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1.
Hum Genet ; 138(10): 1183-1200, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471722

RESUMO

The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Genes Recessivos , Predisposição Genética para Doença , Mutação , Fenótipo , Transaminases/genética , Adolescente , Alelos , Substituição de Aminoácidos , Deficiências do Desenvolvimento/metabolismo , Ativação Enzimática , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Genética Populacional , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Moleculares , Linhagem , Conformação Proteica , Sítios de Splice de RNA , Análise de Sequência de DNA , Relação Estrutura-Atividade , Transaminases/química , Transaminases/metabolismo
2.
Artigo em Chinês | MEDLINE | ID: mdl-31446702

RESUMO

Summary A 4-year-old male patient was found poor development in hearing and speech, without family hereditary history. Hearing screening was failed at birth. From the age of 2, the patient showed poor response to sound and speech, but no audiological examination was carried out. After physical examination, no deformity was found in both ears, and the tympanic membranes were intact; the muscular tension was normal; and the visual acuity was normal. The acoustic immittance showed curve A; DPOAE showed that both ears passed; click ABR threshold was greater than 95 dB nHL, bone conduction was greater than 45 dB nHL; electrocochleogram was bilateral elicited. There were no malformations of cochlea and inner ear showed in temporal bone CT and internal auditory canal MRI. Gene detection indicated a mutation in TIMM8A gene of X chromosome. Combined with the patient's medical history, gene detection, audiological manifestations and imaging examination, the final diagnosis was Mohr-Tranebjærg syndrome, bilateral severe sensorineural hearing loss, and auditory neuropathy.


Assuntos
Transtornos da Surdocegueira/diagnóstico , Distonia/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Deficiência Intelectual/diagnóstico , Atrofia Óptica/diagnóstico , Pré-Escolar , Humanos , Masculino
3.
Hum Genet ; 138(10): 1145-1153, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321490

RESUMO

The objective of this study is to shed light on the phenotype and inheritance pattern of rare 13q33-q34 microdeletions. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature search in PubMed, DECIPHER and ClinVar databases was performed. Local database search yielded eight new patients with 13q33.1-q34 microdeletions (three of which had additional copy number variants). Combined with 15 cases detected by literature search, an additional 23 cases were reported in DECIPHER database, and 17 cases from ClinVar, so overall 60 patients with isolated 13q33.1-q34 microdeletions were described. Developmental delay and/or intellectual disability were noted in the vast majority of affected individuals (81.7% = 49/60). Of the 23 deletions involving the 13q34 cytoband only, in 3 cases, developmental delay and/or intellectual disability was not reported. Interestingly, in two of these cases (66.7%), the deletions did not involve the terminal CHAMP1 gene, as opposed to 3/20 (15%) of patients with 13q34 deletions and neurocognitive disability. Facial dysmorphism and microcephaly were reported in about half of the overall cases, convulsions were noted in one-fifth of the patients, while heart anomalies, short stature and hypotonia each involved about 10-30% of the cases. None of the 13q33-q34 deletions were inherited from a reported healthy parent. 13q33-q34 microdeletions are rare chromosomal aberrations, associated with high risk for neurodevelopmental disability. The rarity of this chromosomal aberration necessitates continuous reporting and collection of available evidence, to improve the ability to provide accurate genetic counseling, especially in the context of prenatal setting.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13 , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Bandeamento Cromossômico , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Adulto Jovem
4.
Arch Endocrinol Metab ; 63(2): 113-120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038592

RESUMO

OBJECTIVE: There is controversy regarding cognitive function in patients with congenital adrenal hyperplasia (CAH). This study is aimed at the assessment of cognitive functions in children with CAH, and their relation to hydrocortisone (HC) therapy and testosterone levels. SUBJECTS AND METHODS: Thirty children with CAH due to 21 hydroxylase deficiency were compared with twenty age- and sex-matched healthy controls. HC daily and cumulative doses were calculated, the socioeconomic standard was assessed, and free testosterone was measured. Cognitive function assessment was performed using the Wechsler Intelligence Scale - Revised for Children and Adults (WISC), the Benton Visual Retention Test, and the Wisconsin Card Sorting Test (WCST). RESULTS: The mean age (SD) of patients was 10.22 (3.17) years [11 males (36.7%), 19 females (63.3%)]. Mean (SD) HC dose was 15.78 (4.36) mg/m 2 /day. Mean (SD) cumulative HC dose 44,689. 9 (26,892.02) mg. Patients had significantly lower scores in all domains of the WISC test, performed significantly worse in some components of the Benton Visual Retention Test, as well as in the Wisconsin Card Sorting Test. There was no significant difference in cognitive performance when patients were subdivided according to daily HC dose (< 10, 10 - 15, > 15 mg/m 2 /day). A positive correlation existed between cumulative HC dose and worse results of the Benton test. No correlation existed between free testosterone and any of the three tests. CONCLUSION: Patients with CAH are at risk of some cognitive impairment. Hydrocortisone therapy may be implicated. This study highlights the need to assess cognitive functions in CAH.


Assuntos
Hiperplasia Suprarrenal Congênita/psicologia , Anti-Inflamatórios/administração & dosagem , Cognição , Hidrocortisona/administração & dosagem , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/metabolismo , Anti-Inflamatórios/farmacologia , Estudos de Casos e Controles , Criança , Cognição/efeitos dos fármacos , Transtornos Cognitivos/diagnóstico , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidrocortisona/farmacologia , Deficiência Intelectual/diagnóstico , Masculino , Testes Neuropsicológicos , Fatores Socioeconômicos , Testosterona/sangue , Percepção Visual/efeitos dos fármacos , Escalas de Wechsler
5.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945684

RESUMO

Microduplications of the X chromosome are a rare cause of X-linked intellectual disability (XLID), a clinically and genetically heterogeneous spectrum of disorders. In the present study, a 950-kb Xp22.12 microduplication including the RPS6KA3 gene was detected in affected members of a family, including the proband (male), his mother and one maternal uncle. Four female carriers had major depression and one of them also had mild intellectual disability. The present and previous cases with overlapping microduplications suggest that Xp22.12 microduplications can be included in the neuropsychiatric copy number variations.


Assuntos
Cromossomos Humanos X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Esquizofrenia/genética , Adulto , Duplicação Cromossômica , Variações do Número de Cópias de DNA , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Esquizofrenia/diagnóstico
6.
J Autism Dev Disord ; 49(7): 3031-3035, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30968316

RESUMO

Myhre syndrome (MS) is a connective tissue disorder with multisystem involvement with or without intellectual disability. In most cases SMAD4 mutations are reported. To date, 55 individuals have been molecularly confirmed. Autism has been proposed among associate clinical features of MS but no standardized diagnosis was available in previous cases. We report a case of a 25-year-old man with a pathogenic heterozygous SMAD4 missense mutation affecting residue Arg496 (SMAD4:p.Arg496Cys). Clinical findings are consistent with MS, commorbid with affective disorder and High Functioning Autism Spectrum Disorder confirmed by a standardized assessment procedure. The thorough clinical assessment of cases with syndromes such as MS can extend our knowledge on both the phenotypic characteristics of the syndrome and the genetic basis of autism.


Assuntos
Transtorno do Espectro Autista , Criptorquidismo , Facies , Transtornos do Crescimento , Deformidades Congênitas da Mão , Deficiência Intelectual , Adulto , Comorbidade , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Mutação , Proteína Smad4
8.
Prax Kinderpsychol Kinderpsychiatr ; 68(3): 183-197, 2019 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-30838949

RESUMO

Discriminative Validity of the Wechsler Intelligence Scale for Children - IV (WIS) in a Social-Pediatric Sample This study presents data on the discriminative validity of the Wechsler Scale of Intelligence for Children - IV (WIS) for clinical diagnoses, different types of schooling, and variables related to migration. The sample comprises 631 children aged 6 to 13 who were tested with the WIS core tests in German centers of social pediatrics (Sozialpädiatrische Zentren) which offer interdisciplinary assessment and intervention for children and youth with developmental disorders, disabilities, and psychological problems. Large effects were found for clinical diagnoses and types of schooling that are related to intellectual abilities: Children with intellectual developmental disorders and pupils of special schools for children with intellectual disability obtained low or very low IQ-scores. Children with migration background scored relatively lower only on the Verbal Comprehension Index.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiência Intelectual/diagnóstico , Inteligência , Pediatria/normas , Escalas de Wechsler/normas , Adolescente , Criança , Deficiências do Desenvolvimento/psicologia , Alemanha , Humanos , Deficiência Intelectual/psicologia
9.
Soc Psychiatry Psychiatr Epidemiol ; 54(6): 693-701, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30850887

RESUMO

PURPOSE: The criteria for autism spectrum disorder (ASD) were revised in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). The objective of this study was to compare the sensitivity and specificity of DSM-IV-Text Revision (DSM-IV-TR) and DSM-5 definitions of ASD in a community-based sample of preschool children. METHODS: Children between 2 and 5 years of age were enrolled in the Study to Explore Early Development-Phase 2 (SEED2) and received a comprehensive developmental evaluation. The clinician(s) who evaluated the child completed two diagnostic checklists that indicated the presence and severity of DSM-IV-TR and DSM-5 criteria. Definitions for DSM-5 ASD, DSM-IV-TR autistic disorder, and DSM-IV-TR Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) were created from the diagnostic checklists. RESULTS: 773 children met SEED2 criteria for ASD and 288 met criteria for another developmental disorder (DD). Agreement between DSM-5 and DSM-IV-TR definitions of ASD were good for autistic disorder (0.78) and moderate for PDD-NOS (0.57 and 0.59). Children who met DSM-IV-TR autistic disorder but not DSM-5 ASD (n = 71) were more likely to have mild ASD symptoms, or symptoms accounted for by another disorder. Children who met PDD-NOS but not DSM-5 ASD (n = 66), or vice versa (n = 120) were less likely to have intellectual disability and more likely to be female. Sensitivity and specificity were best balanced with DSM-5 ASD criteria (0.95 and 0.78, respectively). CONCLUSIONS: The DSM-5 definition of ASD maximizes diagnostic sensitivity and specificity in the SEED2 sample. These findings support the DSM-5 conceptualization of ASD in preschool children.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Lista de Checagem , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Sensibilidade e Especificidade
10.
Mol Autism ; 10: 9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867896

RESUMO

Background: Current global estimates suggest the proportion of the population with autism spectrum disorder (ASD) who have intellectual disability (ID) is approximately 50%. Our objective was to ascertain the existence of selection bias due to under-inclusion of populations with ID across all fields of autism research. A sub-goal was to evaluate inconsistencies in reporting of findings. Methods: This review covers all original research published in 2016 in autism-specific journals with an impact factor greater than 3. Across 301 included studies, 100,245 participants had ASD. A random effects meta-analysis was used to estimate the proportion of participants without ID. Selection bias was defined as where more than 75% of participants did not have ID. Results: Meta-analysis estimated 94% of all participants identified as being on the autism spectrum in the studies reviewed did not have ID (95% CI 0.91-0.97). Eight out of ten studies demonstrated selection bias against participants with ID. The reporting of participant characteristics was generally poor: information about participants' intellectual ability was absent in 38% of studies (n = 114). Where there was selection bias on ID, only 31% of studies mentioned lack of generalisability as a limitation. Conclusions: We found selection bias against ID throughout all fields of autism research. We recommend transparent reporting about ID and strategies for inclusion for this much marginalised group.


Assuntos
Transtorno do Espectro Autista/complicações , Deficiência Intelectual/diagnóstico , Seleção de Pacientes , Transtorno do Espectro Autista/epidemiologia , Pesquisa Biomédica/normas , Humanos , Deficiência Intelectual/epidemiologia , Viés de Seleção
11.
Int J Mol Sci ; 20(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909440

RESUMO

To identify whether parent-of-origin effects (POE) of the 15q11.2 BP1-BP2 microdeletion are associated with differences in clinical features in individuals inheriting the deletion, we collected 71 individuals reported with phenotypic data and known inheritance from a clinical cohort, a research cohort, the DECIPHER database, and the primary literature. Chi-squared and Mann-Whitney U tests were used to test for differences in specific and grouped clinical symptoms based on parental inheritance and proband gender. Analyses controlled for sibling sets and individuals with additional variants of uncertain significance (VOUS). Among all probands, maternal deletions were associated with macrocephaly (p = 0.016) and autism spectrum disorder (ASD; p = 0.02), while paternal deletions were associated with congenital heart disease (CHD; p = 0.004). Excluding sibling sets, maternal deletions were associated with epilepsy as well as macrocephaly (p < 0.05), while paternal deletions were associated with CHD and abnormal muscular phenotypes (p < 0.05). Excluding sibling sets and probands with an additional VOUS, maternal deletions were associated with epilepsy (p = 0.019) and paternal deletions associated with muscular phenotypes (p = 0.008). Significant gender-based differences were also observed. Our results supported POEs of this deletion and included macrocephaly, epilepsy and ASD in maternal deletions with CHD and abnormal muscular phenotypes seen in paternal deletions.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 15/genética , Estudos de Coortes , Feminino , Impressão Genômica , Humanos , Masculino , Fenótipo , Fatores Sexuais , Irmãos
12.
J Autism Dev Disord ; 49(6): 2243-2256, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30701432

RESUMO

There is limited data on long-term outcome of ASD with co-occurring intellectual disabilities (ID) and challenging behaviours in France. The EpiTED period cohort is a 15 years longitudinal study of the developmental trajectories of 281 children initially recruited at mean age of 5 years. Two contrasted developmental trajectories were identified. Low cognitive level, absence of language, and higher ASD scores at baseline were predictive of low growth at follow-up. As adults the participants were predisposed to persistent co-occurring challenging behaviours as well as underlying ID impacting their ability to function independently. The results underscore the need for development of services and supports for adults with ASD in France who may also have already lacked access to adequate interventions and support services.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/psicologia , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , França/epidemiologia , Humanos , Deficiência Intelectual/diagnóstico , Estudos Longitudinais , Masculino , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
13.
J Autism Dev Disord ; 49(6): 2337-2347, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30726535

RESUMO

To date, the phenotypic significance of EEG abnormalities in patients with ASD is unclear. In a population affected by ASD we aimed to evaluate: the phenotypic characteristics; the prevalence of EEG abnormalities; the potential correlations between EEG abnormalities and behavioral and cognitive variables. Sixty-nine patients with ASD underwent cognitive or developmental testing, language assessment, and adaptive behavior skills evaluation as well as sleep/wake EEG recording. EEG abnormalities were found in 39.13% of patients. EEG abnormalities correlated with autism severity, hyperactivity, anger outbursts, aggression, negative or destructive behavior, motor stereotypies, intellectual disability, language impairment and self-harm. Our findings confirmed that EEG abnormalities are present in the ASD population and correlate with several associated phenotypic features.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Eletroencefalografia/métodos , Índice de Gravidade de Doença , Adolescente , Agressão/fisiologia , Agressão/psicologia , Transtorno do Espectro Autista/psicologia , Biomarcadores , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Masculino , Projetos Piloto , Estudos Retrospectivos , Comportamento Estereotipado/fisiologia , Adulto Jovem
14.
Gene ; 696: 21-27, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771478

RESUMO

Intellectual disabilities (ID) are etiologically heterogeneous. Advanced molecular techniques could be helpful in identification of the underlying genetic defects. We aimed to characterize clinical and molecular features of three Thai patients with ID. Patient 1 had ID, hypotonia and lactic acidosis. Patient 2 had ID and growth failure. Patient 3 had ID, seizure, diarrhea and hypoglycemia. Whole exome sequencing found that Patient 1 was homozygous for a nonsense, c.1303C>T (p.Arg435Ter), mutation in FBXL4, a gene responsible for encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13). Patient 2 was compound heterozygous for two novel mutations, c.3226C>T (p.Arg1076Ter) and c.3205C>T (p.Arg1069Ter), in UNC80, a known gene of infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2). Patient 3 was homozygous for a novel missense, c.427T>C (p.Cys143Arg), mutation in ADK, a known gene of adenosine kinase deficiency leading to hypermethioninemia. This study expands the mutational spectra of ID genes.


Assuntos
Adenosina Quinase/genética , Proteínas de Transporte/genética , Proteínas F-Box/genética , Testes Genéticos/métodos , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Ubiquitina-Proteína Ligases/genética , Feminino , Homozigoto , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Mutação , Índice de Gravidade de Doença , Tailândia , Sequenciamento Completo do Exoma
15.
Nat Commun ; 10(1): 410, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679432

RESUMO

The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.


Assuntos
Variações do Número de Cópias de DNA/genética , Variação Genética/genética , Genoma Humano/genética , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Proteína Adaptadora de Sinalização CRADD/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Estudos de Coortes , Exoma , Feminino , Finlândia/epidemiologia , Estudos de Associação Genética , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Geografia , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Herança Multifatorial , Mutação , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Patologia Molecular , Prevalência , Sequenciamento Completo do Exoma
16.
Front Horm Res ; 51: 147-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30641531

RESUMO

Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels. All these disorders are caused by impairments in the cAMP-mediated signal transduction pathway and, in particular, in the PTH/PTHrP signaling pathway: the main subtypes of PHP and related disorders are caused by de novo or autosomal dominantly inherited inactivating genetic mutations, and/or epigenetic, sporadic, or genetic-based alterations within or upstream of GNAS, PRKAR1A, PDE4D, and PDE3A. Here we will review the impressive progress that has been made over the past 30 years on the pathophysiology of these diseases and will describe the recently proposed novel nomenclature and classification. The new term "inactivating PTH/PTHrP signaling disorder," iPPSD: (1) defines the common mechanism responsible for all diseases, (2) does not require a confirmed genetic defect, (3) avoids ambiguous terms like "pseudo," and (4) eliminates the clinical or molecular overlap between diseases.


Assuntos
Doenças Ósseas Metabólicas , Disostoses , Deficiência Intelectual , Ossificação Heterotópica , Osteocondrodisplasias , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/metabolismo , Pseudo-Hipoparatireoidismo , Transdução de Sinais/fisiologia , Dermatopatias Genéticas , Doenças Ósseas Metabólicas/classificação , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/terapia , Disostoses/classificação , Disostoses/diagnóstico , Disostoses/metabolismo , Disostoses/terapia , Humanos , Deficiência Intelectual/classificação , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/terapia , Ossificação Heterotópica/classificação , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/terapia , Osteocondrodisplasias/classificação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/terapia , Pseudo-Hipoparatireoidismo/classificação , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/metabolismo , Pseudo-Hipoparatireoidismo/terapia , Dermatopatias Genéticas/classificação , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/metabolismo , Dermatopatias Genéticas/terapia
17.
Ann Lab Med ; 39(3): 299-310, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30623622

RESUMO

BACKGROUND: To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA). METHODS: We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results. RESULTS: A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively. CONCLUSIONS: Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.


Assuntos
Anormalidades Múltiplas/diagnóstico , Transtorno do Espectro Autista/diagnóstico , Bandeamento Cromossômico/métodos , Cromossomos/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiência Intelectual/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Feminino , Deleção de Genes , Duplicação Gênica , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Cariótipo , Masculino , Estudos Prospectivos , República da Coreia , Adulto Jovem
18.
BMC Med Genet ; 20(1): 11, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30634948

RESUMO

BACKGROUND: Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder resulting in early-onset hearing impairment, gradual dystonia and optic atrophy. MTS is caused by variations in the nuclear TIMM8A gene, which is involved in mitochondrial transport of metabolites. This study aimed to identify the pathogenic gene variations in three Chinese families associated with predicted MTS with or without X-linked agammaglobulinaemia. METHODS: Otologic examinations, vestibular, neurological, optical and other clinical evaluations were conducted on the family members. Targeted genes capture combining next generation sequencing (NGS) was performed, and then Sanger sequencing was used to confirm the causative variation. RESULTS: A novel variation, c.232_233insCAAT, in TIMM8A was identified as the pathogenic variation in one Chinese family. This variation co-segregated with the most frequent phenotypic deafness and was absent in the 1000 Genomes Project, ExAC and 1751 ethnicity-matched controls. Clinically, otological examinations illustrated the typical postsynaptic auditory neuropathy for the proband without the symptoms of dystonia or optic atrophy. MRI demonstrated abnormal small cochlear symmetric nerves, while the vestibular function appeared to be less influenced. Furthermore, we found another two TIMM8A variations, the deletion c.133_135delGAG and a copy number variation (CNV) including the TIMM8A gene, in two independent case, when we performed NGS on an auditory neuropathy population. CONCLUSION: We identified two novel variations in the TIMM8A gene (c.232_233insCAAT and c.133_135delGAG) and a CNV including the TIMM8A gene in three independent Chinese families with predicted MTS. To our knowledge, this is the first report of TIMM8A variations being identified in a Chinese population. Our results enrich the variation spectrum of TIMM8A and clinical heterogeneity of MTS. Genetic detection and diagnosis is a powerful tool for better understanding and managing syndromic hearing impairments, such as MTS, before they become full-blown.


Assuntos
Transtornos da Surdocegueira/diagnóstico , Transtornos da Surdocegueira/genética , Distonia/diagnóstico , Distonia/genética , Testes Genéticos/métodos , Perda Auditiva Central/diagnóstico , Perda Auditiva Central/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Proteínas de Membrana Transportadoras/genética , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Fenótipo , Agamaglobulinemia/genética , Grupo com Ancestrais do Continente Asiático/genética , Variações do Número de Cópias de DNA , Surdez/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Variação Genética , Humanos , Masculino , Mutação , Linhagem
19.
J Obstet Gynaecol ; 39(3): 323-327, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30634886

RESUMO

The 17q12 deletion syndrome is a chromosomal anomaly resulting from the interstitial microdeletion of the long arm of chromosome 17. The aim of this study was to present the experience on prenatal diagnosis of 17q12 deletion to further define the prenatal phenotypes of this syndrome. Eleven pregnancies with foetal 17q12 deletion detected by chromosomal microarray (CMA) were retrospectively included at a single Chinese tertiary medical centre. Clinical data were reviewed for these cases, including the maternal demographics, foetal ultrasound findings, CMA results and pregnancy outcomes. The deletion sizes of 17q12 ranged from 1.42 to 1.94 Mb. The deletion had arisen de novo in 10 cases and inherited from one of the parents in one case. Variable kidney abnormalities were found by ultrasound in all of the cases, with bilateral or unilateral hyperechogenic kidneys being the most common findings. This study indicates that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and prenatal testing with CMA should be offered to the foetal cases of hyperechogenic kidneys. Impact statement What is already known on this subject? 17q12 deletion syndrome is a cause of renal abnormalities, maturity-onset diabetes of the young and neurodevelopmental disorders. Prenatal diagnosis has been reported in several isolated cases with the use of microarray-based technologic means. What do the results of this study add? The results provide further evidence that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and genetic testing should be offered to foetal cases with hyperechogenic kidneys. A rare prenatal case of 17q12 deletion with multiple structural malformations and anhydramnios is presented. What are the implications of these findings for clinical practice and/or further research? There should be a high index of suspicion of carriers in parents when 17q12 deletion is confirmed prenatally. An extremely wide phenotype spectrum of this deletion should be emphasised in the prenatal counselling.


Assuntos
Anormalidades Múltiplas/diagnóstico , Testes Genéticos/métodos , Deficiência Intelectual/diagnóstico , Rim/embriologia , Adulto , Amniocentese , Deleção Cromossômica , Cromossomos Humanos Par 17 , Feminino , Humanos , Rim/diagnóstico por imagem , Medição da Translucência Nucal , Gravidez , Estudos Retrospectivos , Adulto Jovem
20.
Arch Pediatr ; 26(2): 102-107, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638765

RESUMO

BACKGROUND AND OBJECTIVES: Sanjad-Sakati syndrome (SSS; OMIM 241410) is a rare autosomal recessive disorder found almost exclusively in people of Arab origin. It is characterized by congenital hypoparathyroidism, severe prenatal and postnatal growth retardation, and distinct facial dysmorphism. The molecular pathology of this syndrome was shown to be due to a mutation in the tubulin-specific chaperone E (TBCE) gene in chromosomal area 1q42-q43. We aimed to detect and confirm the common mutation responsible for SSS in Tunisian patients and review the literature in order to create a set of clinical diagnostic criteria that might provide appropriate indications for molecular testing. METHODS: Three Tunisian patients with clinical feature of SSS were examined via direct Sanger sequencing of exon 3 of the TBCE gene. RESULTS: Mutation analysis of the TBCE gene revealed the common 12-bp (155-166del) deletion in three new patients, thus raising the number of reported SSS patients to 73. Reviewing the literature, we suggest a scoring system that assigns one point each for major criteria and one half point for minor criteria. INTERPRETATION AND CONCLUSIONS: SSS is an autosomal recessive disorder found in the Middle Eastern population with an estimated incidence of 1 per 40,000-100,000 live births in Saudi Arabia. Reviewing the literature on both its clinical and biochemical characteristics, we suggest for the first time, based on defined major and minor SSS criteria, a clinical scoring system for the diagnosis of SSS. On the one hand, an established scoring system will provide appropriate indications for molecular testing and, on the other hand, reviewed data on SSS will help delineate the phenotype and draw a distinction between differential diagnoses.


Assuntos
Anormalidades Múltiplas/diagnóstico , Transtornos do Crescimento/diagnóstico , Hipoparatireoidismo/diagnóstico , Deficiência Intelectual/diagnóstico , Chaperonas Moleculares/genética , Osteocondrodisplasias/diagnóstico , Convulsões/diagnóstico , Anormalidades Múltiplas/genética , Consenso , Feminino , Marcadores Genéticos , Transtornos do Crescimento/genética , Humanos , Hipoparatireoidismo/genética , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Osteocondrodisplasias/genética , Convulsões/genética , Deleção de Sequência , Tunísia
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