Analysis of FOXL2 detects three novel mutations and an atypical phenotype of blepharophimosis-ptosis-epicanthus inversus syndrome.
BACKGROUND
Mutations in FOXL2 are known to cause autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), variably associated with premature ovarian failure. In this study, we report results of mutational screening in a Czech and Slovak patient population with BPES.


METHODS
Case series.


METHODS
Thirteen probands of Czech and one proband of Slovak origin with BPES and their available family members.


METHODS
Sanger sequencing and multiplex ligation-dependent probe amplification in 14 probands with BPES. Targeted mutational screening in first-degree relatives.


METHODS
Genetic characterization and phenotype evaluation in Czech and Slovak individuals with BPES and their family members.


RESULTS
Eight different mutations were detected including three novel ones: c.5T>G; p.(Met2Arg), c.197C>A; p.(Ala66Glu) and c.701_702insTGCAGCCGCAGCGGCTGCAGCAGCTGCGGCTGCAGCCGC; p.(Ala222_Ala234dup). In one family, the molecular genetic cause of disease was not identified by the methodology used. In 13 pedigrees, a negative family history suggested a de novo origin, which could be confirmed by targeted mutational screening in four families. One 62-year-old female with the c.663_692dup30 mutation had an atypical phenotype presenting as moderate ptosis compensated by frontalis muscle contraction, no epicanthus inversus and no premature ovarian failure.


CONCLUSIONS
The de novo mutation rate in FOXL2 is exceptionally high compared with other dominant disorders manifesting with an ocular phenotype. In cases reporting a negative family history, careful examination of both parents is important to exclude mild features of the BPES phenotype.
Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
Anna
A
Krepelova
Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
Martina
M
Simandlova
Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
Marketa
M
Vlckova
Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Pavel
P
Kuthan
Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
Andrea L
AL
Vincent
Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.|Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Petra
http://orcid.org/0000-0001-7834-8486
P
Liskova
D000293:Adolescent; D000328:Adult; D016569:Blepharophimosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015342:DNA Probes; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D020125:Mutation, Missense; D010641:Phenotype; D012868:Skin Abnormalities / Q000235:genetics*; D014564:Urogenital Abnormalities / Q000235:genetics*
D015342:DNA Probes; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors
FOXL2; blepharophimosis-ptosis-epicanthus inversus syndrome; phenotype