Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders

Rabbani, Bahareh; Mahdieh, Nejat; Hosomichi, Kazuyoshi; Nakaoka, Hirofumi; Inoue, Ituro

doi:10.1038/jhg.2012.91

Cited by 180 publications

(136 citation statements)

References 167 publications

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“…Massively parallel sequencing has proven to have a high potential to detect mutations in patients with rare Mendelian diseases (15). To date, most reports focus on monogenic conditions with no genetic heterogeneity, for which mutations can be recognized from benign variants since they invariantly affect the same gene in different patients.…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Nishiguchi

Tearle

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ∼446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonineprotein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome. medical genetics | ophthalmology | ciliopathy | retinal blindness

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Section: Discussionmentioning

confidence: 99%

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Nishiguchi

Tearle

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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“…These findings, taken together, indicate that the central nervous system possesses a specialized pathway for metabolizing TAGs, disruption of which leads to massive lipid accumulation in neurons and complex HSP syndrome. D etermining the genetic basis for rare hereditary human diseases has benefited from advances in DNA sequencing technologies (1). As a greater number of disease-causing mutations are mapped, however, it is also becoming apparent that many of the affected genes code for poorly characterized proteins.…”

mentioning

confidence: 99%

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

Inloes

Hsu

Dix

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

142

157

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Complex hereditary spastic paraplegia (HSP) is a genetic disorder that causes lower limb spasticity and weakness and intellectual disability. Deleterious mutations in the poorly characterized serine hydrolase DDHD2 are a causative basis for recessive complex HSP. DDHD2 exhibits phospholipase activity in vitro, but its endogenous substrates and biochemical functions remain unknown. Here, we report the development of DDHD2 −/− mice and a selective, in vivo-active DDHD2 inhibitor and their use in combination with mass spectrometry-based lipidomics to discover that DDHD2 regulates brain triglycerides (triacylglycerols, or TAGs). DDHD2 −/− mice show age-dependent TAG elevations in the central nervous system, but not in several peripheral tissues. Large lipid droplets accumulated in DDHD2 −/− brains and were localized primarily to the intracellular compartments of neurons. These metabolic changes were accompanied by impairments in motor and cognitive function. Recombinant DDHD2 displays TAG hydrolase activity, and TAGs accumulated in the brains of wild-type mice treated subchronically with a selective DDHD2 inhibitor. These findings, taken together, indicate that the central nervous system possesses a specialized pathway for metabolizing TAGs, disruption of which leads to massive lipid accumulation in neurons and complex HSP syndrome. D etermining the genetic basis for rare hereditary human diseases has benefited from advances in DNA sequencing technologies (1). As a greater number of disease-causing mutations are mapped, however, it is also becoming apparent that many of the affected genes code for poorly characterized proteins. Assigning biochemical and cellular functions to these proteins is critical to achieve a deeper mechanistic understanding of human genetic disorders and for identifying potential treatment strategies.Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurologic syndrome marked by spasticity and lower extremity weakness (2). Many genetic types of HSP have been identified and are numbered according to their order of discovery [spastic paraplegia (SPG) 1-72] (2, 3). Of these genetic variants, more than 40 have been mapped to causative mutations in protein-coding genes. HSP genes code for a wide range of proteins that do not conform to a single sequence-or function-related class. A subset of HSP genes, including PNPLA6 (or neuropathytarget esterase) (SPG39) (4), DDHD1 (SPG28) (5), and DDHD2 (SPG54) (3, 6-8), code for serine hydrolases. These enzymes have been designated as (lyso)phospholipases based on in vitro substrate assays (9-11), but their endogenous substrates and physiological functions remain poorly understood. The mutational landscape that affects these lipid hydrolases to cause recessive HSP is complex but collectively represents a mix of null and putatively null and/or functional mutations. Moreover, the type of HSP appears to differ in each case, with DDHD1 mutations causing uncomplicated HSP, whereas PNPLA6 and DDHD2 mutations lead to complex forms of the disease that...

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“…To date, approximately 500 genes have been revealed to be related to cardiac development defects in mice when mutated, and 55 human genes have been identified associated with CHDs (Andersen et al, 2013;Fahed et al, 2013;Wilde and Behr, 2013;Zaidi et al, 2013). Complex or rare Mendelian disorders in small CHDs pedigree make the discovery of novel genes difficult or impossible using the traditional approach (Rabbani et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect

Liu

Fan

Chen

et al. 2014

J. Zhejiang Univ. Sci. B

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Liu et al. / J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2014 15(9):830-837 830 A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect Abstract: Congenital heart disease (CHD) is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect (ASD) is one of the most common defects of CHD. Previous studies have demonstrated that mutations in the transcription factor T-box 20 (TBX20) contribute to congenital ASD. Whole-exome sequencing in combination with a CHD-related gene filter was used to detect a family of three generations with ASD. A novel TBX20 mutation, c.526G>A (p.D176N), was identified and co-segregated in all affected members in this family. This mutation was predicted to be deleterious by bioinformatics programs (SIFT, Polyphen2, and MutationTaster). This mutation was also not presented in the current Single Nucleotide Polymorphism Database (dbSNP) or National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP). In conclusion, our finding expands the spectrum of TBX20 mutations and provides additional support that TBX20 plays important roles in cardiac development. Our study also provided a new and cost-effective analysis strategy for the genetic study in small CHD pedigree.

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Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders

Cited by 180 publications

References 167 publications

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect

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