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1.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945686

RESUMO

This study evaluates a family with two siblings having severe growth retardation and facial dysmorphism, born to consanguineous normal healthy parents. Affymetrix CytoScan 750K microarray showed a 34-Mb pericentric homozygous region on chromosome 6 for both siblings. CUL7 was one of the 141 genes present in this region. Sanger sequencing of CUL7 gene detected a 2-bp novel deletion in the 15th exon (c.2943_2944delCT of the cDNA). This deletion leads to a frameshift and a premature termination signal much upstream of the wild-type termination signal, leading to a nonsense mediated decay of the mRNA. CUL7 protein plays an important role in formation of 3M complex, ubiquitination, microtubule dynamics and cell cycle regulation. Mutations in CUL7 gene is known to cause a rare 3M syndrome. Information about the novel mutation has been accepted in the ClinVar database with rs1064792895.


Assuntos
Proteínas Culina/genética , Nanismo/genética , Nanismo/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Mutação , Coluna Vertebral/anormalidades , Criança , Pré-Escolar , Consanguinidade , Feminino , Humanos , Masculino , Prognóstico , Irmãos , Coluna Vertebral/patologia
2.
Medicine (Baltimore) ; 98(8): e14524, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813157

RESUMO

RATIONALE: Trio family-based whole exome sequencing (WES) is a powerful tool in the diagnosis of rare neurodevelopmental diseases, even in patients with the unclear diagnosis. There have been previous reports of variants in the phosphatidylinositol glycan anchor biosynthesis class T (PIGT) gene associated with multiple congenital anomalies, with a total of 14 affected individuals across 8 families. PATIENT CONCERNS: An 18-month-old boy of Greek ancestry presented with global developmental delay, generalized tonic-clonic seizures, hypotonia, renal cysts, esotropia, bilateral undescended testes, bilateral vesicoureteric reflux, marked cardiac dextroposition, bilateral talipes equinovarus, and dysmorphic features. DIAGNOSIS: WES revealed 2 compound heterozygous variants in the PIGT gene, c.[494-2A>G]; [547A>C]/p.[Asp122Glyfs*35]; [Thr183Pro]. The splicing mutation was demonstrated to lead to the skipping of exon 4. INTERVENTIONS: Seizures, infections, and other main symptoms were treated. OUTCOMES: The patient died at 2 years of age before the molecular diagnosis was achieved. Genetic counseling has been offered to the family. LESSONS: Most of the clinical features of the patient are in agreement with the previously described PIGT cases corroborating the usefulness of WES as a diagnostic tool.


Assuntos
Anormalidades Múltiplas/genética , Aciltransferases/genética , Técnicas de Cultura de Células , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Evolução Fatal , Humanos , Lactente , Masculino , Hipotonia Muscular/genética , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Convulsões/genética , Síndrome , Sequenciamento Completo do Exoma/métodos
3.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
4.
Biomed Res Int ; 2018: 4032543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581852

RESUMO

Joubert syndrome (JBTS) is a clinically and genetically heterogeneous group of ciliary diseases. To date, 34 subtypes of JBTS have been classified due to different causative genes or extra clinical features. Most of them are autosomal recessive, while only the subtype 10 (JBTS10) is a quite rare X-linked recessive disorder caused by OFD1 mutations with few reports. In this study, by using whole exome sequencing (WES), a novel OFD1 splicing mutation (c.2488+2T>C) was identified in a male fetus with suspected Dandy-Walker variant (DWV) and syndactyly, for whom abnormal karyotype and pathogenic CNV have been excluded. This mutation was inherited from the mother who has experienced two similar pregnancies before. An abnormal skipping of exon 18 in OFD1 mRNA was confirmed by RT-PCR and sequencing. Result from quantitative RT-PCR also showed that total OFD1 mRNA in the index fetus was significantly lower than the control. After a combined analysis of genetic testing results and genotype-phenotype correlations, the novel mutation c.2488+2T>C in OFD1 was considered to be the genetic cause for the affected fetus. Thus the diagnosis should be JBTS10 rather than the primary clinical diagnosis of DWV. We report the first prenatal case of JBTS10 in Chinese population, which not only helps the family to predict recurrence risks for future pregnancies but also provides more information for understanding such a rare disease. The results also present evidence that WES is an effective method in prenatal diagnosis for those fetuses with Joubert syndrome.


Assuntos
Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Síndrome de Dandy-Walker/genética , Feto/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Mutação/genética , Proteínas/genética , Processamento de RNA/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Exoma/genética , Éxons/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Linhagem , Gravidez , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Exoma/métodos
5.
Neonatal Netw ; 37(4): 212-217, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30567918

RESUMO

Congenital myopathy is an uncommon neonatal disorder that can manifest in the neonatal period with severe features. Presentation with signs of global hypotonia and respiratory insufficiency are among the classic findings. Rapid diagnosis is essential for medical management and family support. This case study reviews the presentation of hypotonia in the newborn, followed by a path to a diagnosis of nemaline myopathy in the form of an ACTA-1 mutation. This review can aid the clinician in the diagnosis of patients in whom hypotonia is present at birth. Included is a discussion of the incidence, pathophysiology, diagnosis, and management of this devastating disease.


Assuntos
Hipotonia Muscular/genética , Hipotonia Muscular/enfermagem , Miopatias da Nemalina/genética , Miopatias da Nemalina/enfermagem , Enfermagem Neonatal/educação , Enfermagem Neonatal/normas , Enfermeiras Neonatologistas/educação , Currículo , Educação Continuada em Enfermagem , Feminino , Humanos , Recém-Nascido , Masculino , Mutação , Guias de Prática Clínica como Assunto
6.
Rev. neurol. (Ed. impr.) ; 67(8): 298-302, 16 oct., 2018. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-175226

RESUMO

Introducción. Los trastornos de la biogénesis de los peroxisomas se deben a mutaciones en los genes PEX, que codifican peroxinas requeridas para la biogénesis peroxisómica. Clínicamente se expresan como un espectro del síndrome de Zellweger, y hay una amplia variedad fenotípica. Su diagnóstico se realiza bioquímicamente y la confirmación es molecular. El objetivo de este caso ilustrativo es resaltar la importancia de la clínica y de las pruebas bioquímicas en el abordaje de una enfermedad peroxisómica. Caso clínico. Niño de 3 años con hipotonía neonatal, retraso global del desarrollo y fallo de medro, con un patrón en resonancia cerebral de leucodistrofia hipomielinizante, en quien se había sospechado un trastorno de la biogénesis de los peroxisomas por encontrarse una variante de significado incierto en PEX5, pero su clínica, los estudios bioquímicos y el análisis crítico de las pruebas moleculares hacían improbable este diagnóstico. Se hace énfasis en el abordaje que debería tenerse cuando se sospecha un trastorno del espectro del síndrome de Zellweger. Conclusión. En el caso descrito se sospechó un trastorno de la biogénesis de los peroxisomas por una secuenciación exómica que, al analizarse críticamente junto con la clínica y los hallazgos bioquímicos, hacía muy poco probable una enfermedad peroxisómica. Cuando se tiene sospecha clínica y por neuroimágenes, el abordaje diagnóstico principal debe partir del análisis bioquímico. Aunque la confirmación es molecular, estas pruebas deben interpretarse con precaución


Introduction. Peroxisomal biogenesis disorders are due to mutations in the PEX genes, which code for peroxins that are required for peroxisomal biogenesis. Clinically, they are expressed as a Zellweger syndrome spectrum, and there is a wide phenotypic variety. They are diagnosed biochemically, and confirmation is molecular. The aim of this illustrative case is to highlight the importance of the clinical features and biochemical testing in the management of a peroxisomal disease. Case report. A 3-year-old boy with neonatal hypotonia, overall developmental delay and failure to thrive and a pattern of hypomyelinating leukodystrophy in brain resonance. The suspected diagnosis was a disorder affecting the biogenesis of the peroxisomes due to having found a variant with an uncertain meaning in PEX5. The clinical features, the biochemical studies and critical analysis, however, made this diagnosis unlikely. Emphasis is placed on the management that must be applied when a Zellweger syndrome spectrum is suspected. Conclusion. In the case reported here, a peroxisomal biogenesis disorder was suspected owing to an exome sequencing which, on being critically analysed together with the clinical features and the biochemical findings, made a peroxisomal disease very unlikely. In cases of clinical suspicion, backed up by neuroimaging, the main diagnostic management must be based on the biochemistry analysis. Although confirmation is molecular, these tests must be interpreted with caution


Assuntos
Humanos , Masculino , Pré-Escolar , Peroxissomos/genética , Bioquímica , Hipotonia Muscular/genética , Síndrome de Zellweger/diagnóstico , Transtornos Peroxissômicos/sangue , Transtornos Peroxissômicos/urina , Espectroscopia de Ressonância Magnética/métodos , Polimicrogiria/diagnóstico por imagem , Neuroimagem , Transtornos Peroxissômicos/diagnóstico
7.
BMC Neurol ; 18(1): 150, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30236064

RESUMO

BACKGROUND: Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2) is an extremely rare disease caused by a heterozygous mutation in the PPP1CB gene on chromosome 2p23. The syndrome causes not only numerous dysmorphic features but also hypotonia, developmental delay, and even intellectual disability. We report the first case of NSLH2 in Asia and the 16th in the world. Moreover, the first case of PPP1CB-related infantile spasms. The clinical and therapeutic significance is outlined in this paper. CASE PRESENTATION: We found a male infant presented with severe intractable epileptic spasms. Although certain clinical features of somatic dysmorphism were noted, numerous laboratory and neuroimaging studies failed to identify the cause. To determine the underlying etiology, whole-exome sequencing was conducted. We identified a de novo heterozygous mutation, NM_206876.1: c.548A > C (p.Glu183Ala), in the PPP1CB gene. His seizures were almost refractory to conventional antiepileptic drugs but relative seizure control was eventually achieved with a ketogenic diet. CONCLUSION: This result expands the clinical spectrum of NSLH2 and strengthens the association between the PPP1CB gene and epileptic seizures. Furthermore, we suggest that the ketogenic diet can offer seizure reduction in particular drug-resistant epilepsy syndromes. Additional studies are warranted to clarify the pathogenic mechanisms underlying this PPP1CB mutation in epileptic seizures.


Assuntos
Doenças do Recém-Nascido/genética , Proteína Fosfatase 1/genética , Espasmos Infantis/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Dieta Cetogênica , Heterozigoto , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Mutação , Neuroimagem , Espasmos Infantis/dietoterapia
8.
Int J Pediatr Otorhinolaryngol ; 109: 96-100, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29728193

RESUMO

Deletion of 2q24.2 is a rare cytogenetic aberration in patients, exhibiting heterogeneous clinical features, and common phenotypes included developmental delay, intellectual disability, hypotonia, and mild dysmorphic features. Hearing impairment and anal atresia are rarely described. Here we described a 9-month-old female patient with hypotonia in all four limbs, developmental delay, and intellectual disability. In addition, congenital anal atresia was diagnosed and treated after birth, and hearing impairment was found in right ear. Single nucleotide polymorphisms (SNP) array detected a 5.2 Mb deletion on 2q24.2q24.3, including 19 genes (ITGB6; TBR1; SLC4A10; KCNH7 SCN3A; SCN2A et al.). Among these genes, it is affirmative that TBR1 is a causative gene for intellectual disability; however, the pathogenic genes of other phenotypes remain unclear. We briefly review the knowledge of genes likely involved in these clinical features, including hearing impairment, anal atresia, and developmental delay.


Assuntos
Anus Imperfurado/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Perda Auditiva/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Cromossomos Humanos Par 2 , Feminino , Humanos , Lactente , Fenótipo , Proteínas com Domínio T/genética
9.
J Appl Genet ; 59(3): 281-289, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845577

RESUMO

Craniosynostosis (CS) refers to the group of craniofacial malformations characterized by the premature closure of one or more cranial sutures. The disorder is clinically and genetically heterogeneous and occurs usually as an isolated trait, but can also be syndromic. In 30-60% of patients, CS is caused by known genetic factors; however, in the rest of the cases, causative molecular lesions remain unknown. In this paper, we report on a sporadic male patient affected by complex CS (metopic and unilateral lambdoid synostosis), muscular hypotonia, psychomotor retardation, and facial dysmorphism. Since a subset of CS results from submicroscopic chromosomal aberrations, we performed array comparative genomic hybridization (array CGH) in order to identify possibly causative copy-number variation. Array CGH followed by breakpoint sequencing revealed a previously unreported de novo 1.26 Mb duplication at chromosome 1q22-q23.1 that encompassed two genes involved in osteoblast differentiation: BGLAP, encoding osteocalcin (OCN), and LMNA, encoding lamin A/C. OCN is a major component of bone extracellular matrix and a marker of osteogenesis, whereas mutations in LMNA cause several genetic disorders called laminopathies, including mandibuloacral dysostosis (MAD) that manifests with low bone mass, severe bone deformities, and delayed closure of the cranial sutures. Since LMNA and BGLAP overexpression promote osteoblast differentiation and calcification, phenotype of our patient may result from misexpression of the genes. Based on our findings, we hypothesize that both LMNA and BGLAP may be implicated in the pathogenesis of CS in humans. However, further studies are needed to establish the exact pathomechanism underlying development of this defect.


Assuntos
Craniossinostoses/genética , Duplicação Gênica , Lamina Tipo A/genética , Hipotonia Muscular/genética , Osteocalcina/genética , Transtornos Psicomotores/genética , Diferenciação Celular , Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Anormalidades Craniofaciais/diagnóstico , Humanos , Lactente , Masculino , Osteoblastos/metabolismo
10.
J Genet ; 97(1): 205-211, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29666339

RESUMO

Emanuel syndrome is caused due to an additional derivative chromosome 22 and is characterized by severe intellectual disability, microcephaly, failure to thrive, preauricular tags or pits, ear anomalies, cleft or high-arched palate, micrognathia, kidney abnormalities, congenital heart defects and genital abnormalities in males. In 99% of the cases, one of the parents is a carrier of balanced translocation between chromosomes 11 and 22. It occurs due to malsegregation of the gametes with 3:1 segregation. In this case series, we describe four patients with diverse manifestations of this condition. The craniosynostosis observed in one case is a novel finding which has never been reported previously. This study aims to widen the phenotypic spectrum of Emanuel syndrome and provide cytogenetic microarray based breakpoints in two of the cases, thus supporting close clustering of the breakpoints of this common recurrent chromosomal rearrangement.


Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Criança , Transtornos Cromossômicos/diagnóstico por imagem , Fissura Palatina/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Cariotipagem , Masculino , Hipotonia Muscular/diagnóstico por imagem , Fenótipo
11.
Gene ; 660: 13-17, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29572195

RESUMO

Biallelic UNC80 mutations cause infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2), which is characterized by hypotonia, developmental delay (DD)/intellectual disability (ID), intrauterine growth retardation, postnatal growth retardation and characteristic facial features. We report two unrelated Chinese patients with compound heterozygous UNC80 mutations inherited from their parents, as identified by whole-exome sequencing (WES). Mutations c.3719G>A (p.W1240*)/c.4926_4937del (p.N1643_L1646del) and c.4963C>T (p.R1655C)/c.8385C>G (p.Y2795*) were identified in patient 1 and patient 2, respectively. Although both patients presented with DD/ID and hypotonia, different manifestations also occurred. Patient 1 presented with infantile hypotonia, epilepsy and hyperactivity without growth retardation, whereas patient 2 presented with persistent hypotonia, growth retardation and self-injury without epilepsy. Furthermore, we herein summarize the genotypes and phenotypes of patients with UNC80 mutations reported in the literature, revealing that IHPRF2 is a phenotypically heterogeneous disease. Common facial dysmorphisms include a thin upper lip, a tented upper lip, a triangular face, strabismus and microcephaly. To some extent, the manifestations of IHPRF2 mimic those of Angelman syndrome (AS)-like syndromes.


Assuntos
Anormalidades Múltiplas , Alelos , Proteínas de Transporte/genética , Deficiência Intelectual , Proteínas de Membrana/genética , Hipotonia Muscular , Mutação , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Grupo com Ancestrais do Continente Asiático , Criança , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/genética , Hipotonia Muscular/patologia
12.
Mol Genet Genomic Med ; 6(3): 393-400, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29573576

RESUMO

BACKGROUND: Patients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co-occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development. METHODS: Patients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein. RESULTS: We give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found. CONCLUSION: Homology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.


Assuntos
Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Adolescente , Agenesia do Corpo Caloso/genética , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Corpo Caloso/patologia , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Hipotonia Muscular/genética , Mutação , Sequenciamento Completo do Exoma/métodos
13.
Brain Dev ; 40(5): 410-414, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29395664

RESUMO

Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinical symptoms are severe cortical visual impairment and Rett-like phenotype such as involuntary movements and regression. This is the first report that patients with HECW2 mutation could show Rett-like feature.


Assuntos
Síndrome de Rett/genética , Ubiquitina-Proteína Ligases/genética , Córtex Visual/patologia , Adolescente , Encéfalo/patologia , Encefalopatias/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Testes Genéticos , Humanos , Deficiência Intelectual/genética , Japão , Proteína 2 de Ligação a Metil-CpG/genética , Hipotonia Muscular/genética , Fenótipo , Síndrome de Rett/fisiopatologia , Ubiquitina-Proteína Ligases/fisiologia , Transtornos da Visão/genética , Transtornos da Visão/fisiopatologia
14.
Brain Dev ; 40(1): 53-57, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28728837

RESUMO

We report an 11-month-old boy with acetazolamide-responsive epileptic apnea and inherited glycosylphosphatidylinositol (GPI)-anchor deficiency who presented with decreased serum alkaline phosphatase associated with compound PIGT mutations. The patient exhibited congenital anomalies, severe intellectual disability, and seizures, including epileptic apnea with epileptiform discharges from bilateral temporal areas. Brain magnetic resonance imaging revealed delayed myelination and progressive atrophy of the brainstem, cerebellum, and cerebrum. Whole-exome sequencing revealed compound heterozygous mutations in PIGT (c.250G>T, p.Glu84X and c.1096G>T, p.Gly366Trp), which encodes a subunit of the GPI transamidase complex. Flow cytometry revealed decreased expression of CD16 (a GPI anchor protein) on granulocytes, supporting the putative pathogenicity of the mutations. Phenobarbital, clonazepam, and potassium bromide decreased the frequency of tonic seizure and acetazolamide decreased epileptic apnea. To our knowledge, this is the first reported case of intractable seizures accompanied by epileptic apnea associated with GPI anchor deficiency and a compound PIGT mutation.


Assuntos
Apneia/genética , Epilepsia/genética , Glicosilfosfatidilinositóis/deficiência , Anormalidades Múltiplas/genética , Aciltransferases/genética , Aciltransferases/metabolismo , Apneia/metabolismo , Atrofia , Deficiências do Desenvolvimento/genética , Epilepsia/metabolismo , Glicosilfosfatidilinositóis/genética , Glicosilfosfatidilinositóis/metabolismo , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Mutação , Convulsões/genética
15.
Biochem Biophys Res Commun ; 495(2): 1730-1737, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29217198

RESUMO

Deficiency of the mitochondrial enzyme succinyl COA ligase (SUCL) is associated with encephalomyopathic mtDNA depletion syndrome and methylmalonic aciduria. This disorder is caused by mutations in both SUCL subunits genes: SUCLG1 (α subnit) and SUCLA2 (ß subnit). We report here, two Tunisian patients belonging to a consanguineous family with mitochondrial encephalomyopathy, hearing loss, lactic acidosis, hypotonia, psychomotor retardation and methylmalonic aciduria. Mutational analysis of SUCLG1 gene showed, for the first time, the presence of c.41T > C in the exon 1 at homozygous state. In-silico analysis revealed that this mutation substitutes a conserved methionine residue to a threonine at position 14 (p.M14T) located at the SUCLG1 protein mitochondrial targeting sequence. Moreover, these analysis predicted that this mutation alter stability structure and mitochondrial translocation of the protein. In Addition, a decrease in mtDNA copy number was revealed by real time PCR in the peripheral blood leukocytes in the two patients compared with controls.


Assuntos
Encefalomiopatias Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/genética , Mutação de Sentido Incorreto , Succinato-CoA Ligases/deficiência , Succinato-CoA Ligases/genética , Acidose Láctica/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Substituição de Aminoácidos , Pré-Escolar , Consanguinidade , DNA Mitocondrial/genética , Estabilidade Enzimática/genética , Feminino , Dosagem de Genes , Perda Auditiva/genética , Homozigoto , Humanos , Lactente , Masculino , Hipotonia Muscular/genética , Succinato-CoA Ligases/química
16.
Am J Med Genet A ; 176(1): 201-208, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28960836

RESUMO

We report the case of a 7-year-old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.


Assuntos
Apraxias/diagnóstico , Apraxias/genética , Proteínas de Transporte/genética , Mutação da Fase de Leitura , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Proteínas Nucleares/genética , Fenótipo , Anormalidades Múltiplas , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Hibridização Genômica Comparativa , Facies , Estudos de Associação Genética , Loci Gênicos , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
17.
Mol Genet Genomic Med ; 6(1): 109-113, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29179256

RESUMO

BACKGROUND: Synaptojanin 1 is encoded by the SYNJ1(MIM 604297) and plays a major role in phosphorylation and recycling of synaptic vesicles. Mutation of SYNJ1 is associated with two distinct phenotypes; a known homozygous missense mutation (p.Arg258Gln) associated with early-onset Parkinson disease (MIM 615530), whereas mutation with complete loss of SYNJ1 function result in a lethal neurodegenerative disease with intractable seizure and tauopathies (MIM 617389). METHODS: We report two related children from consanguineous family presented with intractable seizure, profound developmental delay, failure to thrive, acquired microcephaly, and hypotonia. The brain MRI is normal and EEG showed hypsarrhythmia. RESULT: The diagnosis was achieved via whole-genome sequencing which showed homozygous mutation in SYNJ1 (c.709C>T, p.Gln237*). CONCLUSION: A clinical pattern of neonatal-onset intractable seizure, profound developmental delay, muscular hypotonia, hypsarrhythmia, and no focal abnormality of brain MRI should prompt initiation of molecular genetic analysis of SYNJ1. Establishment of the diagnosis permits genetic counseling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.


Assuntos
Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/fisiologia , Encéfalo/fisiopatologia , Pré-Escolar , Consanguinidade , Feminino , Genes Recessivos , Humanos , Recém-Nascido , Masculino , Microcefalia/genética , Hipotonia Muscular/genética , Mutação , Doenças Neurodegenerativas/genética , Linhagem , Fenótipo , Monoéster Fosfórico Hidrolases/metabolismo , Convulsões/diagnóstico , Convulsões/genética , Vesículas Sinápticas/genética , Tauopatias/genética
18.
Am J Med Genet A ; 176(1): 209-213, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29130599

RESUMO

Over the past decade chromosomal microarray analysis (array CGH) has allowed the discovery of many novel disease-causing recurrent microdeletion and microduplication syndromes. Here we present three unrelated patients (2F; 1M) from three different countries, with developmental delay, intellectual disability, hypotonia, fatigue, and highly similar dysmorphic facial features. Shared facial features are a broad and wide forehead, similar shape of the eyes with long palpebral fissures, a bulbous tip of the nose and thick lips. Intellectual disabilities range from mild to severe. One female patient and the male patient were investigated in childhood for significant hypotonia thought to be suggestive of a neuromuscular disorder. The two female patients also show excessive fatigue with daytime somnolence. The patients carry overlapping, de novo microdeletions of chromosome 17q11.2, with sizes ranging from 0.97 to 1.18 Mb. The smallest region of overlap (SRO) between the three patients is 863 kb, and contains seven genes, five of which are predicted to exhibit haploinsufficiency (CDK5R1, PSMD11, RHOT1, SUZ12, ZNF207) although none has yet been associated with genetic syndromes. Of these five genes, the brain expressed CDK5R1 gene constitutes a good candidate for the developmental delay, while the RHOT1 gene, involved in mitochondrial trafficking, might underlie the hypotonia and the excessive fatigue.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Estudos de Associação Genética , Fenótipo , Adolescente , Criança , Hibridização Genômica Comparativa , Facies , Fadiga/diagnóstico , Fadiga/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética
19.
Int J Hematol ; 108(2): 208-212, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29264741

RESUMO

Variant chromosomal translocations associated with t(8;21) are observed in 3-4% of acute myeloid leukemia (AML) cases with a RUNX1-RUNX1T1 fusion gene. However, the molecular events that occur in variants of t(8;21) are not well characterized. In the present study, we report genetic features of a variant three-way translocation of t(8;12;21)(q22;p11;q22) in a patient with AML. In this patient, leukemia cells lacked azurophilic granules, which does not correspond with the classic features of t(8;21). RNA-seq analysis revealed that TM7SF3 at 12p11 was fused to VPS13B at 8q22 and VPS13B to RUNX1, in addition to RUNX1-RUNX1T1. VPS13B was located near RUNX1T1 and both were localized at the same chromosomal bands. The reading frames of TM7SF3 and VPS13B did not match to those of VPS13B and RUNX1, respectively. Disruption of VPS13B causes Cohen syndrome, which presents intermittent neutropenia with a left-shifted granulopoiesis in the bone marrow. Disruption of VPS13B may thus cause the unusual features of RUNX1-RUNX1T1 leukemia. Our case indicates that rearrangement of VPS13B may be additional genetic events in variant t(8;21).


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Dedos/anormalidades , Rearranjo Gênico/genética , Deficiência Intelectual/genética , Leucemia Mieloide Aguda/genética , Microcefalia/genética , Hipotonia Muscular/genética , Miopia/genética , Obesidade/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Translocação Genética/genética , Proteínas de Transporte Vesicular/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Pessoa de Meia-Idade , Degeneração Retiniana
20.
Obes Rev ; 19(1): 62-80, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29024387

RESUMO

Obesity rates have escalated to the point of a global pandemic with varying prevalence across ethnic groups. These differences are partially explained by lifestyle factors in addition to genetic predisposition to obesity. This review provides a comprehensive examination of the ethnic differences in the genetic architecture of obesity. Using examples from evolution, heritability, admixture, monogenic and polygenic studies of obesity, we provide explanations for ethnic differences in the prevalence of obesity. The debate over definitions of race and ethnicity, the advantages and limitations of multi-ethnic studies and future directions of research are also discussed. Multi-ethnic studies have great potential to provide a better understanding of ethnic differences in the prevalence of obesity that may result in more targeted and personalized obesity treatments.


Assuntos
Grupos Étnicos/genética , Predisposição Genética para Doença , Obesidade/etnologia , Obesidade/genética , Síndrome de Alstrom/etnologia , Síndrome de Alstrom/genética , Síndrome de Bardet-Biedl/etnologia , Síndrome de Bardet-Biedl/genética , Deficiências do Desenvolvimento/etnologia , Deficiências do Desenvolvimento/genética , Dedos/anormalidades , Humanos , Deficiência Intelectual/etnologia , Deficiência Intelectual/genética , Estilo de Vida , Microcefalia/etnologia , Microcefalia/genética , Herança Multifatorial , Hipotonia Muscular/etnologia , Hipotonia Muscular/genética , Miopia/etnologia , Miopia/genética , Síndrome de Prader-Willi/etnologia , Síndrome de Prader-Willi/genética , Prevalência , Degeneração Retiniana
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