Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene
Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.
Vyšlo v časopise:
Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene. PLoS Genet 6(6): e32767. doi:10.1371/journal.pgen.1000991
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000991
Souhrn
Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.
Zdroje
1. BotsteinD
RischN
2003
Discovering genotypes underlying human phenotypes: Past successes for mendelian disease, future approaches for complex disease.
Nat Genet
S33
228
237
2. AntonarakisSE
BeckmannJS
2006
Mendelian disorders deserve more attention.
Nat Rev Genetics
7
277
282
3. RopersH-H
2007
New perspectives for the elucidation of genetic disorders.
Am J Hum Genet
81
199
207
4. AmbergerJ
BocchiniCA
ScottAF
HamoshA
2009
McKusick's Online Mendelian Inheritance in Man (OMIM).
Nucl Acids Res
37
D793
D796
5. GohKI
CusickME
ValleD
ChildsB
VidalM
2007
The human disease network.
PNAS
104
8685
8690
6. NgSB
BuckinghamKJ
LeeC
BighamAW
TaborHK
2010
Exome sequencing identifies the cause of a mendelian disorder.
Nat Genet
42
30
35
7. MardisER
2008
Next-generation DNA sequencing methods.
Annu Rev Genomics Hum Genet
9
387
402
8. NgSB
TurnerEH
RobertsonPD
FlygareSD
BighamAW
2009
Targeted capture and massively parallel sequencing of 12 human exomes.
Nature
461
272
276
9. ChoiM
SchollUI
JiW
LiuT
TikhonovaIR
2009
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing.
PNAS
106
19096
19101
10. MaroteauxP
1971
Metachondromatosis.
Z Kinderheilkd
109
246
261
11. LachmanRS
CohenA
HollisterD
RimoinDL
1974
Metachondromatosis.
Birth Defects Orig Artic Ser
10
171
178
12. KoslowskiK
ScougallJS
1975
Aust Paediatri J
11
42
45
13. BassettGS
CowellHR
1985
Metachondromatosis: A report of four cases.
J Bone Joint Surg Am
67
811
814
14. KennedyLA
1983
Metachondromatosis.
Radiology
148
117
118
15. BoveeJVMG
HameetmanL
KroonHM
AignerT
HogendoomPCW
2006
EXT-related pathways are not involved in the pathogenesis of dysplasia epipysealis hemimelica and metachondromatosis.
J Pathol
209
411
419
16. TidymanWE
RauenKA
2009
The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation.
Curr Opin Genet Devel
19
230
236
17. TartagliaM
GelbBD
2005
Noonan syndrome and related disorders: Genetics and pathogenesis.
Annu Rev Genomics Hum Genet
6
45
68
18. JorgeAAL
MalaquiasAC
ArnholdIJP
MendoncaBB
2009
Noonan syndrome and related disorders: A review of clinical features and mutations in genes of the RAS/MAPK pathway.
Horm Res
71
185
193
19. OishiK
ZhangH
GaultWJ
WangCJ
TanCC
2009
Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development.
Hum Mol Genet
18
193
201
20. SaxtonTM
HenkemeyerM
GascaS
ShenR
RossiDJ
1997
Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2.
EMBO J
16
2352
2364
21. AbecasisGR
ChernySS
CooksonWO
CardonLR
2002
Merlin - rapid analysis of dense genetic maps using spare gene flow trees.
Nat Genet
30
3
4
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
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