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RESEARCH PRODUCT
Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.
Judith St-ongeJudith St-ongeYannis DuffourdSandra WhalenMarjolaine WillemsAnne-claire BursztejnMassimiliano RossiBertrand IsidorPatrick EderyOdile BouteVirginie CarmignacJ. MiquelSébastien BarbarotDaniel AmramFanny Morice-picardA. PhanPierre VabresDidier LacombeMaryse BonnièreJean-baptiste RivièreNadia Bahi-buissonCatherine Vincent-delormeThibaud JouanPaul KuentzCaroline MichotRenaud TouraineJean-benoît CourcetChristine FrancannetMarie VincentSmail Hadj-rabiaValérie Cormier-daireChristine CoubesCyril MignotNathalie MarleJeanne AmielMichèle Mathieu-dramardPhilippe Khau Van KienJuliette Mazereeuw-hautierAnnabel MaruaniSalima El ChehadehGeneviève BaujatChristine ChiaveriniDaphné LehalleArthur SorlinFlorence PetitBruno DelobelLaurence FaivreJulien ThevenonStéphanie ArpinDidier BessisDamien HayeDavid GenevièveTania Attié-bitachClaire Abasq-thomasJelena MartinovicAlain VerloesChristel Thauvin-robinetJuliette AlbuissonMarie-line JacquemontAlice GoldenbergOlivia BoccaraLudovic Martinsubject
0301 basic medicineAdultMalePathologymedicine.medical_specialtyAdolescentGenotypeClass I Phosphatidylinositol 3-KinasesPrenatal diagnosisBioinformaticsmedicine.disease_causeDNA sequencing03 medical and health sciencesYoung Adult0302 clinical medicinePrenatal DiagnosisGenotypemedicineHumansGenetic Predisposition to DiseaseGenetic TestingAlleleChildGenetics (clinical)AllelesGenetic Association StudiesGrowth DisordersGenetic testingMutationmedicine.diagnostic_testbusiness.industryMosaicismInfant NewbornDisease ManagementHigh-Throughput Nucleotide SequencingInfantSequence Analysis DNAPhenotype030104 developmental biologyPhenotypeAmino Acid SubstitutionChild PreschoolMutationAllelic heterogeneityFemalebusiness030217 neurology & neurosurgerydescription
Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10−5). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10−25), regardless of the phenotype. Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions. Genet Med advance online publication 02 February 2017
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-09-01 | Genetics in medicine : official journal of the American College of Medical Genetics |