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Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis

journal contribution
posted on 2023-06-09, 00:31 authored by James T Bennett, Tiong Yang Tan, Diana AlcantaraDiana Alcantara, Martine Tétrault, Andrew E Timms, Dana Jensen, Sarah Collins, Malgorzata J M Nowaczyk, Marjorie J Lindhurst, Katherine M Christensen, Stephen R Braddock, Heather Brandling-Bennett, Raoul C M Hennekam, Brian Chung, Anna Lehman, John Su, SuYuen Ng, David J Amor, Jacek Majewski, Les G Biesecker, Kym M Boycott, William B Dobyns, Mark O'DriscollMark O'Driscoll, Ute Moog, Laura M McDonell
Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.

History

Publication status

  • Published

File Version

  • Published version

Journal

The American Journal of Human Genetics

ISSN

0002-9297

Publisher

Elsevier

Issue

3

Volume

98

Page range

579-587

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2016-03-22

First Compliant Deposit (FCD) Date

2016-03-17

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