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1.
Am J Hum Genet ; 105(5): 1048-1056, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668703

RESUMO

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.


Assuntos
Proteínas Ligadas por GPI/genética , Mutação de Sentido Incorreto/genética , Netrinas/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Criança , Pré-Escolar , Exoma/genética , Feminino , Homozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Linhagem , Sequenciamento do Exoma/métodos , Adulto Jovem
2.
Neurol Sci ; 42(7): 2737-2745, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33123925

RESUMO

At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.


Assuntos
Proteínas de Membrana/genética , Transtornos Peroxissômicos , Síndrome de Zellweger , Criança , Egito , Efeito Fundador , Humanos , Recém-Nascido , Mutação , Transtornos Peroxissômicos/diagnóstico por imagem , Transtornos Peroxissômicos/genética
3.
Clin Genet ; 98(6): 598-605, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32875576

RESUMO

Acid ceramidase deficiency is an orphan lysosomal disorder caused by ASAH1 pathogenic variants and presenting with either Farber disease or spinal muscle atrophy with progressive myoclonic epilepsy (SMA-PME). Phenotypic and genotypic features are rarely explored beyond the scope of case reports. Furthermore, the new biomarker C26-Ceramide requires validation in a clinical setting. We evaluated the clinical, biomarker and genetic spectrum of 15 Egyptian children from 14 unrelated families with biallelic pathogenic variants in ASAH1 (12 Farber and 3 SMA-PME). Recruited children were nine females/six males ranging in age at diagnosis from 13 to 118 months. We detected ASAH1 pathogenic variants in all 30 alleles including three novel variants (c.1126A>G (p.Thr376Ala), c.1205G>A (p.Arg402Gln), exon-5-deletion). Both total C26-Ceramide and its trans- isomer showed 100% sensitivity for the detection of ASAH1-related disorders in tested patients. A 10-year-old girl with the novel variant c.1205G>A (p.Arg402Gln) presented with a new peculiar phenotype of PME without muscle atrophy. We expanded the phenotypic spectrum of ASAH1-related disorders and validated the biomarker C26-Ceramide for supporting diagnosis in symptomatic patients.


Assuntos
Ceramidase Ácida/genética , Miopatias Distais/genética , Lipogranulomatose de Farber/complicações , Epilepsias Mioclônicas Progressivas/genética , Mioclonia/congênito , Pré-Escolar , Miopatias Distais/complicações , Miopatias Distais/patologia , Éxons/genética , Lipogranulomatose de Farber/genética , Lipogranulomatose de Farber/patologia , Feminino , Humanos , Lactente , Masculino , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Mutação/genética , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/patologia , Mioclonia/complicações , Mioclonia/genética , Mioclonia/patologia , Fenótipo
5.
Orphanet J Rare Dis ; 14(1): 209, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455396

RESUMO

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits. It manifests as multiple skin nodules, patchy hyperpigmentation, joint contractures and severe pain with movement. HFS shows some clinical overlap to Farber disease (FD), a recessive lysosomal storage disorder. RESULTS: We here present the largest cohort of independent, genetically confirmed HFS cases reported to date: in 19 unrelated index patients, we identified ten distinct homozygous ANTXR2 mutations, three of which are novel frame-shift variants. The associated clinical data are consistent with the previous hypothesis of non-truncating variants in the terminal exons 13-17 to confer rather mild phenotypes. The novel observation of gender-dependent disease manifestation in our cohort received support from a meta-analysis of all previously published cases. Untargeted blood-based metabolomics revealed patient samples to be biochemically distinct from control samples. Numerous potential HFS biomarker metabolites could thus be identified. We also found metabolomics profiles of HFS patients to highly overlap with those from FD patients. CONCLUSIONS: Our study extends the mutational spectrum for HFS, suggests gender-dependency of manifestation, and provides pilot metabolomics data for biomarker identification and a better pathomechanistic understanding of the disorder.


Assuntos
Síndrome da Fibromatose Hialina/genética , Adolescente , Adulto , Biomarcadores/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Lipogranulomatose de Farber/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação/genética , Receptores de Peptídeos/genética , Adulto Jovem
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