ESPE Abstracts (2014) 82 P-D-1-3-92

aInstitut Pasteur, Paris, France; bUniversité Paris Descartes and Pediatric Endocrinology Unit, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; cDepartment of Paediatrics, G. d’Annunzio, University of Chieti, Chieti, Italy

Background: The genetic causes of disorders of sex development (DSD) are difficult to identify since these conditions are refractory to classic genetic approaches. In particular the underlying genetic mutations of most cases of 46,XY DSD is unknown.

Objective and hypotheses: Using an exome sequencing approach we aimed to identify new genetic factors involved in 46,XY gonadal dysgenesis.

Method: Exon enrichment was performed using Agilent SureSelect Human All Exon V4. Paired-end sequencing was performed on the Illumina HiSeq2000 platform. Read files were generated from the sequencing platform via the manufacturer’s proprietary software. Reads were mapped using the Burrows–Wheeler Aligner and local realignment of the mapped reads around potential insertion/deletion (indel) sites was carried out with the GATK version 1.6. SNP and indel variants were called using the GATK Unified Genotyper for each sample. SNP novelty was determined against dbSNP137. Candidate pathogenic mutations were confirmed by Sanger sequencing.

Results: We identified different missense mutations in the gene encoding the extracellular matrix protein FIBULIN2 (FBLN2) in association with 46,XY gonadal dysgenesis. These included three members of a familial case of 46,XY gonadal dysgenesis and two sporadic cases of 46,XY gonadal dysgenesis. None of these mutations were found in large series of ancestry-matched control samples. FBLN2 is highly expressed in Sertoli cells following SRY expression and it is repressed in the developing ovary by FOXL2 and WNT4. It has previously been proposed as a mammalian sex-determining gene.

Conclusion: We demonstrate that mutations involving FBLN2 are a new cause of 46,XY DSD.

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