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1.
Genet Med ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578471

RESUMO

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

2.
Am J Med Genet A ; 179(4): 615-627, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758909

RESUMO

Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari-1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF-related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan-) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes-Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in some instances, permanent visual impairment due to unsuspected raised intracranial pressure (ICP). Facial dysmorphism (exhibited by all of the probands and many of the affected relatives) took the form of orbital hypertelorism, mild exorbitism and malar hypoplasia resembling Crouzon syndrome but, importantly, a Class I occlusal relationship. Speech delay, poor gross and/or fine motor control, hyperactivity and poor concentration were common. Cranial vault surgery for raised ICP and/or Chiari-1 malformation was expected when multisutural synostosis was observed. Variable expressivity and nonpenetrance among genetically affected relatives was encountered. These observations form the most complete phenotypic and developmental profile of this recently identified craniosynostosis syndrome yet described and have important implications for surgical intervention and follow-up.

4.
Genet Med ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30349098

RESUMO

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30087776

RESUMO

Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient's SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient's father's paraganglioma. Learning points: Pituitary adenomas may be the presenting and/or sole feature of SDHB mutation-related disease. SDHx mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for SDHx mutations.Immunohistochemistry may not always predict the presence of SDHx mutations.

6.
Am J Hum Genet ; 102(1): 175-187, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29276005

RESUMO

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

7.
J Med Genet ; 55(1): 28-38, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29021403

RESUMO

INTRODUCTION: Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. METHODS: Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. RESULTS: Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. CONCLUSIONS: These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.


Assuntos
Proteína Quinase CDC2/química , Proteína Quinase CDC2/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação/genética , Adolescente , Criança , Sequência Conservada , Feminino , Heterozigoto , Humanos , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Domínios Proteicos , Síndrome , Termodinâmica
8.
Am J Hum Genet ; 101(5): 664-685, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100083

RESUMO

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Mutação/genética , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Deficiência Intelectual/genética , Masculino , Recidiva , Convulsões/genética
9.
Cytogenet Genome Res ; 152(3): 132-136, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898887

RESUMO

Angelman syndrome (AS) is characterised by developmental delay, lack of speech, seizures, a characteristic behavioural profile with a happy demeanour, microcephaly, and ataxia. More than two-thirds of cases are due to an approximately 5-Mb interstitial deletion of the imprinted region 15q11.2q13, which is usually de novo. The rest are associated with point mutations in the UBE3A gene, imprinting defects, and paternal uniparental disomy. Small intragenic UBE3A deletions have rarely been described. They are usually maternally inherited, increasing the recurrence risk to 50%, and may be missed by conventional testing (methylation studies and UBE3A gene sequencing). We describe a boy with AS due to an 11.7-kb intragenic deletion. The deletion was identified by array-CGH and was subsequently detected in his affected first cousin and unaffected maternal grandfather, mother, and aunt, confirming the silencing of the paternal allele. The patient had developmental delay, speech impairment, a happy demeanour, microcephaly, and an abnormal EEG, but no seizures by the age of 4 years. Delineation of the underlying genetic mechanism is of utmost importance for reasons of genetic counselling, as well as appropriate management and prognosis. Alternative techniques, such as array-CGH and MLPA, are necessary when conventional testing for AS has failed to identify the underlying genetic mechanism.


Assuntos
Síndrome de Angelman/genética , Éxons/genética , Herança Materna/genética , Deleção de Sequência , Ubiquitina-Proteína Ligases/genética , Alelos , Síndrome de Angelman/fisiopatologia , Braquidactilia/diagnóstico , Braquidactilia/genética , Braquidactilia/fisiopatologia , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 15/genética , Dedos/anormalidades , Humanos , Hipertelorismo/diagnóstico , Hipertelorismo/genética , Hipertelorismo/fisiopatologia , Deficiência Intelectual/genética , Masculino , Fenótipo , Estrabismo/diagnóstico , Estrabismo/genética , Estrabismo/fisiopatologia
10.
Am J Hum Genet ; 100(1): 91-104, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27939640

RESUMO

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromatina/metabolismo , Histonas/metabolismo , Deficiência Intelectual/genética , Mutação , Proteínas Nucleares/genética , Acetilação , Adolescente , Alelos , Animais , Proteínas de Transporte/genética , Criança , Cromatina/química , Deficiências do Desenvolvimento/genética , Face/anormalidades , Feminino , Histona Acetiltransferases/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipotonia Muscular/genética , Síndrome
11.
Am J Med Genet A ; 170(11): 2835-2846, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27667800

RESUMO

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Deleção Cromossômica , Cromossomos Humanos Par 16 , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Masculino , Fenótipo , Proteínas Repressoras/genética
12.
Nat Genet ; 48(9): 1060-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27479907

RESUMO

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.


Assuntos
Autoantígenos/genética , Proteína Quinase CDC2/genética , Cardiopatias Congênitas/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Mutação/genética , Proteína Quinase C/genética , Proteína Quinase CDC2/química , Exoma/genética , Feminino , Humanos , Masculino , Conformação Proteica , Deleção de Sequência , Síndrome
13.
Hum Mutat ; 37(8): 737-44, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27120253

RESUMO

HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5' and 3' UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558-10G>A, that causes an aberrant splice product and a mutation in the 3'UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto , Distúrbios do Metabolismo do Fósforo/genética , Distúrbios do Metabolismo do Fósforo/patologia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Receptores de Superfície Celular/genética , Regiões 3' não Traduzidas , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Íntrons , Masculino , Linhagem , Análise de Sequência de DNA/métodos , Adulto Jovem
14.
Brain ; 139(Pt 4): 1036-44, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26917597

RESUMO

Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with 'early infantile epileptic encephalopathy'. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re-examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, microcephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment.


Assuntos
Edema Encefálico/diagnóstico , Edema Encefálico/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Proteínas de Transporte Vesicular/genética , Animais , Encéfalo/patologia , Criança , Feminino , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Linhagem
15.
J Child Neurol ; 30(5): 654-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24789116

RESUMO

Mitochondrial DNA depletion syndromes are an important cause of mitochondrial cytopathies in both children and adults. We describe a newborn with multiple congenital malformations including a right aberrant subclavian artery and a trachea-oesophageal fistula in whom mitochondrial depletion syndrome was unmasked by perioperative muscle relaxation. After vecuronium infusion, the infant developed an irreversible postoperative paralysis, leading to death 32 days after surgery. The present case highlights (a) the clinical heterogeneity of mitochondrial depletion syndrome; (b) the importance of rigorous antemortem and postmortem investigations when the cause of a severe myopathy is uncertain; (c) the possible coexistence of mitochondrial depletion syndrome and congenital malformations as a result of a likely abnormal antenatal embryofetal development and (d) the importance of a careful anaesthetic management of children with mitochondrial depletion syndrome, which could be prone to complications related to the possible depressive effects on mitochondrial electron transport chain mediated by some anaesthetic agents.


Assuntos
Anormalidades Múltiplas , Recuperação Demorada da Anestesia/etiologia , Miopatias Mitocondriais , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Variações do Número de Cópias de DNA , DNA Mitocondrial/análise , Evolução Fatal , Humanos , Lactente , Recém-Nascido , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Síndrome
16.
Am J Hum Genet ; 94(4): 618-24, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24680889

RESUMO

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations-four nonsense (c.1195A>T [p.Lys399(∗)], c.1333C>T [p.Arg445(∗)], c.1866C>G [p.Tyr622(∗)], and c.3001C>T [p.Arg1001(∗)]) and three frameshift (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3 , Deficiência Intelectual/genética , Metiltransferases/genética , Mutação , Adolescente , Criança , Humanos , Masculino
17.
Genome Res ; 24(4): 673-87, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24356988

RESUMO

Exome sequencing of parent-offspring trios is a popular strategy for identifying causative genetic variants in children with rare diseases. This method owes its strength to the leveraging of inheritance information, which facilitates de novo variant calling, inference of compound heterozygosity, and the identification of inheritance anomalies. Uniparental disomy describes the inheritance of a homologous chromosome pair from only one parent. This aberration is important to detect in genetic disease studies because it can result in imprinting disorders and recessive diseases. We have developed a software tool to detect uniparental disomy from child-mother-father genotype data that uses a binomial test to identify chromosomes with a significant burden of uniparentally inherited genotypes. This tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust for use in platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1057 trios from the Deciphering Developmental Disorders project, a trio-based rare disease study, and detected six validated events, a significant enrichment compared with the population prevalence of UPD (1 in 3500), suggesting that most of these events are pathogenic. One of these events represents a known imprinting disorder, and exome analyses have identified rare homozygous candidate variants, mainly in the isodisomic regions of UPD chromosomes, which, among other variants, provide targets for further genetic and functional evaluation.


Assuntos
Deficiências do Desenvolvimento/genética , Genótipo , Software , Dissomia Uniparental/genética , Criança , Mapeamento Cromossômico , Bases de Dados Genéticas , Humanos , Relações Pais-Filho , Polimorfismo de Nucleotídeo Único , Dissomia Uniparental/etiologia
18.
Am J Med Genet A ; 164A(1): 194-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24243657

RESUMO

Deletions of the long arm of chromosome 2 are rare. Few cases of interstitial deletions of the 2q33q35 region have been reported. Individuals with deletions in this region have growth retardation, psychomotor retardation, micrognathia, microcephaly, and apparently low-set ears. We describe a female fetus with a de novo deletion of 2q33.2 to q35 with delayed gyral formation with widespread neuronal heterotopia of the white matter, small cerebellum, esophageal atresia, laryngeal stenosis, micrognathia, and intrauterine growth retardation. With the use of karyotyping and high-resolution array comparative genomic hybridization the boundaries and gene content of the deletion were identified. Our aim was to determine whether a candidate gene for the brain phenotype was present in the deletion. By this means and based on literature we pinpointed the microtubule associated gene MAP2 as a candidate for the brain anomalies.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2 , Anormalidades Craniofaciais/genética , Atresia Esofágica/genética , Laringoestenose/genética , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Autopsia , Encéfalo/patologia , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/diagnóstico , Atresia Esofágica/diagnóstico , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Laringoestenose/diagnóstico , Microcefalia/diagnóstico , Fenótipo
19.
J Clin Endocrinol Metab ; 98(7): E1248-56, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23666964

RESUMO

CONTEXT: Pheochromocytomas and paragangliomas are notable for a high frequency of inherited cases, many of which present as apparently sporadic tumors. OBJECTIVE: The objective of this study was to establish a comprehensive next generation sequencing (NGS)-based strategy for the diagnosis of patients with pheochromocytoma and paraganglioma by testing simultaneously for mutations in MAX, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. DESIGN: After the methodology for the assay was designed and established, it was validated on DNA samples with known genotype and then patients were studied prospectively. SETTING: The study was performed in a diagnostic genetics laboratory. PATIENTS: DNA samples from 205 individuals affected with adrenal or extraadrenal pheochromocytoma/head and neck paraganglioma (PPGL/HNPGL) were analyzed. A proof-of-principle study was performed using 85 samples known to contain a variant in 1 or more of the genes to be tested, followed by prospective analysis of an additional 120 samples. MAIN OUTCOME MEASURES: We assessed the ability to use an NGS-based method to perform comprehensive analysis of genes implicated in inherited PPGL/HNPGL. RESULTS: The proof-of-principle study showed that the NGS assay and analysis gave a sensitivity of 98.7%. A pathogenic mutation was identified in 16.6% of the prospective analysis cohort of 120 patients. CONCLUSIONS: A comprehensive NGS-based strategy for the analysis of genes associated with predisposition to PPGL and HNPGL was established, validated, and introduced into diagnostic service. The new assay provides simultaneous analysis of 9 genes and allows more rapid and cost-effective mutation detection than the previously used conventional Sanger sequencing-based methodology.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Mutação em Linhagem Germinativa , Neoplasias de Cabeça e Pescoço/diagnóstico , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/economia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Estudos de Coortes , Redução de Custos , Custos e Análise de Custo , Análise Mutacional de DNA/economia , Predisposição Genética para Doença , Testes Genéticos/economia , Testes Genéticos/métodos , Neoplasias de Cabeça e Pescoço/economia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Custos de Cuidados de Saúde , Humanos , Paraganglioma/economia , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/economia , Feocromocitoma/genética , Feocromocitoma/metabolismo , Estudos Prospectivos , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas Proto-Oncogênicas c-ret/química , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Sensibilidade e Especificidade , Succinato Desidrogenase/química , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Reino Unido , Proteína Supressora de Tumor Von Hippel-Lindau/química , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
20.
Clin Endocrinol (Oxf) ; 78(6): 898-906, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23072324

RESUMO

OBJECTIVES: Research studies have reported that about a third of individuals with phaeochromocytoma/paraganglioma (PPGL) have an inherited predisposition, although the frequency of specific mutations can vary between populations. We evaluated VHL, SDHB and SDHD mutation testing in cohorts of patients with non-syndromic PPGL and head and neck paraganglioma (HNPGL). DESIGN: Prospective, observational evaluation of NHS practice. PATIENTS: Individuals with PPGL/HNPGL referred to a supraregional genetics testing service over a 10-year period. MEASUREMENTS: Clinical (age, tumour site, malignancy, etc.), mutation frequencies and characteristics. RESULTS: A total of 501 probands with PPGL (n = 413) or HNPGL (n = 88) were studied. Thirty-one percent of patients with PPGL presented had a pathogenic mutation in SDHB, SDHD or VHL. Mutation detection rates were highest in those with a positive family history (62%), malignancy (53%), multiple tumours (33%) or PGL (44%). Twenty-eight percent of individuals with a single sporadic phaeochromocytoma had a mutation. Overall, 63% of patients with HNPGL had a mutation (92% of those with a family history, 89% of those with multicentric tumours and 34% of those with a single sporadic HNPGL). Penetrance was calculated in 121 SDHB mutation-positive probands and 187 of their mutation-positive relatives. Most relatives were asymptomatic and lifetime penetrance in non-proband SDHB mutation carriers was <50%. CONCLUSIONS: Practice-based evaluations of genetic testing in PPGL reveal high mutation detection rates. Although clinical criteria can be used to prioritize mutation testing, mutations were detected in 'low risk groups' indicating a need for comprehensive and inexpensive genetic testing strategies for PPGL and HNPGL.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Predisposição Genética para Doença/genética , Neoplasias de Cabeça e Pescoço/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
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