Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease

Mori, Mari; Haskell, Gloria T.; Kazi, Zoheb B.; Zhu, Xiaolin; DeArmey, Stephanie; Goldstein, Jennifer; Bali, Deeksha; Rehder, Catherine; Cirulli, Elizabeth T.; Kishnani, Priya S.

doi:10.1016/j.ymgme.2017.10.008

Cited by 21 publications

(20 citation statements)

References 52 publications

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“…The results of this group indicated that abnormality of the metabolism/homeostasis underlined a substantial proportion of pediatric disease burden; a number of IEM have nonspecific biomarkers so that their diagnosis can be challenging depending on the traditional approaches, and a TRS analysis covering appropriate panel of genes has significant clinical utility for this group. Our results also illustrated that some variants not captured by one pipeline were indeed detected by the other (Jacob et al, ; Mori et al, ).…”

Section: Discussionsupporting

confidence: 77%

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Hong

Wang

Zhao

et al. 2019

Molec Gen & Gen Med

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Background Rare diseases are complex disorders with huge variability in clinical manifestations. Decreasing cost of next‐generation sequencing (NGS) tests in recent years made it affordable. We witnessed the diagnostic yield and clinical use of different NGS strategies on a myriad of monogenic disorders in a pediatric setting. Methods Next‐generation sequencing tests are performed for 98 unrelated Chinese patients within their first year of life, who were admitted to Xin Hua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, during a 2‐year period. Results Clinical indications for NGS tests included a range of medical concerns. The mean age was 4.4 ± 4.2 months of age for infants undergoing targeting specific (known) disease‐causing genes (TRS) analysis, and 4.4 ± 4.3 months of age for whole‐exome sequencing (WES) (p > 0.05). A molecular diagnosis is done in 72 infants (73.47%), which finds a relatively high yield with phenotypes of metabolism/homeostasis abnormality (HP: 0001939) (odds ratio, 1.83; 95% CI, 0.56–6.04; p = 0.32) and a significantly low yield with atypical symptoms (without a definite HPO term) (odds ratio, 0.08; 95% CI, 0.01–0.73; p = 0.03). TRS analysis provides molecular yields higher than WES (p = 0.01). Ninety‐eight different mutations are discovered in 72 patients. Twenty‐seven of them have not been reported previously. Nearly half (43.06%, 31/72) of the patients are found to carry 11 common disorders, mostly being inborn errors of metabolism (IEM) and neurogenetic disorders and all of them are observed through TRS analysis. Eight positive cases are identified through WES, and all of them are sporadic, of highly variable phenotypes and severity. There are 26 patients with negative findings in this study. Conclusion This study provides evidence that NGS can yield high success rates in a tertiary pediatric setting, but suggests that the scope of known Mendelian conditions may be considerably broader than currently recognized.

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Section: Discussionsupporting

confidence: 77%

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Hong

Wang

Zhao

et al. 2019

Molec Gen & Gen Med

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“…The most frequent disease-associated variant in the Caucasian population is the IVS1 variant, which occurs in a large majority (90%) of childhood and adult onset patients [[2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]]. Previous work has identified 12 haplotypes in Caucasian IVS1 patients based on 17 single nucleotide polymorphisms that were distributed over the entire GAA gene [16].…”

Section: Discussionmentioning

confidence: 99%

“…The exceptionally broad spectrum of symptom onset within compound heterozygous IVS1 patients observed in many studies has reinforced the suspicion that there are modifying factors for Pompe disease [[2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]]. In theory, residual activity from the second allele could explain clinical heterogeneity in compound heterozygous IVS1 patients.…”

Section: Discussionmentioning

confidence: 99%

A genetic modifier of symptom onset in Pompe disease

et al. 2019

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Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13TNG (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. Methods: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. Findings: In compound heterozygous IVS1 patients, the synonymous variant c.510CNT was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510CNT than it was in patients without c.510CNT. By reducing the extent of leaky wild-type splicing, c.510CNT modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510CNT was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510CNT variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510CNT caused reduced leaky wild-type splicing. Interpretation: c.510CNT is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. Fund: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).

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“…While holding some well-known drawbacks, the clinical utility of NGS approaches for MGT is undeniable. Over the last decade, a significant number of teams have developed targeted panels for LSDs, which allowed for the molecular characterization of an even higher number of LSDs patients, ending up several diagnostic odysseys [39,[42][43][44][45][46][47][48][49][50][51] In general, panel design may vary significantly depending on its underlying rationale: for LSDs in particular, some teams have developed small and fast-targeted NGS approaches, which rely on the analysis of a small number of genes selected on the basis of overlapping clinical manifestations [41], while others have gone for more comprehensive approaches and included virtually all known LSD-causing genes [42,45]. Some authors have even went a step further and developed an investigational panel including a large number of genes from the autophagy-lysosomal pathway (ALP), regardless of their known involvement with genetic disease [46,47].…”

Section: Discussionmentioning

confidence: 99%

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

Encarnação

Coutinho

Silva

et al. 2020

IJMS

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Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients.

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Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease

Cited by 21 publications

References 52 publications

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

A genetic modifier of symptom onset in Pompe disease

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

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