Revisiting Mendelian disorders through exome sequencing

Ku, Chee‐Seng; Naidoo, Nasheen; Pawitan, Yudi

doi:10.1007/s00439-011-0964-2

Cited by 201 publications

(149 citation statements)

References 105 publications

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“…Thus, at present, the utilization of existing and impending knowledge on variants underlying Mendelian disorders to identify the variation underlying polygenic traits may prove a viable, efficient, and cost-effective complement to standard approaches such as GWAS. The present finding highlights the importance of continuing the efforts directed at studying monogenic diseases 50,51 at a time when focus has shifted away from them, as they can advance our understanding of multifactorial traits.…”

Section: Discussionmentioning

confidence: 72%

“…At present, the causal variants for a large number of monogenic disorders have been identified (over 3000 disorders; Online Mendelian Inheritance in Man (OMIM): http:// www.ncbi.nlm.nih.gov/omim), and recent developments in sequencing technologies have made it possible to employ exome sequencing or whole-genome sequencing, possibly in combination with homozygosity mapping, as an efficient approach to identifying novel causal variants underlying Mendelian disorders. [48][49][50] The National Human Genome Research Institute has opened Centers for Mendelian Genomics (NHGRI Genome Sequencing Program, http://www.genome.gov/), whose primary goal is the discovery of as yet unknown variation underlying Mendelian disorders. Thus, at present, the utilization of existing and impending knowledge on variants underlying Mendelian disorders to identify the variation underlying polygenic traits may prove a viable, efficient, and cost-effective complement to standard approaches such as GWAS.…”

Section: Discussionmentioning

confidence: 99%

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Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

et al. 2015

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Multiple inquiries into the genetic etiology of human traits indicated an overlap between genes underlying monogenic disorders (eg, skeletal growth defects) and those affecting continuous variability of related quantitative traits (eg, height). Extending the idea of a shared genetic basis between a Mendelian disorder and a classic polygenic trait, we performed an association study to examine the effect of 43 genes implicated in autosomal recessive cognitive disorders on intelligence in an unselected Dutch population (N = 1316). Using both single-nucleotide polymorphism (SNP)-and gene-based association testing, we detected an association between intelligence and the genes of interest, with genes ELP2, TMEM135, PRMT10, and RGS7 showing the strongest associations. This is a demonstration of the relevance of genes implicated in monogenic disorders of intelligence to normal-range intelligence, and a corroboration of the utility of employing knowledge on monogenic disorders in identifying the genetic variability underlying complex traits.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

et al. 2015

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“…However, while some fraction of obesity can be attributed to the aforementioned Mendelian defects as well as variation in genes identified in GWAS studies such as FTO, there is a reason to expect that many new genes remain to be discovered (Fawcett & Barroso 2010). The use of highthroughput genomic sequencing to look for variation in patients with extreme phenotypes, as pioneered by several authors in this volume, is likely to lead to the identification of new genes (Ku et al 2011). It will be of particular interest to learn whether these new genes also function in the neural circuit that is modulated by leptin and other metabolic signals.…”

Section: Obesity Has a Substantial Genetic Componentmentioning

confidence: 99%

20 YEARS OF LEPTIN: Leptin at 20: an overview

Friedman¹

2014

Journal of Endocrinology

204

146

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Historically, adipose tissue was considered to be a passive storage vessel discharging nutrients in times of famine and accumulating fat in times of surfeit. This view changed with the identification of leptin as an adipocyte hormone. Leptin functions as an afferent signal in a negative feedback loop that regulates food intake and metabolism to maintain homeostatic control of adipose tissue mass. Before this, the existence of a system maintaining homeostatic control of energy balance was unclear. The identification of leptin has thus uncovered a new endocrine system that also links changes in nutrition to adaptive responses in most if not all other physiologic systems. Further studies have revealed a set of clinical syndromes caused by leptin deficiency, including lipodystrophy and hypothalamic amenorrhea. This work has led to new therapeutic approaches for a number of human conditions and has also established a conceptual framework for studying the pathogenesis of obesity.

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“…However, next-generation sequencing technologies such as the whole-exome sequencing approach are improving as rapid, high-throughput, and costeffective approaches to fulfill medical sciences and research demands (Ng et al, 2009;Metzker, 2010;Ku et al, 2011). In our study, the pedigree is really small and it is difficult to discover a new causative gene.…”

Section: Discussionmentioning

confidence: 90%

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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Revisiting Mendelian disorders through exome sequencing

Cited by 201 publications

References 105 publications

Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

20 YEARS OF LEPTIN: Leptin at 20: an overview

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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