Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing

Kufova, Zuzana; Ševčíková, Tereza; Januška, Jaroslav; Vojta, Petr; Bóday, Arpád; Vaníčková, Pavla; Filipova, Jana; Growková, Kateřina; Jelı́nek, Tomáš; Hajdúch, Marián

doi:10.1136/jclinpath-2017-204978

Cited by 13 publications

(11 citation statements)

References 31 publications

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“…Previously, multiple targeted disease‐specific panel NGS efforts including that of LGMD for molecular diagnostics were performed 12, 18, 19, 20, 21, 22, 23, 24. But to our knowledge, this study uniquely surpasses them by recruiting a very large number (4656) of patients clinically suspected of a specific disorder (LGMDs) in the USA irrespective of ethnicities.…”

Section: Introductionmentioning

confidence: 98%

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

143

165

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ObjectiveLimb‐girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other NMDs complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven LGMD clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes’ relative prevalence across US and investigate underlying disease mechanisms.MethodsA total of 4656 patients with clinically suspected‐LGMD across US were recruited to conduct next‐generation sequencing (NGS)‐based gene‐panel testing during June‐2015 to June‐2017 in CLIA‐CAP‐certified Emory‐Genetics‐Laboratory. Thirty‐five LGMD‐subtypes‐associated or LGMD‐like other NMD‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes’ prevalence in a large US LGMD‐suspected population.ResultsMolecular diagnosis was established in 27% (1259 cases; 95% CI, 26–29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease, DNAJB6‐associated LGMD subtype1E and CAPN3‐associated autosomal‐dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.InterpretationOverall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

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Section: Introductionmentioning

confidence: 98%

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

143

165

View full text Add to dashboard Cite

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“…Hereditary amyloidosis (HA) represents a series of single-gene diseases that caused by amyloidogenic precursor protein genes mutations (Chyra Kufova et al, 2018 ). There are four genes, which were gelsolin ( GSN ), cystatin C ( CST3 ), transthyretin ( TTR ), and integral membrane protein 2B ( ITM2B ), whose mutations can lead to autosomal dominant HA, while playing an important role in the pathogenesis of AD (Ray et al, 2000 ; Sastre et al, 2004 ; Hirko et al, 2007 ; Mi et al, 2007 ; Buxbaum et al, 2008 ; Buxbaum and Johansson, 2017 ; Tamayev et al, 2011 ; Matsuda and Senda, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Analyses Mutations in GSN, CST3, TTR, and ITM2B Genes in Chinese Patients With Alzheimer’s Disease

Jiang

Jiao

Liao

et al. 2020

Front. Aging Neurosci.

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Amyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer's disease (AD). Mutations of gelsolin (GSN), cystatin C (CST3), transthyretin (TTR), and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD. Genes targeted sequencing (GTS), including GSN, CST3, TTR, and ITM2B, was performed in a total of 636 patients with clinical AD and 365 normal controls from China. As a result, according to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame-shift mutations (GSN:c.1036delA:p.K346fs and GSN:c.8_35del:p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral β-amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while the other four patients with P3fs mutation had a late onset [(Mean ± SD): 69.50 ± 5.20 years] and a long course of illness [(Mean ± SD): 9.24 ± 4.86 years]. Besides, we also discovered 17 variants of uncertain significance (VUS) in these four genes. To our knowledge, we are the first to report AD phenotype with GSN mutations in patients with AD in the Chinese cohort. Although mutations in the GSN gene are rare, it may explain a small portion of clinically diagnosed AD.

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“…Congo red stained sections show the pathognomonic apple-green birefringence of amyloid 2. The most common classification reflects the localisation of the amyloid (systemic vs localised) or the disease origin (acquired vs hereditary amyloidosis) 3. The Nomenclature Committee of the International Society of Amyloidosis regularly updates amyloid fibril protein nomenclature.…”

Section: Discussionmentioning

confidence: 99%

“…For diagnosis of hereditary amyloidosis, clinicians can use next-generation sequencing using gene panels of various genes associated with different forms of amyloidosis3 but for acquired amyloidosis, a tissue biopsy is the gold standard. Congo red staining is not part of our standard muscle biopsy panel, having little use in the diagnosis of inclusion body myositis in our lab compared with other labs 4.…”

Section: Discussionmentioning

confidence: 99%

AL amyloidosis presenting with limb girdle myopathy

2018

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An elderly Caucasian man presented with a 10-month history of proximal myopathy and dysphagia. His serum creatine kinase (CK) was elevated at 877 U/L (normal 40-320) and electromyography confirmed a myopathic process. Blood and urine tests suggested myeloma; bone marrow examination showed 30% plasma cells and stained positive for amyloid. The muscle biopsy was initially reported as normal but in the light of the bone marrow report, the biopsy specimen was stained for amyloid, which was positive. We diagnosed systemic amyloidosis causing a myopathy and have started treatment for myeloma.

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Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing

Cited by 13 publications

References 31 publications

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Analyses Mutations in GSN, CST3, TTR, and ITM2B Genes in Chinese Patients With Alzheimer’s Disease

AL amyloidosis presenting with limb girdle myopathy

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