Genetic aspects of adolescent idiopathic scoliosis in a family with multiple affected members: a research article

<p>Abstract</p> <p>Background</p> <p>The etiology of idiopathic scoliosis remains unknown and different factors have been suggested as causal. Hereditary factors can also determine the etiology of the disease; however, the pattern of inheritance remains unknown. Autosomal dominant, X-linked and multifactorial patterns of inheritances have been reported. Other studies have suggested possible chromosome regions related to the etiology of idiopathic scoliosis. We report the genetic aspects of and investigate chromosome regions for adolescent idiopathic scoliosis in a Brazilian family.</p> <p>Methods</p> <p>Evaluation of 57 family members, distributed over 4 generations of a Brazilian family, with 9 carriers of adolescent idiopathic scoliosis. The proband presented a scoliotic curve of 75 degrees, as determined by the Cobb method. Genomic DNA from family members was genotyped.</p> <p>Results</p> <p>Locating a chromosome region linked to adolescent idiopathic scoliosis was not possible in the family studied.</p> <p>Conclusion</p> <p>While it was not possible to determine a chromosome region responsible for adolescent idiopathic scoliosis by investigation of genetic linkage using microsatellites markers during analysis of four generations of a Brazilian family with multiple affected members, analysis including other types of genomic variations, like single nucleotide polymorphisms (SNPs) could contribute to the continuity of this study.</p

Spastic Paraplegia, Optic Atrophy, and Neuropathy: New Observations, Locus Refinement, and Exclusion of Candidate Genes

Summary SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive

Molecular-genetic study of discordant patients with Hereditary Spastic Paraplegia type 4

As doenças neuromusculares incluem um grupo muito heterogêneo de patologias que atingem 1 em cada 1.000 indivíduos nascidos vivos. Dentre as doenças neuromusculares destacam-se as paraplegias espásticas hereditárias que acometem, aproximadamente, cerca de 1 em cada 10.000. As paraplegias espásticas hereditárias (PEH) são caracterizadas pela espasticidade e fraqueza muscular dos membros inferiores. São muito heterogêneas tanto em clínica como geneticamente. Diversas formas já foram descritas e a mais comum delas, acometendo por volta de 40% dos casos autossômicos dominantes, causada por mutações no gene SPAST (PEH do tipo 4 ou SPG4). Estudos de correlação genótipo: fenótipo têm mostrado que indivíduos da mesma família carregando a mesma mutação patogênica, podem ter quadro clínico muito distinto. A explicação para esta questão pode estar na procura por genes modificadores, no padrão de expressão, na análise proteômica (seja por ligantes a proteínas ou no dobramento das mesmas), ou em mecanismos epigenéticos. Além disso, em algumas formas observa-se uma diferença na porcentagem de pessoas afetadas de acordo com o sexo. Essa desproporção foi observada numa grande família de com PEH na qual existe um predomínio de afetados do sexo masculino. O objetivo do presente trabalho foi a análise de pacientes discordantes, ou seja, que possuam a mesma mutação, porém com quadro clínico discordante de uma grande família brasileira com SGP4. Para isso foi feito um estudo da abundância de transcritos (mRNA) e de genótipo (polimorfismos de base única) em relação a um fenótipo (sintomático ou assintomático). Os resultados sugerem que o principal sistema envolvido, que poderia explicar as diferenças entre os pacientes discordantes, é o sistema imune, com a principal atuação dos genes C2, HLA-DRB1 e LY6G6C. Esses genes podem ter papel protetor ou tóxico no desenvolvimento do quadro clínico dos pacientes analisadosThe hereditary spastic paraplegia (HSP) is characterized by muscle weakness and lower limb spasticity. They are very heterogeneous both clinically and genetically. Several forms have been described and the most common one, affecting around 40% of autosomal dominant cases, is caused by mutations in the SPAST gene (HSP type 4 or SPG4). Genotype: phenotype correlation studies have shown that affected individuals from the same family, who carry the same pathogenic mutation, can have very distinct phenotypes. The underlying explanation behind this clinical heterogeneity may be found in the search for modifier genes, in expression patterns observed proteomic analyses (either by protein binding or folding), or epigenetic mechanisms. As is observed in other motor neurodisease, there is a disproportion between the number of affected males and females, with males being the predominantly affected. The objective of this study was to analyze discordant patients, i.e., those that possess the same mutation, but show discordant phenotypes, from a large Brazilian family with SGP4. For this study, the abundance of transcripts (mRNA) and genotype (single nucleotide polymorphisms) relative to a phenotype (symptomatic or asymptomatic) were analyzed. The results suggest that the main system involved, which could explain the differences between discordant patients, is the immune system, with the main activity of C2, LY6G6C and HLA-DRB1 genes. These genes may have a protective or toxic role in the development of the analyzed patients\' clinical feature

A Novel Saliva RT-LAMP Workflow for Rapid Identification of COVID-19 Cases and Restraining Viral Spread

Rapid diagnostics is pivotal to curb SARS-CoV-2 transmission, and saliva has emerged as a practical alternative to naso/oropharyngeal (NOP) specimens. We aimed to develop a direct RT-LAMP (reverse transcription loop-mediated isothermal amplification) workflow for viral detection in saliva, and to provide more information regarding its potential in curbing COVID-19 transmission. Clinical and contrived specimens were used to optimize formulations and sample processing protocols. Salivary viral load was determined in symptomatic patients to evaluate the clinical performance of the test and to characterize saliva based on age, gender and time from onset of symptoms. Our workflow achieved an overall sensitivity of 77.2% (n = 90), with 93.2% sensitivity, 97% specificity, and 0.895 Kappa for specimens containing &gt;102 copies/μL (n = 77). Further analyses in saliva showed that viral load peaks in the first days of symptoms and decreases afterwards, and that viral load is ~10 times lower in females compared to males, and declines following symptom onset. NOP RT-PCR data did not yield relevant associations. This work suggests that saliva reflects the transmission dynamics better than NOP specimens, and reveals gender differences that may reflect higher transmission by males. This saliva RT-LAMP workflow can be applied to track viral spread and, to maximize detection, testing should be performed immediately after symptoms are presented, especially in females