A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield

Ankala, Arunkanth; Silva, Cristina da; Gualandi, Francesca; Ferlini, Alessandra; Bean, Lora Jh; Collins, Christin; Tanner, Alice K.; Hegde, Madhuri

doi:10.1002/ana.24303

Cited by 147 publications

(135 citation statements)

References 31 publications

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“…Our LGMD panel diagnostic yield (27%) is smaller than that of our previous NMD panel (46%) since previously yield was for all NMDs, not just for LGMD, and the cohort was much smaller (81 patients) 17. Identification of pathogenic variants in dominant LGMD genes DNAJB6 , MYOT , and CAV3, but not in the TNPO3 gene indicates a higher prevalence of dominant LGMD‐subtypes‐1E,1A,1C, respectively, and the rarity of LGMD‐1F.…”

Section: Discussioncontrasting

confidence: 57%

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

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

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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: Discussioncontrasting

confidence: 57%

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

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

Self Cite

136

165

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“…There is less uniform coverage in wholeexome sequencing, and up to 10% of the region of interest may not be adequately covered. 16 Thus, although whole exome and wholegenome sequencing are amen able to novel gene discovery, the time frame required for characterization and validation of a novel gene is often too long to be of practical help for sick neonates.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

Daoud

Luco

et al. 2016

CMAJ

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Results: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myo pathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome.Interpretation: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU. AbstractSee also www.cmaj.ca/lookup/doi/10.1503/cmaj.160490Research CMAJ, August 9, 2016, 188(11) E255and clinicians providing care. 7 The inability to arrive at a timely and efficient diagnosis repre sents a substantial lost opportunity, as a diagno sis can limit or even halt further invasive, and at times futile, investigations for the neonate. Importantly, an accurate diagnosis informs prog nosis and may guide management decisions.The advent of nextgeneration sequencing has greatly advanced the ability to rapidly identify the novel genes responsible for disease. 8 Whole exome sequencing (sequencing of the coding portion of the genome) is beginning to be used on a clinical basis in tertiary care centres.9,10 In these initial clinical cohort studies, a molecular diagnosis was provided by wholeexome sequencing for about 25% of families. The pro portion increased to 31% when the patient's par ents were also analyzed. 9 Another study used retro spective wholegenome sequencing to make a diagnosis in 57% of 35 children from the inten sive care setting. 11Although wholeexome and wholegenome sequencing are powerful tools, important condi tions are required for translation of these meth ods to the clinic or hospital setting. The avail ability of highthroughput sequencers, complex and costly infrastructure, and personnel with bioinformatics expertise are prerequisites. These resources may not be broadly available within some health care systems, and other strategies may be more relevant and effective.Another attractive alternative is analysis based on nextgeneration sequencing that focuses only on the clinically relevant genes with known associated clinical phenotypes. 12This strategy offers several advantages over wholeexome or wholegenome sequencinginterpretation of variants may be more straight forward, a higher depth of coverage can be read ily achieved, and less infrastructure and fewer personnel are required -all of which contribute to a more rapid return of results.For this pilot study, we evaluated the perform ance of a targeted nextgeneration sequencing panel that included 4813 "diseaserelevant" genes in a cohort of newborns with rare disease in the NICU and assessed the effectiveness of this method to accurately diagnose these critically ill babies. Methods ParticipantsWe recruited patients for this pilot study between January and December 2014 from the NICUs of 2 regional hospi...

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“…A previously published neuromuscular cohort study found a higher diagnosis rate for a 41-gene panel compared with clinician-requested single gene testing (46% vs 15-19%). 24 Coverage of the panel approach, with targeted capture of neuromuscular disease genes and Sanger fill-in of low-coverage exons, was better than WES, with 11 to 18% of pathogenic variants potentially missed by WES. 24 Challenges with coverage apply to both NGS panels and WES, and are frequently gene specific, with GC-rich, repeat regions, and exon 1 often poorly covered.…”

Section: Discussionmentioning

confidence: 99%

“…24 Coverage of the panel approach, with targeted capture of neuromuscular disease genes and Sanger fill-in of low-coverage exons, was better than WES, with 11 to 18% of pathogenic variants potentially missed by WES. 24 Challenges with coverage apply to both NGS panels and WES, and are frequently gene specific, with GC-rich, repeat regions, and exon 1 often poorly covered. FKRP is a good example, with up to 40% of the gene not well covered.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and etiology of congenital muscular dystrophy: We are halfway there

O’Grady

Lek

Lamandé

et al. 2016

Annals of Neurology

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A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield

Abstract: Our results strongly indicate that for molecular diagnosis of heterogeneous disorders such as NMDs, targeted panel testing has the highest clinical yield and should therefore be the preferred first-tier approach.

Cited by 147 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

Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

Diagnosis and etiology of congenital muscular dystrophy: We are halfway there

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