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4.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

5.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

6.
NPJ Genom Med ; 3: 21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30131872

RESUMO

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

7.
Hum Mutat ; 39(8): 1126-1138, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29851191

RESUMO

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.

8.
Presse Med ; 46(11): 1071-1078, 2017 Nov.
Artigo em Francês | MEDLINE | ID: mdl-29097032

RESUMO

In front of external otitis in spite of a well-conducted treatment, especially in immunodeficient patient, it is always necessary to look for an osteomyelitis of the skull base that requires an urgent parenteral antibiotic treatment of several weeks. Acute otitis media (AOM) is the most common bacterial infection of the child. In children under 2 years with purulent AOM, antibiotic therapy with amoxicilline is systematic for a period of 8-10 days. After 2 years of age and with mild symptoms of AOM, symptomatic treatment may be justified as first-line treatment. Chronic otitis media is frequent after an episode of AOM and becomes chronic only after 3 months of evolution. Grommets reduce the frequency of AOM episodes. All AOM complicated with meningitis requires monitoring by audiogram and MRI of the ear.


Assuntos
Otite Externa , Otite Média , Doença Aguda , Criança , Pré-Escolar , Árvores de Decisões , Humanos , Lactente , Otite Externa/diagnóstico , Otite Externa/tratamento farmacológico , Otite Média/diagnóstico , Otite Média/tratamento farmacológico
9.
J Clin Endocrinol Metab ; 102(2): 460-469, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27870580

RESUMO

Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

10.
Am J Hum Genet ; 99(6): 1368-1376, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27889060

RESUMO

Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.


Assuntos
Complexo 3 de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Epilepsia/complicações , Epilepsia/genética , Genes Recessivos/genética , Mutação , Atrofia Óptica/complicações , Atrofia Óptica/genética , Idade de Início , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/genética , Linhagem , Síndrome
11.
Am J Med Genet A ; 170(9): 2338-48, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27271787

RESUMO

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Adolescente , Adulto , Aneuploidia , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Tomada de Decisão Clínica , Feminino , Doenças Genéticas Inatas/terapia , Testes Genéticos , Variação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
12.
Cold Spring Harb Mol Case Stud ; 2(1): a000661, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27148580

RESUMO

We identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore-microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.

14.
Am J Med Genet C Semin Med Genet ; 169(4): 293-301, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26473616

RESUMO

Children with disabilities (CWD) are victims of abuse more frequently than children in the general population. The features of their underlying conditions make it more difficult to detect abuse and on occasion can be mistaken for abuse. Thus, the expertise of the clinical geneticist is often vital to properly identifying maltreatment in this vulnerable population. The purpose of this article is to review the magnitude of abuse in the population of CWD, to identify the aggravating factors, and to suggest practice changes in order to both diagnose and reduce the likelihood of abuse in CWD.


Assuntos
Maus-Tratos Infantis/diagnóstico , Maus-Tratos Infantis/prevenção & controle , Crianças com Deficiência/estatística & dados numéricos , Criança , Maus-Tratos Infantis/estatística & dados numéricos , Feminino , Humanos , Deficiência Intelectual , Masculino , Notificação de Abuso
15.
Otol Neurotol ; 35(5): 899-904, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24662627

RESUMO

OBJECTIVE: To analyze the difference between the endolymphatic sac tumors (ELSTs) in sporadic cases and in von Hippel-Lindau (VHL) disease. STUDY DESIGN: Retrospective case review in a tertiary referral center. PATIENTS AND METHODS: Fourteen cases of ELST, occurring since 1998, were reviewed. We analyzed the initial symptoms, characteristics of the tumor, treatment, sequelae, and follow-up for each group. RESULTS: The ELSTs were sporadic in 6 cases and associated with VHL disease in 8 cases. The mean age at the time of the first surgery was 26 years (range, 12-41). All except two of the patients presented with a unilateral tumor. The initial symptoms were hearing loss (n = 9), tinnitus (n = 7), and/or vertigo (n = 5). Hearing loss was more prevalent in the sporadic cases. Preoperative arteriography was performed for 4 patients, with embolization performed for 1 patient. The size of the tumor was significantly larger in the sporadic cases (31.7 mm) than in the cases of VHL disease (19.3 mm). The surgical approach was more extensive in the sporadic cases. The surgeons found 2 types of tumors. Cystic tumors with massive bleeding invading the surrounding structures (the dura mater or jugular bulb) were more common in the sporadic cases. Fibrous tumors that infiltrate the bone and have moderate bleeding were more common in the cases associated with VHL disease.Two patients with small lesions were not operated on but were followed for 6 years without tumor growth. They died of metastasis from gastric and kidney cancer. Four recurrences occurred during the 14 years of follow-up. Four facial palsies and 8 cases of profound deafness were encountered postoperatively. CONCLUSION: Sporadic tumors are more aggressive than those associated with VHL disease. Complete surgical resection should be the goal of treatment. Preoperative angiography with embolization is recommended. In some cases, embolization may be impossible, and preoperative or postoperative radiotherapy should be discussed.


Assuntos
Neoplasias da Orelha/cirurgia , Saco Endolinfático/cirurgia , Perda Auditiva/cirurgia , Hemangioblastoma/cirurgia , Zumbido/cirurgia , Vertigem/cirurgia , Doença de von Hippel-Lindau/cirurgia , Adolescente , Adulto , Criança , Neoplasias da Orelha/complicações , Neoplasias da Orelha/patologia , Saco Endolinfático/patologia , Feminino , Perda Auditiva/etiologia , Perda Auditiva/patologia , Hemangioblastoma/complicações , Hemangioblastoma/patologia , Humanos , Masculino , Estudos Retrospectivos , Zumbido/etiologia , Zumbido/patologia , Resultado do Tratamento , Vertigem/etiologia , Vertigem/patologia , Adulto Jovem , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/patologia
17.
J Med Genet ; 47(5): 299-311, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20452996

RESUMO

BACKGROUND: Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes. METHODS: Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3. RESULTS: Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms. CONCLUSIONS: The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Lisencefalia/genética , Adolescente , Encéfalo/anormalidades , Criança , Pré-Escolar , Deleção Cromossômica , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/patologia , Anormalidades Craniofaciais/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Lisencefalia/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Duplicações Segmentares Genômicas
19.
Genet Med ; 10(7): 469-94, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18580689

RESUMO

Cardiovascular abnormalities, especially structural congenital heart defects, commonly occur in malformation syndromes and genetic disorders. Individuals with syndromes comprise a significant proportion of those affected with selected congenital heart defects such as complete atrioventricular canal, interrupted arch type B, supravalvar aortic stenosis, and pulmonary stenosis. As these individuals age, they contribute to the growing population of adults with special health care needs. Although most will require longterm cardiology follow-up, primary care providers, geneticists, and other specialists should be aware of (1) the type and frequency of cardiovascular abnormalities, (2) the range of clinical outcomes, and (3) guidelines for prospective management and treatment of potential complications. This article reviews fundamental genetic, cardiac, medical, and reproductive issues associated with common genetic syndromes that are frequently associated with a cardiovascular abnormality. New data are also provided about the cardiac status of adults with a 22q11.2 deletion and with Down syndrome.


Assuntos
Anormalidades Cardiovasculares/genética , Anormalidades Cardiovasculares/terapia , Aberrações Cromossômicas , Cromossomos Humanos Par 22/genética , Síndrome de Down/genética , Adulto , Anormalidades Cardiovasculares/patologia , Feminino , Aconselhamento Genético , Doenças Genéticas Inatas/genética , Humanos , Masculino , Gravidez , Reprodução/genética , Síndrome
20.
Semin Pediatr Neurol ; 14(3): 140-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17980311

RESUMO

The phakomatoses of particular interest to neurologists including Sturge-Weber syndrome, neurofibromatosis type 1, neurofibromatosis type 2, Bannayan-Riley-Ruvalcaba syndrome, and Proteus syndrome are presented. The physical manifestations required for clinical diagnosis, the neurologic features, and recommendations for management are given. The molecular etiology and genetic aspects of these disorders are briefly discussed as well as future implications of on-going research.


Assuntos
Doenças do Sistema Nervoso/etiologia , Síndromes Neurocutâneas/complicações , Síndromes Neurocutâneas/patologia , Dermatopatias/etiologia , Anormalidades Múltiplas , Síndrome do Hamartoma Múltiplo , Humanos , Doenças do Sistema Nervoso/patologia , Síndromes Neurocutâneas/classificação , Síndromes Neurocutâneas/genética , Neurofibromatose 1 , Dermatopatias/patologia , Síndrome de Sturge-Weber
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