Identification of copy number variants associated with BPES-like phenotypes

• Published in: Human genetics 2008-12, Vol.124 (5), p.489-498
• Main Authors: Gijsbers, Antoinet C. J., D’haene, Barbara, Hilhorst-Hofstee, Yvonne, Mannens, Marcel, Albrecht, Beate, Seidel, Joerg, Witt, David R., Maisenbacher, Melissa K., Loeys, Bart, van Essen, Ton, Bakker, Egbert, Hennekam, Raoul, Breuning, Martijn H., De Baere, Elfride, Ruivenkamp, Claudia A. L.
• Format: Article
• Language: English
• Subjects: Analysis; Arrays; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blepharophimosis - genetics; Blepharoptosis - genetics; Chromosome Aberrations; Classical genetics, quantitative genetics, hybrids; Eyelids - abnormalities; Female; Fundamental and applied biological sciences. Psychology; Gene Dosage; Gene Function; Genetic aspects; Genetic transcription; Genetic Variation; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Genotype & phenotype; Human; Human Genetics; Humans; In Situ Hybridization, Fluorescence; Intellectual disabilities; Intellectual Disability - genetics; Male; Metabolic Diseases; Molecular Medicine; Mutation; Original Investigation; Ovaries; Patients; Pediatrics; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Syndrome; Transcription factors
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-008-0574-9

Blepharophimosis–Ptosis–Epicanthus inversus syndrome (BPES) is a well-characterized rare syndrome that includes an eyelid malformation associated with (type I) or without premature ovarian failure (type II). Patients with typical BPES have four major characteristics: blepharophimosis, ptosis, epicanthus inversus and telecanthus. Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for the majority of both types of BPES. However, many patients with BPES-like features, i.e., having at least two major characteristics of BPES, have an unidentified cause. Here, we report on a group of 27 patients with BPES-like features, but without an identified genetic defect in the FOXL2 gene or flanking region. These patients were analyzed with whole-genome high-density arrays in order to identify copy number variants (CNVs) that might explain the BPES-like phenotype. In nine out of 27 patients (33%) CNVs not previously described as polymorphisms were detected. Four of these patients displayed psychomotor retardation as an additional clinical characteristic. In conclusion, we demonstrate that BPES-like phenotypes are frequently caused by CNVs, and we emphasize the importance of whole-genome copy number screening to identify the underlying genetic causes of these phenotypes.