Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

Lindhurst, Marjorie J.; Parker, Victoria; Payne, Felicity; Sapp, Julie C.; Rudge, Simon A.; Harris, Julie; Witkowski, Alison M; Zhang, Zuo‐Feng; Groeneveld, Matthijs; Scott, Carol; Daly, Allan; Huson, Susan M.; Tosi, Laura L.; Cunningham, Michael L.; Darling, Thomas N.; Geer, Joseph S.; Gucev, Zoran; Sutton, V. Reid; Tziotzios, Christos; Dixon, Adrian K.; Helliwell, Tim; O’Rahilly, Stephen; Savage, David B.; Wakelam, Michael J.O.; Barroso, Inês; Biesecker, Leslie G.; Semple, Robert K.

doi:10.1038/ng.2332

Cited by 276 publications

(253 citation statements)

References 34 publications

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“…Sample preparation was performed as described previously (25), and the captured samples were eluted, amplified, and sequenced on the Illumina Hi-Seq platform (Illumina) as 75-bp paired-end reads. The full methods used for whole exome sequencing and mutation analysis, confirmatory Sanger sequencing, and haplotype analysis are described in SI Methods.…”

Section: Methodsmentioning

confidence: 99%

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Payne

Lim

Girousse

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The characterization of rare monogenic human disorders can and has yielded unique biological insights. Our phenotypic description and functional characterization of human loss-of-function mutations in PCYT1A is both clinically important for patients and their families afflicted with this rare but serious metabolic disease and biologically helpful in advancing understanding of the physiological consequences of impaired PCYT1A activity in humans.

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Section: Methodsmentioning

confidence: 99%

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Payne

Lim

Girousse

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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130

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“…The power of implementing precision medicine in the clinic is epitomised in the case of a patient with mosaic overgrowth with fibroadipose hyperplasia [17]. Parts of the patient's body were unaffected by the condition while other parts were massively overgrown.…”

Section: The Emergence Of Precision Medicinementioning

confidence: 99%

“…This case clearly indicates how precision medicine approaches can be employed clinically to determine the genetic lesion driving a disease and predict the appropriate therapeutic treatment at the level of an individual patient. In addition, once this personalised approach was implemented the investigators went on to perform targeted PI3KCA sequencing in other patients with overlapping syndromes and identified mutations in the same gene in nine out of ten cases [17]. This clinical study epitomises both the potential power and versatility of precision medicine, and demonstrates the clinical applicability of both global and targeted approaches.…”

Section: The Emergence Of Precision Medicinementioning

confidence: 99%

Problems, challenges and promises: perspectives on precision medicine

Duffy¹

2015

Brief Bioinform

110

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Conflicts of interest:The author discloses no potential conflicts of interest. Summary key points•Introduction of precision medicine/systems medicine concepts and approaches• Review of some of the challenges to the clinical implementation of precision medicine• Outline of methodologies being employed to overcome these challenges• Examination of the claims that precision medicine has overpromised Author biographyDavid J. Duffy is primarily an experimentalist, based at Systems Biology Ireland in University College Dublin. His research interests include cancer biology and evolutionary developmental biology and the application of omic technologies and systems medicine approaches to address questions in these fields. AbstractThe precision medicine (systems medicine) concept promises to achieve a shift to future

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“…11,12 Recently, variants in the PI3K-AKT pathway have been described to be associated with megalencephaly and overgrowth syndromes, such as MCAP and MPPH, 5-7 but also CLOVES (congenital lipomatous asymmetric overgrowth, epidermal naevi, skeletal and spinal anomalies) syndrome, 13,14 as well as hemimegalencephaly 15 and isolated macrodactyly. 16 Although both the RAS-MAPK pathway and the PI3K-AKT pathway are very complex and still only partly understood, interactions between these two signaling pathways are well known: most importantly but not exclusively, activated GTP-bound RAS not only induces the MAP-kinase cascade through association with RAF, but can also bind to PI3K to increase the generation of PIP3 out of PIP2, thereby activating several downstream effectors such as mTOR, BAX or FOXO-each directing to distinct cellular results leading to inhibition of apoptosis, initiation of translation, cell proliferation and loss of cell differentiation (see Figure 2).…”

Section: Ptpn11 Variant and Mcap Syndrome D Döcker Et Almentioning

confidence: 99%

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

et al. 2014

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Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactylythus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A4G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (4100 Â coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (41000 Â coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G4A; p. (Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.

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Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

Cited by 276 publications

References 34 publications

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Problems, challenges and promises: perspectives on precision medicine

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

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