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1.
Am J Hum Genet ; 105(5): 933-946, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31607427

RESUMO

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

2.
Am J Hum Genet ; 104(4): 709-720, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905399

RESUMO

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

3.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

4.
Epilepsia ; 58(4): 565-575, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28166369

RESUMO

OBJECTIVE: The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation. METHOD: Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained. RESULTS: Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. SIGNIFICANCE: Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Epilepsia/genética , Mutação/genética , Convulsões/genética , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/complicações , Feminino , Heterozigoto , Humanos , Masculino , Convulsões/complicações
5.
Mol Genet Genomic Med ; 4(4): 465-74, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27441201

RESUMO

BACKGROUND: Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, encoding a neuromuscular specific translation elongation factor, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each with a different mutation, of which five are newly described. METHODS: New cases were identified and sequenced through the Deciphering Developmental Disabilities project, via direct contact with neurologists or geneticists, or recruited via our website. RESULTS: All the mutations cause epilepsy and intellectual disability, but with a much wider range of severity than previously identified. All new cases share specific subtle facial dysmorphic features. Each mutation occurs at an evolutionarily highly conserved amino acid position indicating strong structural or functional selective pressure. CONCLUSIONS: EEF1A2 should be considered as a causative gene not only in cases of epileptic encephalopathy but also in children with less severe epilepsy and intellectual disability. The emergence of a possible discernible phenotype, a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth may help in identifying patients with mutations in EEF1A2.

6.
Neurology ; 87(1): 77-85, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27281533

RESUMO

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.


Assuntos
Proteínas de Transporte/genética , Epilepsia/genética , Epilepsia/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/metabolismo , Crescimento Celular , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/psicologia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Camundongos , Mutação , Neuritos/fisiologia , Exame Físico , Adulto Jovem
7.
Am J Med Genet A ; 167A(3): 461-75, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25604898

RESUMO

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.


Assuntos
Colágeno Tipo II/genética , Mutação , Osteocondrodisplasias/congênito , Fenótipo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Radiografia , Adulto Jovem
8.
J Med Genet ; 50(11): 765-71, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23922384

RESUMO

BACKGROUND: Stickler syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1, COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler syndrome exist that are due to mutations in genes encoding type IX collagen (COL9A1 type 4 Stickler syndrome and COL9A2 type 5 Stickler syndrome). Recently, recessive mutations in the COL11A1 gene have been demonstrated to result in fibrochondrogenesis, a much more severe skeletal dysplasia, which is often lethal. Here we demonstrate that some mutations in COL11A1 are recessive, modified by alternative splicing and result in type 2 Stickler syndrome rather than fibrochondrogenesis. METHODS: Patients referred to the national Stickler syndrome diagnostic service for England, UK were assessed clinically and subsequently sequenced for mutations in COL11A1. Additional in silico and functional studies to assess the effect of sequence variants on pre-mRNA processing and collagen structure were performed. RESULTS: In three different families, heterozygous COL11A1 biallelic null, null/missense or silent/missense mutations, were found. They resulted in a recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss and are clinically distinct from the recessive types 4 and 5 variants of Stickler syndrome. One mutant allele in each family is capable of synthesising a normal α1(XI) procollagen molecule, via variable pre-mRNA processing. CONCLUSION: This new variant has important implications for molecular diagnosis and counselling families with type 2 Stickler syndrome.


Assuntos
Processamento Alternativo , Colágeno Tipo XI/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva/genética , Mutação , Descolamento do Vítreo/genética , Adulto , Sequência de Aminoácidos , Pré-Escolar , Colágeno Tipo XI/deficiência , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem
9.
Nat Genet ; 44(7): 793-6, 2012 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-22610116

RESUMO

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cardiomegalia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipertricose/genética , Mutação de Sentido Incorreto , Osteocondrodisplasias/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Adulto , Linhagem Celular Transformada , Criança , Pré-Escolar , Exoma , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Lactente , Recém-Nascido , Canais KATP/genética , Masculino , Estrutura Terciária de Proteína/genética , Receptores Sulfonilureia , Adulto Jovem
10.
Orphanet J Rare Dis ; 7: 4, 2012 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-22236771

RESUMO

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.


Assuntos
Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Síndromes Orofaciodigitais/diagnóstico , Síndromes Orofaciodigitais/patologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Doenças Cerebelares/classificação , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Anormalidades do Olho/classificação , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/classificação , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Síndromes Orofaciodigitais/classificação , Síndromes Orofaciodigitais/genética , Fenótipo , Polidactilia/diagnóstico , Polidactilia/patologia , Retina/anormalidades , Retina/patologia , Adulto Jovem
11.
Pediatr Nephrol ; 26(8): 1331-4, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21597970

RESUMO

Sotos syndrome is characterized by overgrowth, a typical facial appearance, and learning difficulties. It is caused by heterozygous mutations, including deletions, of NSD1 located at chromosome 5q35. Here we report two unrelated cases of Sotos syndrome associated with nephrocalcinosis. One patient also had idiopathic infantile hypercalcemia. Genetic investigations revealed heterozygous deletions at 5q35 in both patients, encompassing NSD1 and SLC34A1 (NaPi2a). Mutations in SLC34A1 have previously been associated with hypercalciuria/nephrolithiasis. Our cases suggest a contiguous gene deletion syndrome including NSD1 and SLC34A1 and provide a potential genetic basis for idiopathic infantile hypercalcemia.


Assuntos
Hipercalcemia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Nefrocalcinose/genética , Proteínas Nucleares/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Síndrome de Sotos/complicações , Síndrome de Sotos/genética , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , Feminino , Deleção de Genes , Humanos , Hipercalcemia/fisiopatologia , Lactente , Recém-Nascido , Mutação , Nefrocalcinose/fisiopatologia , Síndrome de Sotos/fisiopatologia
12.
Neuromuscul Disord ; 21(6): 379-86, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21440438

RESUMO

Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Miopatias Congênitas Estruturais/tratamento farmacológico , Miopatias Congênitas Estruturais/fisiopatologia , Junção Neuromuscular/fisiopatologia , Transmissão Sináptica/fisiologia , Adolescente , Animais , Biópsia , Criança , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Eletromiografia , Feminino , Técnicas de Inativação de Genes , Humanos , Lactente , Masculino , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/genética , Junção Neuromuscular/efeitos dos fármacos , Proteínas Tirosina Fosfatases não Receptoras/genética , Brometo de Piridostigmina/farmacologia , Brometo de Piridostigmina/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos , Resultado do Tratamento , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
14.
Am J Hum Genet ; 84(5): 698-705, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19409524

RESUMO

We describe a recessively inherited frontonasal malformation characterized by a distinctive facial appearance, with hypertelorism, wide nasal bridge, short nasal ridge, bifid nasal tip, broad columella, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. Additional recurrent features present in a minority of individuals have been upper eyelid ptosis and midline dermoid cysts of craniofacial structures. Assuming recessive inheritance, we mapped the locus in three families to chromosome 1 and identified mutations in ALX3, which is located at band 1p13.3 and encodes the aristaless-related ALX homeobox 3 transcription factor. In total, we identified seven different homozygous pathogenic mutations in seven families. These mutations comprise missense substitutions at critical positions within the conserved homeodomain as well as nonsense, frameshift, and splice-site mutations, all predicting severe or complete loss of function. Our findings contrast with previous studies of the orthologous murine gene, which showed no phenotype in Alx3(-/-) homozygotes, apparently as a result of functional redundancy with the paralogous Alx4 gene. We conclude that ALX3 is essential for normal facial development in humans and that deficiency causes a clinically recognizable phenotype, which we term frontorhiny.


Assuntos
Anormalidades Craniofaciais/genética , Proteínas de Homeodomínio/genética , Osso Nasal/anormalidades , Criança , Cromossomos Humanos Par 1/genética , Humanos , Recém-Nascido , Mutação
15.
Nat Genet ; 41(3): 359-64, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19234473

RESUMO

Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.


Assuntos
Síndrome de Pierre Robin/genética , Fatores de Transcrição SOX9/genética , Regiões não Traduzidas/genética , Animais , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 17 , Sequência Conservada , Família , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Linhagem , Polimorfismo Genético/fisiologia , Elementos Reguladores de Transcrição/genética
16.
J Pediatr Surg ; 43(9): 1736-40, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18779018

RESUMO

Biliary atresia is a disease of unknown etiology but not usually thought to have a significant genetic predisposition. We report 5 infants with various forms of chromosome 22 aneuploidy as follows: 2 infants who have classical cat-eye syndrome, 2 who have partial duplication of chromosome 22 (supernumerary der(22) syndrome), and 1 who is mosaic for trisomy 22. All of these infants had significant congenital bile duct anomalies (specifically biliary atresia, n = 4)-that was the most important component of their clinical presentation. We consider whether this has possible implications about the genetic contribution to the etiology of biliary atresia.


Assuntos
Aneuploidia , Atresia Biliar/genética , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Recém-Nascido , Masculino
17.
Am J Med Genet A ; 143A(24): 3290-4, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17963218

RESUMO

We report a brother and sister born to consanguineous parents. The siblings have hypertelorism, bifid nose, upturned nares, histologically proven intranasal dermoid, and soft-tissue swellings of the philtrum. One sibling also has a midline cleft lip and the other has narrowing of the posterior choanae. We suggest that they have craniorhiny, despite the absence of an abnormal skull shape. The differential diagnosis is discussed.


Assuntos
Anormalidades Congênitas/diagnóstico , Nariz/anormalidades , Criança , Pré-Escolar , Fenda Labial/complicações , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Diagnóstico Diferencial , Facies , Saúde da Família , Feminino , Genes Recessivos , Humanos , Hipertelorismo/diagnóstico , Masculino , Irmãos
18.
Am J Hum Genet ; 81(1): 104-13, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17564967

RESUMO

Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.


Assuntos
Anormalidades Múltiplas/genética , Antígenos de Neoplasias/genética , Encéfalo/anormalidades , Nefropatias/genética , Dente Molar/anormalidades , Proteínas de Neoplasias/genética , Transtornos da Motilidade Ocular/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Nefropatias/diagnóstico , Imagem por Ressonância Magnética , Masculino , Mutação , Transtornos da Motilidade Ocular/diagnóstico , Fenótipo , Síndrome
19.
Clin Dysmorphol ; 15(3): 155-9, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16760735

RESUMO

A family with midline nasal dermoids in four members over five generations is described. Two of these individuals also had a midline cleft lip. The pattern of inheritance appears to be autosomal dominant with variable expression. To our knowledge, no familial cases of midline clefting with nasal dermoids have previously been reported in the literature. Cranial imaging to look for intracerebral extension of the dermoid is recommended in such cases.


Assuntos
Anormalidades Múltiplas/genética , Fenda Labial/patologia , Cisto Dermoide/patologia , Genes Dominantes/genética , Neoplasias Nasais/patologia , Anormalidades Múltiplas/patologia , Cisto Epidérmico/patologia , Saúde da Família , Feminino , Humanos , Lactente , Masculino , Linhagem , Síndrome
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