Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak–like primary immunodeficiency syndrome

Badolato, Raffaele; Prandini, Alberto; Caracciolo, Sonia; Colombo, Francesca; Tabellini, Giovanna; Giacomelli, Mauro; Cantarini, Maria Elena; Pession, Andrea; Bell, Callum J.; Dinwiddie, Darrell L.; Miller, Neil; Hateley, Shannon; Saunders, Carol J.; Zhang, Lu; Schroth, Gary P.; Plebani, Alessandro; Parolini, Silvia; Kingsmore, Stephen F.

doi:10.1182/blood-2012-01-404350

Cited by 73 publications

(71 citation statements)

References 12 publications

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“…Our findings clearly demonstrate the utility of using a standard exome kit for examining the mtDNA and discovery of both homoplasmic and heteroplasmic variants. However, in our experience there are multiple factors that affect the level of coverage obtained by target enrichment [22,24,41]. Specifically, we have observed, as reported by others, that there is a difference in the coverage of the mtDNA given the same amount of sequence using exome kits from different manufactures (unpublished data, [39]).…”

Section: Discussionsupporting

confidence: 56%

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Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

et al. 2013

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Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations.

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Section: Discussionsupporting

confidence: 56%

“…Many of the early successes of genomic medicine have come from monogenic disease discovery [24–26] and diagnosis [11,27,28], particularly in disorders that feature clinical and genetic heterogeneities. Mitochondrial diseases have both types of heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

et al. 2013

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“…Functionally, known mutations result in impairment of cytokine production after TLR stimulation (36, 37). Patients 006 and 007 were found to carry homozygous deleterious mutations in PLDN and DOCK8/CLEC7A gene, respectively, whose phenotypic peculiarity has been described in detail (29, 31). …”

Section: Resultsmentioning

confidence: 99%

“…Of note, exome sequencing allowed the identification of PLDN variants associated with a novel genetic cause of partial albinism and with PID (29). This study reported six patients who had undergone a diagnostic odyssey of 10–21 months driven by worldwide accepted protocols (40).…”

Section: Discussionmentioning

confidence: 99%

Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing

et al. 2016

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BackgroundRecently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome.ObjectiveTo evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures.MethodsWe retrospectively analyzed genetic variants identified through targeted NGS or WES in 45 patients with complex PID of unknown etiology.ResultsForty-seven variants were identified using targeted NGS, while 5 were identified using WES. Newly identified genetic variants were classified into four groups: (I) variations associated with a well-defined PID, (II) variations associated with atypical features of a well-defined PID, (III) functionally relevant variations potentially involved in the immunological features, and (IV) non-diagnostic genotype, in whom the link with phenotype is missing. We reached a conclusive genetic diagnosis in 7/45 patients (~16%). Among them, four patients presented with a typical well-defined PID. In the remaining three cases, mutations were associated with unexpected clinical features, expanding the phenotypic spectrum of typical PIDs. In addition, we identified 31 variants in 10 patients with complex phenotype, individually not causative per se of the disorder.ConclusionNGS technologies represent a cost-effective and rapid first-line genetic approach for the evaluation of complex PIDs. WES, despite a moderate higher cost compared to targeted, is emerging as a valuable tool to reach in a timely manner, a PID diagnosis with a considerable potential to draw genotype–phenotype correlation. Nevertheless, a large fraction of patients still remains without a conclusive diagnosis. In these patients, the sum of non-diagnostic variants might be proven informative in future studies with larger cohorts of patients.

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“…Albinism is a highly heterogeneous genetic disorder with an autosomal recessive, autosomal dominant, or X-linked inheritance pattern. To date, approximately 16 albinismrelated genes (GPR143,TYR,OCA2,TYRP1,SLC45A2,SLC24A5,C10ORF11,HPS1,AP3B1,HPS3,HPS4,HPS5,HPS6,DTNBP1,BLOC1S3,and BLOC1S6) have been identified (Morgan et al, 2006;Badolato et al, 2012;Lowe et al, 2013). Today, patients with albinism are primarily diagnosed by Sanger sequencing of one or more of these candidate genes.…”

Section: Introductionmentioning

confidence: 99%

Case Report Identification of a novel SLC45A2 mutation in albinism by targeted next-generation sequencing

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Albinism is a diverse group of hypopigmentary disorders caused by multiple-genetic defects. The genetic diagnosis of patients affected with albinism by Sanger sequencing is often complex, expensive, and time-consuming. In this study, we performed targeted next-generation sequencing to screen for 16 genes in a patient with albinism, and identified 21 genetic variants, including 19 known single nucleotide polymorphisms, one novel missense mutation (c.1456 G>A), and one disease-causing mutation (c.478 G>C). The novel mutation was not observed in 100 controls, and was predicted to be a damaging mutation by SIFT and Polyphen. Thus, we identified a novel mutation 2 J.J. Xue et al. Genetics and Molecular Research 15 (3): gmr.15038743 in SLC45A2 in a Chinese family, expanding the mutational spectrum of albinism. Our results also demonstrate that targeted next-generation sequencing is an effective genetic test for albinism.

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Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak–like primary immunodeficiency syndrome

Cited by 73 publications

References 12 publications

Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing

Case Report Identification of a novel SLC45A2 mutation in albinism by targeted next-generation sequencing

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