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1.
J Med Genet ; 60(10): 999-1005, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37185208

RESUMO

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.


Assuntos
Deficiência Intelectual , Microcefalia , Heterotopia Nodular Periventricular , Humanos , Encéfalo/diagnóstico por imagem , Genótipo , Deficiência Intelectual/genética , Fenótipo , Convulsões/genética
2.
Genet Med ; 25(1): 135-142, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36399134

RESUMO

PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.


Assuntos
Braquidactilia , Nanismo , Deficiência Intelectual , Anormalidades Musculoesqueléticas , Transtornos do Neurodesenvolvimento , Humanos , Transtornos do Neurodesenvolvimento/genética , Deficiência Intelectual/genética , Nanismo/genética , Obesidade/genética , Fenótipo , Proteína-Arginina N-Metiltransferases/genética
3.
J Med Genet ; 59(11): 1058-1068, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35232796

RESUMO

BACKGROUND: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. METHODS: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. RESULTS: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. CONCLUSION: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.


Assuntos
Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Transtornos do Neurodesenvolvimento , Humanos , Micrognatismo/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Síndrome , Fenótipo , DNA , Fatores de Transcrição SOXC/genética
4.
Am J Hum Genet ; 103(4): 602-611, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30269814

RESUMO

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36∗) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36∗ variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.


Assuntos
Anormalidades Múltiplas/genética , Aciltransferases/genética , Artrogripose/genética , Ataxia Cerebelar/genética , Epilepsia Generalizada/genética , Linhagem Celular , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Células HEK293 , Humanos , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Mutação , Malformações do Sistema Nervoso/genética , Linhagem , Convulsões/genética , Síndrome , Sequenciamento do Exoma/métodos
5.
NPJ Genom Med ; 9(1): 15, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409289

RESUMO

Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12-73%), 33% (6-86%) in cohorts with prior genetic testing, and 33% (9-60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24-100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations.

6.
Nat Commun ; 14(1): 6770, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37914730

RESUMO

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling.


Assuntos
Interferon Tipo I , Humanos , Fator 1 de Ribosilação do ADP/genética , Fator 1 de Ribosilação do ADP/metabolismo , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Transdução de Sinais
7.
Genes (Basel) ; 13(1)2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35052493

RESUMO

POGZ-related disorders (also known as White-Sutton syndrome) encompass a wide range of neurocognitive abnormalities and other accompanying anomalies. Disease severity varies widely among POGZ patients and studies investigating genotype-phenotype association are scarce. Therefore, our aim was to collect data on previously unreported POGZ patients and perform a large-scale phenotype-genotype comparison from published data. Overall, 117 POGZ patients' genotype and phenotype data were included in the analysis, including 12 novel patients. A severity scoring system was developed for the comparison. Mild and severe phenotypes were compared with the types and location of the variants and the predicted presence or absence of nonsense-mediated RNA decay (NMD). Missense variants were more often associated with mild phenotypes (p = 0.0421) and truncating variants predicted to escape NMD presented with more severe phenotypes (p < 0.0001). Within this group, variants in the prolin-rich region of the POGZ protein were associated with the most severe phenotypes (p = 0.0004). Our study suggests that gain-of-function or dominant negative effect through escaping NMD and the location of the variants in the prolin-rich domain of the protein may play an important role in the severity of manifestations of POGZ-associated neurodevelopmental disorders.


Assuntos
Estudos de Associação Genética , Mutação , Transtornos do Neurodesenvolvimento/patologia , Transposases/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/genética , Adulto Jovem
8.
Orphanet J Rare Dis ; 16(1): 446, 2021 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-34688299

RESUMO

BACKGROUND: Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. MAIN BODY: The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. CONCLUSION: The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.


Assuntos
Osteocondrodisplasias , Doenças Raras , Humanos , Doenças Raras/genética
9.
Clin Dysmorphol ; 28(4): 175-183, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31162149

RESUMO

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder caused by biallelic variants in UBE3B. Kaufman oculocerebrofacial syndrome is characterized by a recognizable pattern of malformations including moderate to severe intellectual disability, growth deficiency, microcephaly and a distinctive facial gestalt. Common craniofacial features include short upslanting palpebral fissures, blepharophimosis or ptosis, ear anomalies, hearing loss, palate anomalies and stridor/laryngomalacia. The aim of this study was to describe the phenotypic features and the genotype of five new individuals from three unrelated families, and to review systematically the published information of 26 cases. The main features are summarized contributing to further characterize the natural history of the disease. Novel phenotypic features and two novel pathogenic variants in UBE3B are reported: A splice site variant (c.2569-1G > C) and a nonsense variant (c.518C > A, p.Ser173Ter). Kaufman oculocerebrofacial syndrome is likely an underdiagnosed disorder which can be clinically recognized based on its distinctive facial gestalt and relatively homogenous natural history.


Assuntos
Anormalidades do Olho/diagnóstico , Deficiência Intelectual/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Microcefalia/diagnóstico , Fenótipo , Pré-Escolar , Anormalidades do Olho/genética , Fácies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Masculino , Microcefalia/genética , Mutação , Irmãos , Ubiquitina-Proteína Ligases/genética , Sequenciamento Completo do Genoma
10.
NPJ Genom Med ; 4: 5, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30792901

RESUMO

Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.

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