ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 12q24.13
  • GRCh37/hg19 chr12: 112,856,702-112,947,722
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr12: 112,418,915-112,509,918
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
20577567 Sobreira et al. (2010): Two unrelated families with AD metachondromatosis were reported. In the first family, an 11 bp deletion in exon four of PTPN11 was identified via whole genome sequencing. This change was said to alter frame, result in premature translation termination, and 11 co-segregation with the phenotype in the family (documented within the 4 generations of a 5-generation family with available individuals). Individuals found to carry the mutation initially described as unaffected were determined to be affected by radiological evidence. Sequencing of all PTPN11 exons and flanking splice sites was performed for a second family with three affected individuals - a grandfather and two grandsons. A heterozygous nonsense mutation, p.R138X, was identified in all three affected individuals. This mutation was found in the unaffected individuals with an affected parent and affected children, indicating a role for incomplete penetrance within this condition. Neither mutation was found in 469 control individuals.
21533187 Bowen et al. (2011) did linkage analysis in 17 metachondromatosis (MC) affected families and found a region segregating with affected members encompassing 100 genes. After sequencing all 100 genes, variants were identified in a single gene, PTPN11, in 11 of 17 families, including 6 frameshift, 2 nonsense, and 3 splice site variants. Each family had a different variant and variants were scattered across the gene. Among these 11 families, 9 were inherited (segregation not shown) and 2 were sporadic (assumed de novo). Western blot was performed on a sample from at least one individual with a truncating frameshift variant, demonstrating loss of the wild-type protein. Variants in PTPN11 were not found in other cartilage tumor syndromes, including Ollier disease and Maffucci syndrome.
26984661 McFarlane et al. (2016) A case report of a 5 year old girl who had both exostoses and enchondromas and was diagnosed with metachondromatosis. Analysis of the PTPN11 gene revealed a splice site mutation at the end of exon 1, confirming the diagnosis.

Haploinsufficiency phenotype comments:

Mutations in PTPN11 are most frequently associated with Noonan syndrome and LEOPARD syndrome, however, to date, haploinsufficiency has not been established as a mutational mechanism resulting in these conditions. Noonan syndrome is believed to be caused by gain-of-function defects in PTPN11 (PMID:11992261), and LEOPARD syndrome is believed to be caused by dominant-negative mechanisms (PMID: 16358218). Evidence gathered for the haploinsufficiency rating for this gene is related to the metachondromatosis phenotype.

Evidence for triplosensitivity phenotype
PubMed ID Description
18348260 Shchelochkov et al. (2008): A 3.5 year old female with history of aortic coarctation, minor dysmorphic features, failure to thrive, and developmental delay was found to have a gain in copy number in the distal region of chromosome 12 between bands 12q24.11 (RP11-946P6) and 12q24.23 (RP11-33N14). The duplication encompassed PTPN11, TBX3, and TBX5, in addition to approximately 86 other genes. A diagnosis of Noonan syndrome was initially suspected for this individual. The authors describe 4 additional reports from the literature of large duplications encompassing PTPN11 in which the patients have features that overlap with Noonan syndrome; at least one of these individuals was clinically suspected to have Noonan syndrome.
19760651 Graham et al. (2009): A 4 year old male with hypotonia, developmental delay, and dysmorphic features suggestive of Noonan syndrome was found to have an 8.98 Mb duplication on chromosome 12q encompassing the PTPN11, TBX3, and TBX5 genes (amongst others). This child was clinically suspected to have Noonan syndrome, and molecular analyses of genes known to be associated with Noonan syndrome were negative. Copy number analyses for an additional 250 individuals suspected to have Noonan syndrome but without an identified genetic cause did not reveal any additional duplications.

Triplosensitivity phenotype comment:

Though these reports suggest that duplications of PTPN11 may result in Noonan syndrome, it is important to note that these reported duplications encompassed genes other than PTNP11, notably TBX3 and TBX5, both of which are believed to be dosage sensitive. It cannot be definitively stated that the duplication of PTPN11 is causative of Noonan syndrome, as no focal duplications have yet been reported. These reports have been included here for informational purposes, but as they do not provide specific evidence that duplication of this particular individual gene causes a phenotype, they will not be counted as evidence toward the triplosensitivity score.