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1.
N Engl J Med ; 384(25): 2406-2417, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161705

RESUMO

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).


Assuntos
Anormalidades Múltiplas/genética , Ataxia/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/fisiologia , Células Cultivadas , Cerebelo/anormalidades , Simulação por Computador , Face/anormalidades , Feminino , Fibroblastos , Genes Recessivos , Humanos , Lactente , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
2.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071723

RESUMO

Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance.


Assuntos
Anormalidades Múltiplas/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Megalencefalia/genética , Transtornos Mentais/genética , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 1/genética , Estudo de Associação Genômica Ampla , Humanos , Microcefalia/genética , Doenças Neurodegenerativas/genética , Transtornos do Neurodesenvolvimento/genética , Esquizofrenia/genética
3.
Am J Hum Genet ; 108(6): 1053-1068, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33909990

RESUMO

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.


Assuntos
Anormalidades Múltiplas/patologia , Adenosina Trifosfatases/genética , Anormalidades Craniofaciais/patologia , Metilação de DNA , Epigênese Genética , Transtornos do Crescimento/patologia , Comunicação Interventricular/patologia , Mutação , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Anormalidades Múltiplas/genética , Estudos de Casos e Controles , Estudos de Coortes , Anormalidades Craniofaciais/genética , Feminino , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Comunicação Interventricular/genética , Humanos , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/genética
4.
Mol Genet Genomics ; 296(4): 809-821, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33866394

RESUMO

Holt-Oram syndrome (HOS) is a rare disorder characterized by cardiac and upper-limb defects. Pathogenic variants in TBX5-a gene encoding a transcription factor important for heart and skeletal development-are the only known cause of HOS. Here, we present the identification and functional analysis of two novel TBX5 pathogenic variants found in two individuals with HOS presenting distinct phenotypes. The individual with the c.905delA variant has a severe cardiac phenotype but mild skeletal defects, unlike the individual with the c.246_249delGATG variant who has no cardiac problems but severe upper limbs malformations, including phocomelia. Both frameshift variants, c.246_249delGATG and c.905delA, generate mRNAs harbouring premature stop codons which, if not degraded by nonsense mediated decay, will lead to the production of shorter TBX5 proteins, p.Gln302Argfs*92 and p.Met83Phefs*6, respectively. Immunocytochemistry results suggest that both mutated proteins are produced and furthermore, like the wild-type protein, p.Gln302Argfs*92 mutant appears to be mainly localized in the nucleus, in contrast with p.Met83Phefs*6 mutant that displays a higher level of cytoplasmic localization. In addition, luciferase activity analysis revealed that none of the TBX5 mutants are capable of transactivating the NPPA promoter. In conclusion, our results provide evidence that both pathogenic variants cause a severe TBX5 loss-of-function, dramatically reducing its biological activity. The absence of cardiac problems in the individual with the p.Met83Phefs*6 variant supports the existence of other mechanisms/genes underlying the pathogenesis of HOS and/or the existence of an age-related delay in the development of a more serious cardiac phenotype. Further studies are required to understand the differential effects observed in the phenotypes of both individuals.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Comunicação Interatrial/genética , Comunicação Interatrial/patologia , Deformidades Congênitas das Extremidades Inferiores/genética , Deformidades Congênitas das Extremidades Inferiores/patologia , Proteínas com Domínio T/genética , Deformidades Congênitas das Extremidades Superiores/genética , Deformidades Congênitas das Extremidades Superiores/patologia , Adulto , Idoso de 80 Anos ou mais , Células Cultivadas , Análise Citogenética , Análise Mutacional de DNA , Estudos de Associação Genética , Heterogeneidade Genética , Células HEK293 , Humanos , Masculino , Mutação/fisiologia , Fenótipo , Proteínas com Domínio T/fisiologia
5.
Hum Genet ; 140(7): 1061-1076, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33811546

RESUMO

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.


Assuntos
Anormalidades Múltiplas/genética , Caderinas/genética , Adesão Celular/genética , Anormalidades Craniofaciais/genética , Deformidades Congênitas do Pé/genética , Variação Genética/genética , Deformidades Congênitas da Mão/genética , Hipertelorismo/genética , Sequência de Aminoácidos , Movimento Celular/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo
6.
BMC Neurol ; 21(1): 180, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910511

RESUMO

BACKGROUND: The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients. CASE PRESENTATION: A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant-NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)-in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes. CONCLUSIONS: Due to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the "RABopathies" term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Córnea/anormalidades , Hipogonadismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Óptica/genética , Proteínas rab3 de Ligação ao GTP/genética , Catarata/genética , Pré-Escolar , Feminino , Humanos , Irã (Geográfico) , Masculino , Mutação , Linhagem , Splicing de RNA , Sequenciamento Completo do Exoma
7.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-33707360

RESUMO

Interstitial 6p25.1p24.3 microdeletions are rare events and a clear karyotype/phenotype correlation has not yet been determined. In this study, we present the clinical and molecular description of a child with a de novo 6p25.1p24.3 microdeletion, characterized by array-CGH, associated with mild intellectual disability, facial dysmorphisms, hypopigmentation of the skin of the abdomen, heart defects, mild pontine hypoplasia and hypotonia. This deleted region contains 14 OMIM genes (NRN1, F13A1, RREB1, SSR1, RIOK1, DSP, BMP6, TXNDC5, BLOC1S5, EEF1E1, SLC35B3 and HULC). To the best of our knowledge until now only six cases have been reported presenting an interstitial microdeletion, but a unique case carries a deleted region containing the same genes of our patient. We compared clinical features and genetic data with that of the previously reported patient. We also analysed the gene content of the deleted region to investigate the possible role of specific genes in the clinical phenotype of our patient.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 6 , Anormalidades Múltiplas/diagnóstico por imagem , Adolescente , Pré-Escolar , Feminino , Humanos , Fenótipo
8.
Neurol India ; 69(1): 181-183, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642297

RESUMO

The chromosome 22q11.2 region is highly susceptible to both microdeletions and microduplications that have been known to be responsible for multiple congenital anomaly disorders. We describe a patient of 22q11.2 duplication syndrome presenting with bilateral ptosis who has normal psychomotor development. Cranial magnetic resonance imaging and electromyography with repetitive nerve stimulation were normal. Chromosome microarray analysis was performed, and the patient was found to have a de novo 2.8 Mb duplication at 22q11.21. To our knowledge, bilateral ptosis and normal psychomotor development with 22q11.2 duplication syndrome has not been described. The 22q11.2 duplication syndrome should be considered in the differential diagnosis of ptosis. This case report contributes to an expanding clinical spectrum of patients with 22q11.2 duplication syndrome.


Assuntos
Anormalidades Múltiplas , Síndrome de DiGeorge , Anormalidades Múltiplas/genética , Duplicação Cromossômica , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Humanos , Síndrome
9.
Hum Genet ; 140(7): 1047-1060, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33721060

RESUMO

Mutations in proteins involved in cell division and chromosome segregation, such as microtubule-regulating, centrosomal and kinetochore proteins, are associated with microcephaly and/or short stature. In particular, the kinetochore plays an essential role in mitosis and cell division by mediating connections between chromosomal DNA and spindle microtubules. To date, only a few genes encoding proteins of the kinetochore complex have been identified as causes of syndromes that include microcephaly. We report a male patient with a rare de novo missense variant in NUF2, after trio whole-exome sequencing analysis. The patient presented with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect. NUF2 encodes a subunit of the NDC80 complex in the outer kinetochore, important for correct microtubule binding and spindle assembly checkpoint. The mutated residue is buried at the calponin homology (CH) domain at the N-terminus of NUF2, which interacts with the N-terminus of NDC80. The variant caused the loss of hydrophobic interactions in the core of the CH domain of NUF2, thereby impairing the stability of NDC80-NUF2. Analysis using a patient-derived lymphoblastoid cell line revealed markedly reduced protein levels of both NUF2 and NDC80, aneuploidy, increased micronuclei formation and spindle abnormality. Our findings suggest that NUF2 may be the first member of the NDC80 complex to be associated with a human disorder.


Assuntos
Anormalidades Múltiplas/genética , Aneuploidia , Proteínas de Ciclo Celular/genética , Transtornos Cromossômicos/genética , Segregação de Cromossomos , Mutação de Sentido Incorreto , Anormalidades Múltiplas/patologia , Adolescente , Estatura/genética , Linhagem Celular , Transtornos Cromossômicos/patologia , Proteínas do Citoesqueleto/genética , Regulação para Baixo , Transtornos do Crescimento/genética , Humanos , Masculino , Microcefalia/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Fuso Acromático/patologia , Ubiquitina/metabolismo , Sequenciamento Completo do Genoma
10.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669056

RESUMO

Warsaw breakage syndrome (WABS) is a genetic disorder characterized by sister chromatid cohesion defects, growth retardation, microcephaly, hearing loss and other variable clinical manifestations. WABS is due to biallelic mutations of the gene coding for the super-family 2 DNA helicase DDX11/ChlR1, orthologous to the yeast chromosome loss protein 1 (Chl1). WABS is classified in the group of "cohesinopathies", rare hereditary diseases that are caused by mutations in genes coding for subunits of the cohesin complex or protein factors having regulatory roles in the sister chromatid cohesion process. In fact, among the cohesion regulators, an important player is DDX11, which is believed to be important for the functional coupling of DNA synthesis and cohesion establishment at the replication forks. Here, we will review what is known about the molecular and cellular functions of human DDX11 and its role in WABS etiopathogenesis, even in light of recent findings on the role of cohesin and its regulator network in promoting chromatin loop formation and regulating chromatin spatial organization.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Cromátides/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , RNA Helicases DEAD-box/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Doenças Raras/metabolismo , Anormalidades Múltiplas/genética , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/genética , Cromátides/patologia , Cromatina/patologia , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos , RNA Helicases DEAD-box/genética , Replicação do DNA/genética , Regulação da Expressão Gênica/genética , Humanos , Mutação , Filogenia , Doenças Raras/congênito , Doenças Raras/enzimologia , Doenças Raras/fisiopatologia
11.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669083

RESUMO

Phelan McDermid syndrome (PMcD) is a neurogenetic disease associated with haploinsufficiency of the SHANK3 gene due to a spectrum of anomalies in the terminal region of the long arm of chromosome 22. SHANK3 is the abbreviation for SH3 domain and ankyrin repeat-containing protein, a gene that encodes for proteins of the postsynaptic density (PSD) of excitatory synapses. This PSD is relevant for the induction and plasticity of spine and synapse formation as a basis for learning processes and long-term potentiation. Individuals with PMcD present with intellectual disability, muscular hypotonia, and severely delayed or absent speech. Further neuropsychiatric manifestations cover symptoms of the autism spectrum, epilepsy, bipolar disorders, schizophrenia, and regression. Regression is one of the most feared syndromes by relatives of PMcD patients. Current scientific evidence indicates that the onset of regression is variable and affects language, motor skills, activities of daily living and cognition. In the case of regression, patients normally undergo further diagnostics to exclude treatable reasons such as complex-focal seizures or psychiatric comorbidities. Here, we report, for the first time, the case of a young female who developed progressive symptoms of regression and a dystonic-spastic hemiparesis that could be traced back to a comorbid multiple sclerosis and that improved after treatment with methylprednisolone.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Transtornos Cromossômicos/complicações , Metilprednisolona/administração & dosagem , Esclerose Múltipla/complicações , Regressão Psicológica , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Administração Intravenosa , Adulto , Transtorno do Espectro Autista/complicações , Doenças Autoimunes/líquido cefalorraquidiano , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Deleção Cromossômica , Transtornos Cromossômicos/líquido cefalorraquidiano , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/genética , Cromossomos Humanos 21-22 e Y/genética , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/líquido cefalorraquidiano , Proteínas do Tecido Nervoso/genética , Deleção de Sequência , Punção Espinal
12.
Genet Med ; 23(6): 1041-1049, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33531668

RESUMO

PURPOSE: Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. METHODS: Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. RESULTS: We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. CONCLUSION: IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Anormalidades Múltiplas/genética , Animais , Cerebelo/anormalidades , Anormalidades do Olho/genética , Proteínas Hedgehog , Humanos , Doenças Renais Císticas/genética , Monoéster Fosfórico Hidrolases/genética , Retina/anormalidades , Peixe-Zebra/genética
14.
Ned Tijdschr Geneeskd ; 1652021 01 21.
Artigo em Holandês | MEDLINE | ID: mdl-33560600

RESUMO

Introduction of new genetic test technologies in the last decade have accelerated genetic diagnosis in many medical specialties and have increased diagnostic yield considerably. SNP-arrays have been established as first tier diagnostic tools, more and more being replaced by next generation sequencing strategies, like targeted genomic panels and whole exome sequencing. We present the diagnostic work-up of a clinical case, a girl with congenital vertebral and rib anomalies. This case illustrates the complexity of genetic tests and the need for knowledge and experience to interpret the results. Intensive collaboration between pediatrician, clinical geneticist and laboratory specialist is mandatory, as is long-term commitment to involve parents in the diagnostic journey .


Assuntos
Anormalidades Múltiplas/diagnóstico , Testes Genéticos/métodos , Costelas/anormalidades , Coluna Vertebral/anormalidades , Sequenciamento Completo do Exoma/métodos , Anormalidades Múltiplas/genética , Criança , Feminino , Humanos
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(2): 138-140, 2021 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-33565066

RESUMO

OBJECTIVE: To explore the genetic basis for a child with unexplained global developmental delay (GDD), seizure, and facial deformity. METHODS: Whole exome sequencing (WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of the patient and his parents. RESULTS: WES revealed that the patient has carried a previously unreported de novo heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene, Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.4906C>T variant of KMT2A gene was predicted to be pathogenic (PVS1+ PS2+ PM2+PP3). CONCLUSION: The heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene probably underlay the disease in the child. Above finding has enriched the spectrum of pathogenic variants of the KMT2A gene.


Assuntos
Anormalidades Múltiplas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Humanos , Masculino , Síndrome
17.
Protein J ; 40(1): 68-77, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33389473

RESUMO

Mucopolysaccharidosis type I is a rare autosomal recessive genetic disease caused by deficient activity of α-L-iduronidase. As a consequence of low or absent activity of this enzyme, glycosaminoglycans accumulate in the lysosomal compartments of multiple cell types throughout the body. Mucopolysaccharidosis type I has been classified into 3 clinical subtypes, ranging from a severe Hurler form to the more attenuated Hurler-Scheie and Scheie phenotypes. Over 200 gene variants causing the various forms of mucopolysaccharidosis type I have been reported. DNA isolated from dried blood spot was used to sequencing of all exons of the IDUA gene from a patient with a clinical phenotype of severe mucopolysaccharidosis type I syndrome. Enzyme activity of α-L-iduronidase was quantified by fluorimetric assay. Additionally, a molecular dynamics simulation approach was used to determine the effect of the Ser633Trp mutation on the structure and dynamics of the α-L-iduronidase. The DNA sequencing analysis and enzymatic activity shows a c.1898C>G mutation associated a patient with a homozygous state and α-L-iduronidase activity of 0.24 µmol/L/h, respectively. The molecular dynamics simulation analysis shows that the p.Ser633Trp mutation on the α-L-iduronidase affect significant the temporal and spatial properties of the different structural loops, the N-glycan attached to Asn372 and amino acid residues around the catalytic site of this enzyme. Low enzymatic activity observed for p.Ser633Trp variant of the α-L-iduronidase seems to lead to severe mucopolysaccharidosis type I phenotype, possibly associated with a perturbation of the structural dynamics in regions of the enzyme close to the active site.


Assuntos
Anormalidades Múltiplas/genética , Dermatan Sulfato/química , Heparitina Sulfato/química , Iduronidase/química , Mucopolissacaridose I/genética , Mutação Puntual , Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/terapia , Domínio Catalítico , Cristalografia por Raios X , Dermatan Sulfato/metabolismo , Terapia de Reposição de Enzimas/métodos , Expressão Gênica , Heparitina Sulfato/metabolismo , Humanos , Iduronidase/genética , Iduronidase/metabolismo , Lactente , Masculino , Simulação de Dinâmica Molecular , Mucopolissacaridose I/enzimologia , Mucopolissacaridose I/patologia , Mucopolissacaridose I/terapia , Análise de Componente Principal , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Especificidade por Substrato
18.
Am J Med Genet A ; 185(3): 937-944, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33438842

RESUMO

Townes-Brocks syndrome (TBS) is a rare autosomal dominant syndrome, resulting from heterozygous variant in SALL1 gene and initially characterized by the triad of anorectal, thumb, and ear malformations. Essentially described in children, adult case reports are uncommon. Renal involvement has already been reported in adults and children but poorly described. Structural abnormalities such as hypodysplasia, unilateral renal agenesis or multicystic kidneys have been described, as well as functional impairment (with or without structural abnormalities) that may progress to end-stage renal disease (ESRD). We report two adult cases (mother and daughter) which exhibited kidney hypoplasia (focal and segmental glomerulosclerosis for the mother) and ESRD. The mother had unilateral polydactyly. TBS was suggested after physical examination. TBS diagnosis was confirmed by identification of a SALL1 variant. We conducted a literature review to evaluate the renal anomalies in TBS cases diagnosed in adulthood. Among 44 adult cases of TBS with genetic confirmation (including our two cases), 10 had kidney disease. The circumstances of renal failure diagnosis were incidental findings (2/5), gout (2/5), or repeated episodes of pyelonephritis (1/5). The median age of kidney disease diagnosis was 30 years old and of renal transplant 49 years old. The most frequent renal malformation was bilateral kidney hypoplasia. TBS is probably underestimated in adulthood and this report highlights that less obvious elements of morphology such as dysplasic ears can facilitate the diagnosis of TBS. As long-term prognosis of renal involvement in TBS patients remains largely unknown, a regular evaluation is required throughout life for patients.


Assuntos
Anus Imperfurado/complicações , Perda Auditiva Neurossensorial/complicações , Falência Renal Crônica/etiologia , Polegar/anormalidades , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Aborto Habitual/genética , Anus Imperfurado/diagnóstico , Anus Imperfurado/genética , Diagnóstico Tardio , Orelha Externa/anormalidades , Feminino , Síndrome do Dedo do Pé em Martelo/genética , Perda Auditiva Bilateral/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Falência Renal Crônica/cirurgia , Falência Renal Crônica/terapia , Transplante de Rim , Pessoa de Meia-Idade , Linhagem , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Polidactilia/genética , Diálise Renal , Distrofias Retinianas/genética
19.
BMC Pediatr ; 21(1): 46, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478401

RESUMO

BACKGROUND: Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare syndrome with only 27 cases reported worldwide so far, but none was reported in the population of Eastern Asia. Such extremely low prevalence might be contributed by misdiagnosis due to its similarities in ocular manifestations with facial cleft. In our study, we discovered the first case of MOTA syndrome in the population of China, with 2 novel FRAS1 related extracellular matrix 1 (FREM1) gene stop-gain mutations confirmed by whole exome sequencing. CASE PRESENTATION: A 12-year-old Chinese girl presented with facial cleft-like deformities including aberrant hairline, blepharon-coloboma and broad bifid nose since birth. Whole exome sequencing resulted in the identification of 2 novel stop-gain mutations in the FREM1 gene. Diagnosis of MOTA syndrome was then established. CONCLUSIONS: We discovered the first sporadic case of MOTA syndrome according to clinical manifestations and genetic etiology in the Chinese population. We have identified 2 novel stop-gain mutations in FREM1 gene which further expands the spectrum of mutational seen in the MOTA syndrome. Further research should be conducted for better understanding of its mechanism, establishment of an accurate diagnosis, and eventually the exploitation of a more effective and comprehensive therapeutic intervention for MOTA syndrome.


Assuntos
Anormalidades Múltiplas , Coloboma , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Criança , China , Feminino , Humanos , Manitoba , Mutação
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