RESUMO
Alazami syndrome is a rare disorder with an autosomal recessive inheritance caused by pathogenic biallelic variants in the LARP7 gene. Clinically, it is mainly characterized by short stature, intellectual disability, and dysmorphic facial features. However, the phenotype is not yet well-defined because less than 50 cases have been described to date. Here, we report three new patients from two unrelated Spanish families who, in addition to the defined features of Alazami syndrome, also exhibit unique features that broaden the phenotypic spectrum of the syndrome. Moreover, we describe the novel frameshift variant c.690_699delins27 in the LARP7 gene, in which loss of function is a known mechanism of Alazami syndrome.
Assuntos
Deficiência Intelectual , Microcefalia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Fenótipo , Microcefalia/genética , Mutação da Fase de Leitura , Síndrome , Ribonucleoproteínas/genéticaRESUMO
Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion.
Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Mutação/genética , Inativação do Cromossomo X/genética , Encéfalo/patologia , Criança , Feminino , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/diagnóstico , Atrofia Muscular/diagnóstico , Fenótipo , Simportadores/genéticaRESUMO
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. RESULTS: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. CONCLUSION: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.
Assuntos
Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Proteínas de Ligação a DNA/genética , Feminino , Flavoproteínas/genética , Demência Frontotemporal/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Monoéster Fosfórico Hidrolases/genética , Proteínas Serina-Treonina Quinases/genética , Receptor ErbB-4/genética , Estudos Retrospectivos , Proteína Sequestossoma-1/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Proteína com Valosina/genéticaRESUMO
INTRODUCTION: The contribution of genetic causes to sensorineural hearing loss (SNHL) in adults is less clear than in children, and genetic diagnosis is still not standardized in adults. In this study we present the genetic results obtained in a cohort of adult patients with SNHL. MATERIALS AND METHODS: We included 63 adults with SNHL that received genetic testing between 2019 and 2022. Whole exome sequencing was performed and variants in genes related to hearing loss (virtual panel with 244 genes) were prioritised and analysed. RESULTS: 24% (15/63) of patients were genetically diagnosed: 87% (13/15) of patients had non-syndromic hearing loss and 13% (2/15) had syndromic hearing loss. We identified pathogenic and likely pathogenic variants in 11 different genes. CONCLUSIONS: Our results show that a significant proportion of adults with SNHL have a genetic origin, and that implementation of genetic testing improves diagnostic accuracy and allows personalized management of these patients.
Assuntos
Sequenciamento do Exoma , Testes Genéticos , Perda Auditiva Neurossensorial , Humanos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto JovemRESUMO
INTRODUCTION: Congenital/early-onset sensorineural hearing loss (SNHL) is one of the most common hereditary disorders in our environment. There is increasing awareness of the importance of an etiologic diagnosis, and genetic testing with next-generation sequencing (NGS) has the highest diagnostic yield. Our study shows the genetic results obtained in a cohort of patients with bilateral congenital/early-onset SNHL. MATERIALS AND METHODS: We included 105 children with bilateral SNHL that received genetic testing between 2019 and 2022. Genetic tests were performed with whole exome sequencing, analyzing genes related to hearing loss (virtual panel with 244 genes). RESULTS: 48% (50/105) of patients were genetically diagnosed. We identified pathogenic and likely pathogenic variants in 26 different genes, and the most frequently mutated genes were GJB2, USH2A and STRC. 52% (26/50) of variants identified produced non-syndromic hearing loss, 40% (20/50) produced syndromic hearing loss, and the resting 8% (4/50) could produce both non-syndromic and syndromic hearing loss. CONCLUSIONS: Genetic testing plays a vital role in the etiologic diagnosis of bilateral SNHL. Our cohort shows that genetic testing with NGS has a high diagnostic yield and can provide useful information for the clinical workup of patients.
Assuntos
Testes Genéticos , Síndromes de Usher , Criança , Humanos , Síndromes de Usher/complicações , Perda Auditiva Bilateral/etiologia , Sequenciamento de Nucleotídeos em Larga Escala , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.
Assuntos
Esclerose Lateral Amiotrófica/genética , Expansão das Repetições de DNA/genética , Predisposição Genética para Doença/genética , Proteínas/genética , África/etnologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/etnologia , Povo Asiático/genética , Proteína C9orf72 , China/etnologia , Análise Mutacional de DNA , Etnicidade/genética , Europa (Continente)/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Haplótipos , Heterozigoto , Humanos , Japão/etnologia , Estimativa de Kaplan-Meier , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , EspanhaRESUMO
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive vascular disorder caused by biallellic variants in HTRA1. Recently, it has been reported that several heterozygous mutations in HTRA1 are responsible for a milder late-onset cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. The majority of them are missense that affects the Htr1A protease activity due to a dominant-negative effect caused by defective trimerization or monomer activation. The molecular mechanism related to the structural destabilization of the protein supports the practical utility of integrating computational stability predictors to prioritize candidate variants in this gene. In this work, we report a family with several members diagnosed with subcortical ischemic events and progressive cognitive impairment caused by the novel c.820C > G, p.(Arg274Gly) heterozygous variant in HTRA1 segregating in an autosomal dominant manner and propose its molecular mechanism by a three-dimensional model of the protein's structure.
Assuntos
Doenças de Pequenos Vasos Cerebrais , Transtornos Cerebrovasculares , Leucoencefalopatias , Doenças de Pequenos Vasos Cerebrais/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Humanos , Leucoencefalopatias/genética , Mutação , Estabilidade Proteica , Serina Endopeptidases/genéticaRESUMO
Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.
Assuntos
Transtorno do Espectro Autista/diagnóstico , Sequenciamento do Exoma/métodos , Proteína do X Frágil da Deficiência Intelectual/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adolescente , Adulto , Fatores Etários , Algoritmos , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Cromossomos Humanos/genética , Diagnóstico Precoce , Feminino , Testes Genéticos , Humanos , Lactente , Masculino , Sensibilidade e Especificidade , Adulto JovemRESUMO
BCR-ABL1-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly characterized in adults. We sought to establish the frequency and outcome of adolescent and adult BCR-ABL1-like ALL using a novel RNA-Seq signature in a series of patients with BCP-ALL. To this end, we developed and tested an RNA-Seq custom panel of 42 genes related to a BCR-ABL1-like signature in a cohort of 100 patients with BCP-ALL and treated with risk-adapted ALL trials. Mutations related to BCR-ABL1-like ALL were studied in a panel of 33 genes by next-generation sequencing (NGS). Also, CRLF2 overexpression and IKZF1/CDKN2A/B deletions were analyzed. Twenty out of 79 patients (12-84 years) were classified as BCR-ABL1-like (25%) based on heatmap clustering, with significant overexpression of ENAM, IGJ, and CRLF2 (P ≤ 0.001). The BCR-ABL1-like subgroup accounted for 29% of 15-60-year-old patients, with the following molecular characteristics: CRLF2 overexpression (75% of cases), IKZF1 deletions (64%), CDKN2A/B deletions (57%), and JAK2 mutations (57%). Among patients with postinduction negative minimal residual disease, those with the BCR-ABL1-like ALL signature had a higher rate of relapse and lower complete response duration than non-BCR-ABL1-like patients (P = 0.007). Thus, we have identified a new molecular signature of BCR-ABL1-like ALL that correlates with adverse prognosis in adult patients with ALL.