Next Generation DNA Sequencing and Its Application in Clinical Medicine

Sechin Cho

doi:10.14734/kjp.2014.25.3.133

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Cho: Next Generation DNA Sequencing and Its Application in Clinical Medicine

Original Article

Korean J Perinatol 2014;25(3):133-139.

Published online: 21 September 2014

DOI: https://doi.org/10.14734/kjp.2014.25.3.133

Next Generation DNA Sequencing and Its Application in Clinical Medicine

Sechin Cho

M.D. FAAP, Founding Fellow ACMG Professor

University of Kansas School of Medicine, Wichita, Kansas, USA

Correspondence: Sechin Cho, M.D. Genetic Consultant, 2140 Turnberry Way, Woodstock, Maryland 21163, USA Tel : +1-410-750-9188, E-mail : cho3gene@gmail.com

Received 22 September 201425 September 2014 Accepted 28 September 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Watson and Crick published a paper on the double helical structure of DNA in Nature in April 25, 1953. The human genome is contained in the 23 pairs of chromosomes and in the mitochondrial DNA of each cell. The Human Genome Project was launched in 1990 under the direction of Watson and concluded in 2003, on the 50th anniversary of Watson and Crick paper. Over 6 billion of nucleotides of genetic codes are in single cells. There are 23,000 protein coding genes and the remainder are non-coding DNA, regulatory DNA. Since the completion of Human Genome Project, these huge genomic information has been translated into clinically usable medical information. With the advent of massively parallel DNA sequencing, known as next generation DNA sequencing, the cost and turn-around time were significantly reduced so that the era of Whole Genome Sequencing entered into hospitals and medical clinics. On June 16, 2014 American Society of Human Genetics revised its mission statement as follows. “Our mission is to advance human genetics in science, health and society through research, education and advocacy”. Finally medical genetics nestled its roots in the midst of genetics and genomics.

Keywords: New generation DNA sequencing, Whole genome/exome sequencing, Human genetic disease

REFERENCES

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Table 1.

Disease gene panels that use next-generation sequencing

Hypertrophic cardiomyopathy

Dilated cardiomyopathy

Hereditary arrhythmias (channelopathies)

Retinitis pigmentosa

Albinism

Intellectual disability

DNA repair defects

Skeletal dysplasia

Disorders of sexual development

Hearing loss

Table 2.

Conditions, genes, and variants recommended for return of incidental findings in clinical sequencing

Phenotype	MIM-disorder	PMID-Gene Reviews entry	Typical age of onset	Gene	MIM-gene	Inheritance^a	Variants^a to report^b
Hereditary breast and ovarian cancer	604370	20301425	Adult	BRCA1	113705	AD	KP and EP
	612555			BRCA2	600185
Li-Fraumeni syndrome	151623	20301488	Child/adult	TP53	191170	AD	KP and EP
Peutz-Jeghers syndrome	175200	20301443	Child/adult	STK11	602216	AD	KP and EP
Lynch syndrome	120435	20301390	Adult	MLH1	120436	AD	KP and EP
				MSH2	609309
				MSH6	600678
				PMS2	600259
Familial adenomatous polyposis	175100	20301519	Child/adult	APC	611731	AD	KP and EP
MYH-associated polyposis; adeno-mas, multiple colorectal, FA type 2; colorectal adenomatous Polyposis, autosomal recessive, with pilomatricomas	608456	23035301	Adult	MUTYH	604933	ARC	KP and EP
	132600
Von Hippel-Lindau syndrome	193300	20301636	Child/adult	VHL	608537	AD	KP and EP
Multiple endocrine neoplasia type1	131100	20301710	Child/adult	MEN1	613733	AD	KP and EP
Multiple endocrine neoplasia type2	171400	20301434	Child/adult	RET	164761	AD	KP
	162300
Familial medullary thyroid cancerd	1552401	20301434	Child/adult	RET	164761	AD	KP
PTENhamartoma tumor syndrome	153480	20301661	Child/adult	PTEN	601728	AD	KP and EP
Retinoblastoma	180200	20301625	Child	RB1	614041	AD	KP and EP
Hereditary paraganglioma-pheochromocytoma syndrome	168000 (PGL1)	20301715	Child/adult	SDHD	602690	AD	KP and EP
	601650 (PGL2)			SDHAF2	613019
	605373 (PGL3)			SDHC	602413		KP and EP
	115310 (PGL4)			SDHB	185470
Tuberous sclerosis complex	191100	20301399	Child	TSC1	605284	AD	KP and EP
	613254			TSC2	191092
WT1-related Wilms tumor	194070	20301471	Child	WT1	607102	AD	KP and EP
Neurofibromatosis type2	101100	20301380	Child/adult	NF2	607379	AD	KP and EP
Ehlers-Danlos syndrome, vascular type	130050	20301667	Child/adult	COL3A1	120180	AD	KP and EP
Marfan syndrome, Loeys-Dietz syndromes, and familial thoracic Aortic aneurysms and dissections	154700	20301510	Child/adult	FBN1	134797	AD	KP and EP
	609192	20301312		TGFBR1	190181
	608967	20301299		TGFBR1	190182
	610168			SMAD3	603109
				ACTA2	102620
				MYLK	600922
				MYH11	160745

^a Some conditions that may demonstrate semidominant inheritance (SD) have been indicated as autosomal dominant (AD) for the sake of simplicity. Others have been labeled as X-linked (XL);

^b KP: known pathogenic, sequence variation is previously reported and is a recognized cause of the disorder; EP: expected pathogenic, sequence variation is previously unreported and is of the type that is expected to cause the disorder. Note: The recommendation to not repot expected pathogenic variants for some genes is due to the recognition that truncating variants, the primary type of expected pathogenic variants, are not an established cause of some diseases on the list.

^c Although carriers may have modestly increased risk, we recommend searching only for individuals with biallelic mutations;

^d On the basis of evidence presented to the Working Group after the online posting of these recommendations, the decision was made to remove one gene, NTRK1, from the recommended list. Abbreviations: MIM, Mendelion Inheritance in Man; PMID, PuMed identifier; MYH, mutY homolog; FAP, familial adenomatous polyposis; WT1, Wilms tumor1

Table 2.

Continued

Phenotype	MIM-disorder	PMID-Gene Reviewsentry	Typical age y of onset	Gene	MIM-gene	Inheritance ^a	Variants to report^b
Hypertrophic cardiomyopathy, dilated cardiomyopathy	115197	20301725	Child/adult	MYBPC3	600958	AD	KP and EP
	192600			MYH7	160760		KP
	601494			TNNT2	191045		KP and EP
	613690			TNNI3	191044		KP
	115196			TPM1	191010
	608751			MYL3	160790
	612098			ACTC1	102540
	600858			PRKAG2	602743
	301500			GLA	300644	XL	KP and EP (hemi, het, hom)
	608758
	115200
				MYL2	160781	AD	KP
				LMNA	150330		KP and EP
Catecholaminergic polymorphic ventricular tachycardia	604772			RYR2	180902	AD	KP
Arrhythmogenic right-ventricular cardiomyopathy	609040	20301310	Child/adult	PKP2	602861	AD	KP and EP
	604400			DSP	125647
	610476			DSC2	125645
	607450			TMEM43	612048		KP
	610193			DSG2	125671		KP and EP
Romano-Ward long QT syndrome Types 1, 2, and 3, Brugada syndrome	192500	20301308	Child/adult	KCNQ1	607542	AD	KP and EP
	613688			KCNH2	152427
	603830			SCN5A	600163
	601144
Familial hypercholesterolemia	143890	No	Child/adult	LDLR	606945	SD	KP and EP
	603776	Gene reviews		APOB	107730	SD	KP
		Entry		PCSK9	607786	AD
Malignant hyperthermia susceptibility	145600	20301325	Child/adult	RYR1	180901	AD	KP
				CACNA1S	114208

^a Some conditions that may demonstrate semidominant inheritance (SD) have been indicated as autosomal dominant (AD) for the sake of simplicity. Others have been labeled as X-linked (XL);

^b KP: known pathogenic, sequence variation is previously reported and is a recognized cause of the disorder; EP: expected pathogenic, sequence variation is previously unreported and is of the type that is expected to cause the disorder. Note: The recommendation to not report expected pathogenic variants for some genes is due to the recognition that truncating variants, the primary type of expected pathogenic variants, are not an established cause of some diseases on the list.

^c Although carriers may have modestly increased risk, we recommend searching only for individuals with biallelic mutations;

^d On the basis of evidence presented to the Working Group after the online posting of these recommendations, the decision was made to remove one gene, NTRK1, from the recommended list.

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