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1.
Am J Med Genet A ; 179(7): 1304-1309, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004414

RESUMO

The spectrum of clinical consequences of variants in the Platelet derived growth factor receptor beta (PDGFRB) gene is wide. Missense variants leading to variable loss of signal transduction in vitro have been reported in the idiopathic basal ganglia calcification (IBGC) syndrome Type 4. In contrast, gain-of-function variants have been reported in infantile myofibromatosis, Penttinen syndrome, and Kosaki overgrowth syndrome. Here, we report a patient harboring a novel postzygotic variant in PDGFRB (c.1682_1684del, p.[Arg561_Tyr562delinsHis]) and presenting severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. This observation expands the phenotype associated with PDGFRB variants and illustrates the wide clinical spectrum linked to dysregulation of PDGFRB.

2.
J Clin Endocrinol Metab ; 103(11): 4023-4032, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137364

RESUMO

Context: Most cases of autosomal dominant isolated hypoparathyroidism are caused by gain-of-function mutations in CASR or GNA11 or dominant negative mutations in GCM2 or PTH. Objective: To identify the genetic etiology for dominantly transmitted isolated hypoparathyroidism in two multigenerational families with 14 affected family members. Methods: We performed whole exome sequencing of DNA from two families and examined the consequences of mutations by minigene splicing assay. Results: We discovered disease-causing mutations in both families. A splice-altering mutation in TBX1 (c.1009+1G>C) leading to skipping of exon 8 (101 bp) was identified in 10 affected family members and five unaffected subjects of family A, indicating reduced penetrance for this point mutation. In a second family from France (family B), we identified another splice-altering mutation (c.1009+2T>C) adjacent to the mutation identified in family A that results in skipping of the same exon; two subjects in family B had isolated hypoparathyroidism, whereas a third subject manifested the clinical triad of the 22q11.2 deletion syndrome, indicative of variable expressivity. Conclusions: We report evidence that heterozygous TBX1 mutations can cause isolated hypoparathyroidism. This study adds knowledge to the increasingly expanding list of causative and candidate genes in isolated hypoparathyroidism.


Assuntos
Síndrome de DiGeorge/genética , Hipercalciúria/genética , Hipocalcemia/genética , Hipoparatireoidismo/congênito , Proteínas com Domínio T/genética , Idoso , Síndrome de DiGeorge/sangue , Síndrome de DiGeorge/diagnóstico , Éxons/genética , Feminino , Heterozigoto , Humanos , Hipercalciúria/sangue , Hipercalciúria/diagnóstico , Hipocalcemia/sangue , Hipocalcemia/diagnóstico , Hipoparatireoidismo/sangue , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/genética , Lactente , Masculino , Mutação , Linhagem , Penetrância , Sítios de Splice de RNA/genética , Sequenciamento Completo do Exoma
3.
Eur J Hum Genet ; 26(3): 340-349, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29330547

RESUMO

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.


Assuntos
Efeito Fundador , Hérnia Diafragmática/genética , Deformidades Congênitas dos Membros/genética , Mutação com Perda de Função , Fosfotransferases/genética , Facies , Feminino , Deleção de Genes , Hérnia Diafragmática/patologia , Humanos , Lactente , Recém-Nascido , Deformidades Congênitas dos Membros/patologia , Masculino
4.
Clin Dysmorphol ; 27(2): 31-35, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29381487

RESUMO

Mandibulofacial dysostosis type Guion-Almeida (MFDGA) is a rare disease entity that results in congenital craniofacial anomalies that are caused by abnormal development of the first and second pharyngeal arches. MFDGA is characterized by malar and mandibular hypoplasia, microcephaly, developmental delay, dysplastic ears, and a distinctive facial appearance. Extracraniofacial malformations include esophageal atresia, congenital heart disease, and radial ray abnormalities. Heterozygous mutations in the elongation factor Tu GTP-binding domain containing 2 (EFTUD2) gene have been shown to result in MFDGA. To date, there have been a total of 108 individuals reported in the literature, of whom 95 patients have a confirmed EFTUD2 mutation. The majority of individuals reported in the literature have been of White ethnic origin. Here, we report two individuals of Asian ancestry with MFDGA, each harboring a novel, pathogenic splice site variant in EFTUD2.


Assuntos
Deficiências do Desenvolvimento/genética , Disostose Mandibulofacial/genética , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Disostose Mandibulofacial/fisiopatologia , Mutação , Isoformas de Proteínas/genética
5.
Am J Med Genet A ; 176(1): 181-186, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29159987

RESUMO

We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L-related disorders are a possible differential diagnosis for syndromic PRS.


Assuntos
Mutação com Perda de Função , Complexo Mediador/genética , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Encéfalo/anormalidades , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Fenótipo , Análise de Sequência de DNA
6.
Am J Hum Genet ; 101(6): 995-1005, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198722

RESUMO

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.


Assuntos
Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos Neurocognitivos/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/embriologia , Códon sem Sentido/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deformidades Congênitas dos Membros/genética , Disostose Mandibulofacial/genética , Sistema Nervoso Periférico/anormalidades , Sistema Nervoso Periférico/enzimologia
7.
Am J Hum Genet ; 101(4): 630-637, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28965846

RESUMO

Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.


Assuntos
Ferredoxina-NADP Redutase/genética , Perda Auditiva Central/genética , Proteínas com Ferro-Enxofre/metabolismo , Ferro/metabolismo , Doenças Mitocondriais/genética , Mutação , Atrofia Óptica/genética , Adolescente , Adulto , Sequência de Aminoácidos , Pré-Escolar , Feminino , Ferredoxina-NADP Redutase/química , Ferredoxina-NADP Redutase/metabolismo , Teste de Complementação Genética , Perda Auditiva Central/enzimologia , Perda Auditiva Central/patologia , Humanos , Proteínas com Ferro-Enxofre/genética , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/patologia , Atrofia Óptica/enzimologia , Atrofia Óptica/patologia , Linhagem , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Adulto Jovem
8.
Am J Hum Genet ; 100(4): 592-604, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28285769

RESUMO

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.


Assuntos
Anormalidades Múltiplas/genética , Ciclofilinas/genética , Mutação , Peptidilprolil Isomerase/genética , Degeneração Retiniana/genética , Adolescente , Animais , Criança , Pré-Escolar , Ciclofilinas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Linhagem , Peptidilprolil Isomerase/metabolismo , Adulto Jovem
9.
Nat Genet ; 49(2): 249-255, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28067911

RESUMO

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.


Assuntos
Atresia das Cóanas/genética , Proteínas Cromossômicas não Histona/genética , Microftalmia/genética , Mutação de Sentido Incorreto/genética , Nariz/anormalidades , Animais , Linhagem Celular , Pré-Escolar , Epigênese Genética/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distrofia Muscular Facioescapuloumeral/genética , Xenopus laevis/genética
10.
Am J Hum Genet ; 99(3): 666-673, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27523598

RESUMO

Sudden unexpected death in infancy occurs in apparently healthy infants and remains largely unexplained despite thorough investigation. The vast majority of cases are sporadic. Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family. PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes inorganic pyrophosphate into two phosphates. This is an essential activity for many biosynthetic reactions and for energy metabolism of the cell. We show that deletion of the orthologous gene in yeast (ppa2Δ) compromises cell viability due to the loss of mitochondria. Expression of wild-type human PPA2, but not PPA2 containing the mutations identified in affected individuals, preserves mitochondrial function in ppa2Δ yeast. Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the subsequent disappearance of mitochondria from the mutant yeast cells. Altogether these data demonstrate that PPA2 is an essential gene in yeast and that biallelic mutations in PPA2 cause a mitochondrial disease leading to sudden cardiac arrest in infants.


Assuntos
Alelos , Morte Súbita Cardíaca/etiologia , Pirofosfatase Inorgânica/genética , Proteínas Mitocondriais/genética , Mutação/genética , Morte Súbita Cardíaca/patologia , Difosfatos , Exoma/genética , Feminino , Deleção de Genes , Genes Essenciais/genética , Teste de Complementação Genética , Heterozigoto , Humanos , Lactente , Pirofosfatase Inorgânica/metabolismo , Masculino , Potencial da Membrana Mitocondrial/genética , Viabilidade Microbiana , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Mutação de Sentido Incorreto , Bombas de Próton/deficiência , Bombas de Próton/genética , Bombas de Próton/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
11.
Nat Genet ; 47(11): 1260-3, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26437028

RESUMO

Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.


Assuntos
Padronização Corporal/genética , Síndrome de Heterotaxia/genética , Metaloproteinases da Matriz Secretadas/genética , Mutação Puntual , Vertebrados/genética , Animais , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Saúde da Família , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Recessivos , Coração/embriologia , Cardiopatias Congênitas/genética , Humanos , Hibridização In Situ , Masculino , Camundongos , Linhagem , Análise de Sequência de DNA/métodos , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
12.
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
13.
Sleep Breath ; 19(1): 55-60, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24792884

RESUMO

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare lifelong disorder characterized by an abnormal ventilatory response with persistent hypercapnia and hypoxia, which worsen during sleep. About 90 % of CCHS individuals are heterozygous for a mutation in the exon 3 of the PHOX2B gene. With higher awareness and better diagnostic tools, cases are identified in late childhood and adulthood, often with distinct mutations. CLINICAL CASE: The authors present a 4-year-old girl admitted to the intensive care unit at 9, 11 and 13 months suffering from severe hypercapnic respiratory failure during viral respiratory infections. Hypercapnia during sleep improved with wakefulness. CCHS was confirmed genetically (heterozygous insertion of an adenine at position 23, leading to a premature stop codon in exon 1 of the PHOX2B gene). The parents' DNA showed no PHOX2B mutations. Hypoventilation was observed by polysomnography, with no autonomic response to declining oxygen or increasing carbon dioxide values. A subsequent sleep study showed less hypoxia and hypercapnia. The patient has been on non-invasive ventilation during sleep, showing good growth and neurocognitive development. DISCUSSION: A greater awareness is required to diagnose late-onset CCHS. A respiratory infection can trigger the disease, with a significant difference in CO2 between sleep and wakefulness as the warning signal. Given the clinical suspicion, a genetic study should be performed. Polysomnography is essential for patient characterization. Follow-up and ventilator support adjustment prevent serious hypoxia and hypercapnia, which impair cardiovascular and neurocognitive functions. This patient's mutation has not been previously described; hence, clinical evolution cannot be predicted.


Assuntos
Adenina , Éxons/genética , Proteínas de Homeodomínio/genética , Hipoventilação/congênito , Mutagênese Insercional/genética , Apneia do Sono Tipo Central/genética , Fatores de Transcrição/genética , Pré-Escolar , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Hipoventilação/diagnóstico , Hipoventilação/genética , Hipoventilação/terapia , Lactente , Polissonografia , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/terapia
14.
Hum Mutat ; 35(4): 478-85, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24470203

RESUMO

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.


Assuntos
Anormalidades Múltiplas/patologia , Anus Imperfurado/patologia , Deformidades Congênitas da Mão/patologia , Perda Auditiva Bilateral/patologia , Deficiência Intelectual/patologia , Disostose Mandibulofacial/patologia , Microcefalia/patologia , Oftalmoplegia/patologia , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Trombocitopenia/patologia , Anormalidades Múltiplas/genética , Anus Imperfurado/genética , Criança , Pré-Escolar , Diagnóstico Diferencial , Orelha Externa/patologia , Feminino , Deformidades Congênitas da Mão/genética , Haploinsuficiência , Perda Auditiva Bilateral/genética , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Oftalmoplegia/genética , Fenótipo , Gravidez , Diagnóstico Pré-Natal , Trombocitopenia/genética
15.
Am J Hum Genet ; 93(6): 1118-25, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24268655

RESUMO

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.


Assuntos
Otopatias/genética , Orelha/anormalidades , Genes Dominantes , Genes Recessivos , Mutação , Fenótipo , Sequência de Aminoácidos , Substituição de Aminoácidos , Análise Mutacional de DNA , Otopatias/diagnóstico , Otopatias/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Alinhamento de Sequência , Transdução de Sinais
16.
J Med Genet ; 50(3): 174-86, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23315542

RESUMO

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.


Assuntos
Otopatias/genética , Orelha/anormalidades , Mutação , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Orelha/patologia , Otopatias/patologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Linhagem , Fosfolipase C beta/genética , Reação em Cadeia da Polimerase
17.
J Med Genet ; 49(12): 737-46, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23188108

RESUMO

BACKGROUND: Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated. RESULTS: We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS). CONCLUSIONS: These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.


Assuntos
Atresia Esofágica/genética , Haploinsuficiência , Fatores de Alongamento de Peptídeos/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 17 , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Lactente , Masculino , Fenótipo , Ribonucleoproteína Nuclear Pequena U5 , Síndrome
18.
Hum Mutat ; 32(3): 272-6, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21972109

RESUMO

Neuroblastoma (NB) is a frequent embryonal tumor of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harboring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.


Assuntos
Tronco Encefálico/anormalidades , Mutação em Linhagem Germinativa , Neuroblastoma/genética , Neuroblastoma/patologia , Receptores Proteína Tirosina Quinases/genética , Adulto , Quinase do Linfoma Anaplásico , Sistema Nervoso Central/embriologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Mutação de Sentido Incorreto , Neuroblastoma/congênito , Oncogenes , Síndrome
19.
Nat Genet ; 43(10): 1026-30, 2011 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-21892160

RESUMO

MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.


Assuntos
Deleção de Genes , Mutação em Linhagem Germinativa , MicroRNAs/genética , Família Multigênica , Desenvolvimento Musculoesquelético/genética , Animais , Cromossomos Humanos Par 13/genética , Bases de Dados Genéticas , Obstrução Duodenal/genética , Embrião de Mamíferos , Atresia Esofágica/genética , Pálpebras/anormalidades , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual , Deformidades Congênitas dos Membros/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/metabolismo , Microcefalia/genética , Modelos Animais , Linhagem , Reação em Cadeia da Polimerase , Fístula Traqueoesofágica
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