMO

6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Obesidade/genética , Penetrância , Síndrome de Prader-Willi/genética , Proteínas Repressoras/genética , Feto Abortado , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 6/genética , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Obesidade/complicações , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/patologia , Gravidez
18.
J Med Genet ; 51(10): 689-97, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25097206

RESUMO

BACKGROUND: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS. METHODS AND RESULTS: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. CONCLUSIONS: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.


Assuntos
Leucemia Mielomonocítica Juvenil/complicações , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/fisiopatologia , Masculino , Mutação , Síndrome de Noonan/mortalidade , Síndrome de Noonan/fisiopatologia , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
19.
Neuromuscul Disord ; 24(11): 993-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25070542

RESUMO

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject's HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major "retractile" phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders.


Assuntos
Aminoacil-tRNA Sintetases/genética , Fusos Musculares/patologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Mutação/genética , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Imagem por Ressonância Magnética
20.
J Clin Endocrinol Metab ; 99(4): 1180-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24471566

RESUMO

CONTEXT: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions. OBJECTIVE: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test). DESIGN AND SETTING: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice. PATIENTS: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included. INTERVENTION: DEX was offered after informed consent to pregnant women. MAIN OUTCOME MEASURE: The sensitivity of an early SRY test was evaluated after data collection. RESULTS: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero. CONCLUSIONS: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported.


Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Dexametasona/uso terapêutico , Terapias Fetais , Troca Materno-Fetal , Diagnóstico Pré-Natal/métodos , Análise para Determinação do Sexo/métodos , Hiperplasia Suprarrenal Congênita/sangue , Análise Química do Sangue , Estudos de Coortes , Feminino , Terapias Fetais/métodos , Terapias Fetais/estatística & dados numéricos , França/epidemiologia , Humanos , Masculino , Gravidez/sangue , Diagnóstico Pré-Natal/estatística & dados numéricos , Fatores de Risco , Virilismo/epidemiologia , Virilismo/prevenção & controle
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