RGD Reference Report - Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. - Rat Genome Database

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Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene.

Authors: Sobreira, NL  Cirulli, ET  Avramopoulos, D  Wohler, E  Oswald, GL  Stevens, EL  Ge, D  Shianna, KV  Smith, JP  Maia, JM  Gumbs, CE  Pevsner, J  Thomas, G  Valle, D  Hoover-Fong, JE  Goldstein, DB 
Citation: Sobreira NL, etal., PLoS Genet. 2010 Jun 17;6(6):e1000991. doi: 10.1371/journal.pgen.1000991.
RGD ID: 11069623
Pubmed: PMID:20577567   (View Abstract at PubMed)
PMCID: PMC2887469   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pgen.1000991   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
chondroma  IAGP 11069623DNA:deletion more ...RGD 
chondroma  ISOPTPN11 (Homo sapiens)11069623; 11069623DNA:deletion more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Enchondroma  IAGP 11069623DNA:deletion more ...RGD 
Exostoses  IAGP 11069623DNA:deletion more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Ptpn11  (protein tyrosine phosphatase, non-receptor type 11)

Genes (Mus musculus)
Ptpn11  (protein tyrosine phosphatase, non-receptor type 11)

Genes (Homo sapiens)
PTPN11  (protein tyrosine phosphatase non-receptor type 11)


Additional Information