The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing

Feng, Yanming; Ge, Xiaoyan; Meng, Linyan; Scull, Jennifer; Li, Jianli; Tian, Xia; Zhang, Tao; Jin, Weihong; Cheng, Hanyin; Wang, Xia; Tokita, Mari; Liu, Pengfei; Mei, Hui; Wang, Yue; Li, Fangyuan; Schmitt, Éric; Zhang, Wei V.; Muzny, Donna M.; Wen, Shu; Zhao, Chen; Yang, Yaping; Beaudet, Arthur L.; Liu, Xiaoming; Eng, Christine M.; Xia, Fan; Wong, Lee‐Jun C.; Zhang, Jinglan

doi:10.1038/gim.2016.215

Cited by 76 publications

(76 citation statements)

References 34 publications

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“…Ocorre em, aproximadamente, 1:6000 a 1:10000 nascidos vivos 3,4,6,13 e sua frequência de portador varia entre 1/40 a 1/100 em diferentes grupos étnicos, sendo mais comum em caucasianos 14 . O sinal clínico mais característico é a hipotonia muscular 15 , que geralmente tem início nos membros superiores, atingindo posteriormente os membros inferiores e, também, os músculos bulbares.…”

Section: Resultsunclassified

“…A AME é, portanto, uma doença em que ambos os sexos são afetados igualmente e que, para aparecer, é necessária a presença do defeito genético em suas duas cópias do gene 21 . Um ponto importante a ser destacado é o fato de que a quantidade de cópias intactas de SMN-2 é determinante para a severidade da doença 3,5,14 . Todo paciente com AME possui pelo menos uma cópia de SMN-2 normal; assim, cerca de 80% dos pacientes com AME tipo I tem apenas uma ou duas cópias do gene SMN-2, 82% dos pacientes com AME tipo II tem três cópias do gene SMN-2 e 96% dos pacientes com AME tipo III tem três ou quatro cópias do gene SMN-2 21 .…”

Section: Resultsunclassified

“…O diagnóstico da doença de Werdnig-Hoffmann é feito com base no quadro clínico, nos antecedentes familiares e em exames como: biópsia muscular, achados de estudos neurofisiológicos e eletroneuromiografia 22 . O teste molecular, além de ser necessário para a confirmação da suspeita clínica, é o único que permite o diagnóstico na fase pré-sintomática e a identificação dos portadores 14 . É realizado através da detecção de marcadores na região do cromossomo 5q, permitindo a análise do gene SMN-1.…”

Section: Resultsunclassified

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Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Chrun

Costa

Miranda

et al. 2017

Rev. Med. (São Paulo)

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Discussão: A doença de Werdnig-Hoffmann, atrofia muscular espinhal tipo I, é uma doença hereditária caracterizada pela atrofia e fraqueza muscular progressiva, resultando em elevada e precoce mortalidade. As atrofias musculares espinhais são doenças neuromusculares caracterizadas pela degeneração dos motoneurônios inferiores e são transmitidas seguindo o padrão mendeliano autossômico recessivo. Suas manifestações clínicas são: hipotonia, atrofia, debilidade muscular e diminuição ou ausência dos reflexos osteotendinosos. O tratamento inclui medidas de suporte e medicação específica, o Nusinersen (Spinraza®), administrado por via intratecal, e pode retardar ou até impedir a evolução da doença, caso seja iniciado precocemente. Conclusão: A doença tem características semelhantes na maioria dos casos e evolui de forma grave. Entretanto, o tratamento emergencial e intensivo, incluindo a medicação específica e atuação de equipe multidisciplinar, pode redefinir e prolongar a sobrevida dos pacientes.Descritores: Atrofia muscular espinal/fisiopatologia; Atrofias musculares espinais da infância/fisiopatologia;Doenças neuromusculares; Doenças da medula espinal/fisiopatologia. ABSTRACT:Objective: To produce a literature review about etiology, diagnosis, treatment and future perspectives around spinal muscular atrophy type I (Werdnig-Hoffmann disease). Methods: Using databases like Medline, Lilacs and Scielo; the most important articles about this issue were chosen, using the keywords: spinal muscular atrophy; spinal muscular atrophy of childhood; neuromuscular diseases; spinal cord diseases; Werdnig-Hoffmann disease. Results: 68 articles were collected. After analysis process, 43 studies which focus on the clinical and/or pathophysiological aspects, were selected. Discussion: Werdnig-Hoffmann disease, the spinal muscular atrophy type I, is a hereditary disorder that causes progressive hypotony and muscular weakness. This process evolves with the loss of essential functions, resulting in high and early mortality. The spinal muscular atrophies are neuromuscular diseases characterized by degeneration of lower motor neurons. They are transmitted following the pattern mendelian autosomal recessive. The clinic signs are: hypotony, atrophy, muscular weakness and decrease or absence of osteotendinous reflexes. Treatment includes supportive care and specific medication, Nusinersen (Spinraza®), administered by intrathecal injection, and can delay or even stop disease progression if started early. Conclusions: The sickness has similar features on most cases and worsens sorely. However, the intensive and immediate treatment, with the specific medication and the multidisciplinary team -can promote a better quality of life to patients.

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Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Chrun

Costa

Miranda

et al. 2017

Rev. Med. (São Paulo)

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“…We note that the duplication of sequences in the MHC region, or other ‘alt’ contigs are distinct from other truly duplicated regions of the genome, including highly homologous pseudogenes, or the pseudoautosomal regions. Innovative approaches are beginning to resolve some regions of the genome previously classified as inaccessible to short‐read sequencing, e.g., SMN1 and SMN2 (Feng et al., ).…”

Section: Phenotypic Features Present In the Proband And Affected Siblingmentioning

confidence: 99%

Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection

et al. 2019

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Rapid advances in genomic technologies have facilitated the identification pathogenic variants causing human disease. We report siblings with developmental and epileptic encephalopathy due to a novel, shared heterozygous pathogenic 13 bp duplication in SYNGAP1 (c.435_447dup, p.(L150Vfs*6)) that was identified by whole genome sequencing (WGS). The pathogenic variant had escaped earlier detection via two methodologies: whole exome sequencing and high‐depth targeted sequencing. Both technologies had produced reads carrying the variant, however, they were either not aligned due to the size of the insertion or aligned to multiple major histocompatibility complex (MHC) regions in the hg19 reference genome, making the critical reads unavailable for variant calling. The WGS pipeline followed different protocols, including alignment of reads to the GRCh37 reference genome, which lacks the additional MHC contigs. Our findings highlight the benefit of using orthogonal clinical bioinformatic pipelines and all relevant inheritance patterns to re‐analyze genomic data in undiagnosed patients.

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“…However, next-generation sequencing (NGS) technology is rapidly becoming a cost-effective approach for clinical testing (Boycott, et al, 2019). Despite the difficulties that the accurate determination of two genes almost identical inherent to short read technologies, some strategies to process NGS data have already been proposed to detect SMA carriers (Feng, et al, 2017;Larson, et al, 2015). However, to our knowledge, there are not freely available tools that could be derive the mutational status of SMA form primary massive sequencing data.…”

Section: Introductionmentioning

confidence: 99%

SMN1copy-number and sequence variant analysis from next generation sequencing data

López-López

Loucera

Carmona

et al. 2020

Preprint

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Spinal Muscular Atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next generation sequencing (NGS) very difficult Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copynumber using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available on Github at: www.github.com/babelomics/SMAca

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The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing

Cited by 76 publications

References 34 publications

Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection

SMN1copy-number and sequence variant analysis from next generation sequencing data

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