RESUMO
Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.
Assuntos
Hibridização Genômica Comparativa/métodos , Aconselhamento Genético/ética , Aconselhamento Genético/métodos , Achados Incidentais , Revelação/ética , Feminino , França , Genes Dominantes/genética , Genes Recessivos/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Análise em Microsséries/métodos , Relações Médico-Paciente/ética , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
During limb development, the spatio-temporal expression of sonic hedgehog (SHH) is driven by the Zone of polarizing activity Regulatory Sequence (ZRS), located 1 megabase upstream from SHH. Gain-of-function mutations of this enhancer, which cause ectopic expression of SHH, are known to be responsible for congenital limb malformations with variable expressivity, ranging from preaxial polydactyly or triphalangeal thumbs to polysyndactyly, which may also be associated with mesomelic deficiency. In this report, we describe a patient affected with mirror-image polydactyly of the four extremities and bilateral tibial deficiency. The proband's father had isolated preaxial polydactyly type II (PPD2). Using Sanger sequencing, a ZRS point mutation (NC_000007.14, g.156584153A>G, UCSC, Build hg.19) was only identified in the patient. However, pyrosequencing analysis enabled the detection of a 10% somatic mosaic in the blood and saliva from the father. To our knowledge, this is the first description of a ZRS mosaic mutation. This report highlights the complexity of genotype-phenotype correlation in ZRS-associated syndromes and the importance of detecting somatic mosaicism for accurate genetic counselling.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Congênitas/genética , Ectromelia/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Proteínas Hedgehog/genética , Disostose Mandibulofacial/genética , Mosaicismo , Nariz/anormalidades , Mutação Puntual , Anormalidades Múltiplas/metabolismo , Adulto , Anormalidades Congênitas/metabolismo , Análise Mutacional de DNA , Ectromelia/metabolismo , Deformidades Congênitas do Pé/metabolismo , Deformidades Congênitas da Mão/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Disostose Mandibulofacial/metabolismo , Mucosa Nasal/metabolismo , LinhagemRESUMO
Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.
Assuntos
Predisposição Genética para Doença/genética , Haploinsuficiência/genética , Disostose Mandibulofacial/genética , Fenótipo , Proteínas de Ligação a RNA/genética , Sequência de Bases , Feminino , Genes Dominantes/genética , Humanos , Masculino , Disostose Mandibulofacial/patologia , Dados de Sequência Molecular , Mutação/genética , Fatores de Processamento de RNA , Análise de Sequência de DNARESUMO
Split hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Genes Duplicados , Deformidades Congênitas dos Membros/genética , Tíbia/anormalidades , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Linhagem , Fenótipo , Tíbia/fisiopatologiaRESUMO
We have identified three missense mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome. Our findings indicate that, in addition to Crohn disease, CARD15 is involved in the susceptibility to a second granulomatous disorder.
Assuntos
Artrite/genética , Proteínas de Transporte/genética , Exantema/genética , Peptídeos e Proteínas de Sinalização Intracelular , Artropatias/genética , Mutação , Uveíte/genética , Feminino , Humanos , Masculino , Proteína Adaptadora de Sinalização NOD2 , Linhagem , SíndromeRESUMO
Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell-Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long-term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.
Assuntos
Síndrome de Silver-Russell/diagnóstico , Trissomia/diagnóstico , Dissomia Uniparental/diagnóstico , Amniocentese , Cromossomos Humanos Par 7/genética , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Retardo do Crescimento Fetal , Humanos , Cariótipo , Masculino , Mosaicismo , Gravidez , Diagnóstico Pré-Natal , Síndrome de Silver-Russell/genética , Trissomia/genética , Dissomia Uniparental/genéticaAssuntos
Doenças do Desenvolvimento Ósseo/genética , Luxação Congênita de Quadril/genética , Quadril/anormalidades , Ísquio/anormalidades , Patela/anormalidades , Proteínas com Domínio T/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/epidemiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Pré-Escolar , Feminino , Quadril/fisiopatologia , Luxação Congênita de Quadril/complicações , Luxação Congênita de Quadril/epidemiologia , Luxação Congênita de Quadril/fisiopatologia , Humanos , Ísquio/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Patela/fisiopatologia , Linhagem , Fenótipo , Adulto JovemRESUMO
Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.
Assuntos
Anormalidades Múltiplas/diagnóstico , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 7/genética , Deficiência Intelectual/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Pré-Escolar , Hibridização Genômica Comparativa , Genótipo , Humanos , Deficiência Intelectual/genética , Cariótipo , FenótipoRESUMO
BACKGROUND: Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. METHOD: Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. RESULTS: 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. CONCLUSION: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.
Assuntos
Cérebro/anormalidades , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas de Domínio MADS/genética , Fatores de Regulação Miogênica/genética , Transtorno de Movimento Estereotipado/genética , Cérebro/metabolismo , Criança , Pré-Escolar , Haploidia , Humanos , Lactente , Fatores de Transcrição MEF2RESUMO
Fraser syndrome (MIM#219000) is an autosomal recessive disorder, characterized by the association of cryptophthtalmos, syndactyly of the four extremities, urinary tract abnormalities and laryngo-tracheal anomalies. This condition is due to homozygous or compound heterozygous mutations in the FRAS/FREM complex genes: FRAS1, FREM2 and GRIP1. Here we report two atypical cases of Fraser syndrome due to mutations in the FRAS1 gene without cryptophthalmos. The first proband had syndactyly of three extremities, bilateral nostril coloboma, dysplastic ears with bilateral conductive hearing loss, blepharophimosis and lacrimal duct abnormalities. FRAS1 sequencing identified two pathogenic compound heterozygous variants: a nonsense variant in exon 70 and a missense variant in exon 24. The second proband had membranous syndactyly of the four extremities, left renal agenesis, laryngeal and ano-rectal malformations, dysplastic ears and bilateral conductive hearing loss. FRAS1 sequencing identified a pathogenic homozygous variant in the last exon of the gene. This first description of molecularly confirmed cases with Fraser syndrome without cryptophthalmos could contribute to further delineation of the clinical spectrum of Fraser syndrome, especially for possible phenotypically milder cases. Larger cohorts are required to try to refer the hypothesis of genotype-phenotype correlation.
Assuntos
Proteínas da Matriz Extracelular/genética , Síndrome de Fraser/genética , Pré-Escolar , Feminino , Humanos , Lactente , Sindactilia/genéticaRESUMO
The limbs have an essential function in all vertebrates. In animals, the key genes that are involved in the growth and patterning of the limb buds, and of the development of the complex extremities, have been identified and their interactions recognized. Aided by these discoveries, human genetics has also been able to identify, or at least localize, certain genes responsible for anomalies of the limbs. These malformations are isolated or associated with anomalies of other developmental fields, according to the expression domain of the gene involved. Increasing knowledge of the embryology and genes involved has lead to a regrouping of malformation manifestations in genetics terms. Clear genotype-phenotype correlations are difficult to establish owing to the interlinking network of genetic signals underlying limb development.
Assuntos
Deformidades Congênitas dos Membros/genética , Transativadores , Animais , Padronização Corporal , Fatores de Crescimento de Fibroblastos/fisiologia , Proteínas Hedgehog , Humanos , Proteínas/metabolismo , Transdução de SinaisRESUMO
Limb malformations are frequent. These malformations are isolated or associated with anomalies of other developmental fields and accurate diagnostic is essential for prognosis evaluation, treatment and genetic counseling. Animal embryology and molecular biology techniques, have given us a better understanding of the processes of growth and patterning of the limb buds. The key genes that are involved in these processes have been identified and their interactions recognized. Human genetics has been able to identify, or at least localize, several genes implicated in limb development. We here review the present knowledge on these genes and their mutations responsible for limb anomalies.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/cirurgia , Ortopedia , Extremidades/embriologia , Aconselhamento Genético , Testes Genéticos , Humanos , PrognósticoRESUMO
A new case of GAPO syndrome is described in a 4-year-old Algerian girl born of first-cousin parents. This patient also had a right pyelic kidney stone and cerebral venous circulation anomalies inducing scalp vein expansion.
Assuntos
Anormalidades Múltiplas , Alopecia , Anodontia , Transtornos do Crescimento , Atrofia Óptica , Pré-Escolar , Feminino , Humanos , SíndromeRESUMO
We report on a French boy with cleft mandible, pre/postaxial hand anomalies, and clubfoot born to consanguineous parents. These findings are comparable to those of previous cases of the autosomal recessive Richieri-Costa and Pereira syndrome of short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot. This is the first case in a non-Brazilian infant.
Assuntos
Pé Torto Equinovaro/genética , Disostoses/genética , Deformidades Congênitas da Mão/genética , Anormalidades Maxilomandibulares/genética , Mandíbula/anormalidades , Consanguinidade , Disostoses/diagnóstico por imagem , Fácies , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Anormalidades Maxilomandibulares/diagnóstico por imagem , Masculino , Mandíbula/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
We report on a brother and sister with hyperinsulinism and nesidioblastosis of the pancreas. In addition, one brother and one sister who died in the neonatal period were probably affected. The parents of these children were healthy and consanguineous. We think that this is strongly suggestive of autosomal recessive inheritance. Seven other reports of presumed autosomal recessive hyperinsulinism are reviewed. To our knowledge, we report the first case in sibs whose parents were consanguineous. We think that early recognition of the condition is of obvious importance not only for therapy, but also for purposes of genetic counseling.
Assuntos
Genes Recessivos , Hiperinsulinismo/genética , Pancreatopatias/genética , Consanguinidade , Feminino , Histocitoquímica , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/patologia , Recém-Nascido , Masculino , Pancreatopatias/complicações , Pancreatopatias/patologiaRESUMO
Blau syndrome (MK186580) comprises granulomatous arthritis, iritis, and skin rash, and is an autosomal-dominant trait with variable expressivity. So far it was described in 5 families. We report on a sixth family with severe progression of eye involvement and discuss the nosology with similar diseases, such as early-infantile sarcoidosis.
Assuntos
Artrite/patologia , Exantema/patologia , Granuloma/patologia , Irite/patologia , Adolescente , Adulto , Artrite/genética , Cegueira/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 16 , Exantema/genética , Feminino , Retardo do Crescimento Fetal , Genótipo , Granuloma/genética , Humanos , Lactente , Irite/genética , Masculino , Linhagem , Sarcoidose/patologia , Síndrome , Sinovite/genética , Sinovite/patologia , Gêmeos MonozigóticosRESUMO
Hereditary multiple atresias involving the gastrointestinal tract from pylorus to rectum are the most unusual form of intestinal atresia; the type of inheritance was suggested to be autosomal recessive. The inheritance of the severe combined immunodeficiency syndrome can be autosomal recessive or X-linked. We report on 3 sibs with multiple-level intestinal atresias. One sib had severe combined immunodeficiency syndrome and clinical histories of the other 2 sibs strongly suggested a congenital immunodeficiency syndrome. The parents of those children were healthy and nonconsanguineous. To our knowledge, this is the first report of the association of multiple gastrointestinal atresias and immunodeficiency which appears to have an autosomal recessive pattern of transmission. Our family report suggests that, in the presence of multiple gastrointestinal atresias, attention should be given to possible associated immunological disorders.
Assuntos
Anormalidades Múltiplas/genética , Síndromes de Imunodeficiência/genética , Atresia Intestinal/genética , Estômago/anormalidades , Feminino , Genes Recessivos , Humanos , Síndromes de Imunodeficiência/complicações , Lactente , Atresia Intestinal/complicações , Masculino , LinhagemRESUMO
We describe a 24-weeks-old fetus with Fryns' syndrome (FS) and two erupted incisors. The present observations is another example of prenatal diagnosis of FS, based on ultrasonographically detected hernia diaphragmatica and cystic hygroma. It also adds an hitherto non described finding in FS. The presence of prenatally erupted teeth without any similar family history is discussed.
Assuntos
Aberrações Cromossômicas/embriologia , Hérnia Diafragmática/embriologia , Linfangioma Cístico/embriologia , Dentes Natais/embriologia , Erupção Dentária , Transtornos Cromossômicos , Hérnia Diafragmática/complicações , Hérnia Diafragmática/diagnóstico , Humanos , Linfangioma Cístico/complicações , Linfangioma Cístico/diagnóstico , SíndromeRESUMO
The association of pelvi-ureteric junction obstruction (PUJO) and rapidly fatal persistent pulmonary hypertension of the newborn (PPHN) has been observed in two male siblings. PUJO was also observed in a maternal uncle, whose daughter suffered from vesico-ureteral reflux (VUR). In both patients, histopathologic study of the lungs showed misalignment of pulmonary veins (MAPV), which is a rare autosomal recessive condition leading to severe PPHN and death within the neonatal period. It has occasionally been described associated with PUJO. The authors point out that: i: MAPV has to be carefully searched in case of PPHN; ii: PUJO could be an important finding associated with MAPV, and the only prenatal indication of this lethal condition.
Assuntos
Hidronefrose/complicações , Hipertensão Pulmonar/complicações , Pulmão/irrigação sanguínea , Veias Pulmonares/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Lactente , Recém-Nascido , Pulmão/fisiopatologia , Masculino , Veias Pulmonares/ultraestruturaRESUMO
This 3.5-year retrospective study report 300 fetus autopsies after pregnancy termination because of prenatal diagnosis of malformation. The objective was to evaluate the usefulness of postnatal examination of fetuses and to compare the post mortem findings with the prenatal diagnosis. This study included ultrasonography, radiology, karyotype, microbiology, genetic counseling and detailed pathological evaluation of the fetus: external, macroscopic, microscopic, brain and placenta examination. The results of post mortem examination were of paramount importance: they either changed the prenatal diagnosis hypothesis (20.3%), provided extensive additional information (41%), or confirmed the diagnosis hypothesis (38.7%). This study confirms the need for fetopathology examination after medical abortion. The pathologist's contribution to the multidisciplinary management of prenatally diagnosed fetal abnormalities is fundamental in particular for further genetic counseling; a specialized pathologist should be present in all prenatal diagnosis centers.