Shortfall of exome analysis for diagnosis of <scp>Shwachman‐Diamond</scp> syndrome: Mismapping due to the pseudogene <scp><i>SBDSP1</i></scp>

Yamada, Mamiko; Uehara, Tomoko; Suzuki, Hisato; Tamura, Toshiki; Inui, Ayano; Ikemiyagi, Masako; Kamimaki, Isamu; Kosaki, Kenjiro

doi:10.1002/ajmg.a.61598

Cited by 14 publications

(15 citation statements)

References 11 publications

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“…Yamada et al reported two SDS patients with compound heterozygous mutations in the SBDS gene (c.258+2T>C on one allele and c.183_184delinsCT together with c.201A>G on the other), validated by Sanger sequencing. However, the c.183_184delinsCT and c.201A>G variants were not identified by whole-exome sequencing (WES) in either patient due to mismapped reads, which pointed out the shortcomings of NGS data analysis for SDS diagnosis [22] . Since SDS usually presents with clinical heterogeneity and is thought to be underdiagnosed in the general population [12] , the omittance of pathogenic variants limited by ambiguous read mapping during conventional NGS analysis might be one of the possible causes.…”

Section: Introductionmentioning

confidence: 99%

“…Disentangling the disease-causing variants through short NGS reads is frequently limited since SBDS shares 97% identity with SBDSP1 [21][22][23] . Yamada et al reported two SDS patients with compound heterozygous mutations in the SBDS gene (c.258+2T>C on one allele and c.183_184delinsCT together with c.201A>G on the other), validated by Sanger sequencing.…”

Section: Introductionmentioning

confidence: 99%

“…Although the American College of Medical Genetics and Genomics (ACMG) guidance has pointed out that "laboratories must develop a strategy for detecting disease-causing variants within regions with known homology" [24] , to our knowledge, few studies have confronted the analysis of variants arising from gene conversion based on short-read NGS data. In addition, although inaccurate molecular pathogenesis detection of the two most common SBDS gene PSVs has been scatteredly reported [22] , a systematic description of the degree of error of standard analysis has seldom been assessed.…”

Section: Introductionmentioning

confidence: 99%

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Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome

Peng

Dong

Wang

et al. 2021

Preprint

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Purpose: Shwachman-Diamond syndrome (SDS) is predominately caused by biallelic mutations in the SBDS gene and is characterized by exocrine pancreatic insufficiency, skeletal abnormalities and pancytopenia. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. We established an efficient approach, HapICE, to infer the haplotype of SBDS based on short-read next-generation sequencing (NGS). Methods: HapICE based on the Expectation-Maximization algorithm was developed to detect variants in exon 2 of SBDS arising from gene conversion. We retrospectively analyzed two common pathogenic variants (c.183_184delinsCT and c.258+2T>C) in suspected SDS patients and compared the results with those from conventional NGS analysis. Results: In 47 SDS high-risk individuals and 64 available parents, HapICE improved the diagnostic rate by 27.7% compared with conventional methods and revealed 100% (95% CI: 92.5%-100%) concordance with Sanger sequencing. In addition to eighteen patients having consistent genetic results by both methods, HapICE further reported 8 patients with more accurate variant detection and 13 cases with the c.183_184delinsCT variant missing by conventional methods. HapICE also showed better performance in screening for carrier and wild-type status. Conclusion: We have developed a novel SBDS variant detection tool through regular NGS data that demonstrated precise variant detection performance in clinical scenarios.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome

Peng

Dong

Wang

et al. 2021

Preprint

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“…[12][13][14][15] Sequencing analysis may miss mutations in SBDS due to large deletions or difficulties with the highly homologous pseudogene, so further evaluation should be pursued when clinical suspicion is high. 16,17 SDS registries in France and Italy recently reported characteristics of severe cytopenias, clonal cytogenetic abnormalities, and malignancies in patients with biallelic SBDS mutations. The French Neutropenia Registry, which included 102 patients with biallelic SBDS mutations, reported a 20-year cumulative risk of both non-malignant and malignant severe cytopenias of 24.3%.…”

Section: Introductionmentioning

confidence: 99%

Hematologic complications with age in Shwachman-Diamond syndrome

Furutani

Liu²,

Galvin

et al. 2022

Blood Advances

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Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258+2T>C variant was present in all but one patient. To evaluate association of blood counts with age, a total of 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P<0.0001). Hemoglobin was also positively associated with age up to 18 years (P<0.0001) but thereafter the association was negative (P=0.0079). Platelet counts and marrow cellularity were negatively associated with age (P<0.0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 MDS and 10 AML) at a median age of 12.3 years (range 0.5-45.0) for MDS, and 28.4 years (range 14.4-47.3) for AML. A lymphoid malignancy developed in one patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths, 85%). These data inform surveillance of hematologic complications in SDS.

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“…Since the common SBDS pathogenic variants c.185_184TA>GT and c.258+2T>C are at the functional PSV loci, it has been suggested that recombination and gene conversion might occur between SBDS and SBDSP1 [11] . Based on the above factors, researchers have recognized the complexity and challenges of NGS analysis of the SBDS gene, and therefore suggest using PCR, RT-PCR or specific bioinformatics tools to increase the sensitivity and specificity of detecting pathogenic variants in SBDS [12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Improved detection of SBDS gene mutation by a new method of next-generation sequencing analysis based on the Chinese mutation spectrum

Wu¹,

Zhang²,

Qiang³

et al. 2021

Preprint

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Next-generation sequencing (NGS) is a useful molecular diagnostic tool for genetic diseases. However, due to the presence of highly homologous pseudogenes, it is challenging to use short-read NGS for analyzing mutations of the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The SBDS mutation spectrum was analyzed in the Chinese population, which revealed that SBDS variants were primarily from sequence exchange between SBDS and its pseudogene at the base-pair level, predominantly in the coding region and splice junction of exon two. The c.258+2T>C and c.185_184TA>GT variants were the two most common pathogenic SBDS variants in the Chinese population, resulting in a total carrier frequency of 1.19%. When analyzing pathogenic variants in the SBDS gene from the NGS data, the misalignment was identified as a common issue, and there were different probabilities of misalignment for different pathogenic variants. Here, we present a novel mathematical method for identifying pathogenic variants in the SBDS gene from the NGS data, which utilizes read-depth of the paralogous sequence variant (PSV) loci of SBDS and its pseudogene. Combined with PCR and STR orthogonal experiments, the results of SBDS gene mutation analysis were improved in 40% of clinical samples, and various types of mutations such as homozygous, compound heterozygous, and uniparental diploid were explored. The findings effectively reduce the impact of misalignment in NGS-based SBDS mutation analysis and are helpful for the clinical diagnosis of SBDS-related diseases, the research into population variation, and the carrier screening.

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Shortfall of exome analysis for diagnosis of Shwachman‐Diamond syndrome: Mismapping due to the pseudogene SBDSP1

Cited by 14 publications

References 11 publications

Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome

Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome

Hematologic complications with age in Shwachman-Diamond syndrome

Improved detection of SBDS gene mutation by a new method of next-generation sequencing analysis based on the Chinese mutation spectrum

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