ESPE Abstracts (2015) 84 P-1-59

Novel Genetic Associations in Children with Disorders of Sex Development and Neurodevelopment Disorders - Insights from the Deciphering Developmental Disorders study

Gabriella Gazdagha, DDD Studyb, Edward S Tobiasc, S Faisal Ahmedd & Ruth McGowana

aWest of Scotland Regional Genetics Service, Laboratory Medicine Building, Southern General Hospital, Glasgow, UK; bWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; cSchool of Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; dDevelopmental Endocrinology Research Group, Royal Hospital For Sick Children, University of Glasgow, Glasgow, UK

Background: Collaborative project to review the phenotypic and genotypic data from children recruited to the UK wide deciphering developmental disorders (DDD) study.

Objective and hypotheses: To report the frequency and range of disorders of sex development (DSD) phenotypes observed in DDD participants who have one or more associated ‘neurodevelopmental delay’ diagnostic human phenotype ontology (HPO) term.

Method: Retrospective review of anonymized data from participants in the DDD study.

Results: Of 7439 DDD participants recruited, 603 (8%) had at least one HPO term in the ‘abnormalities of the genital system’ and 6621 individuals had neurodevelopmental delay. Of these 603 children, 370 (61%) had at least one ‘neurodevelopmental delay’ diagnosis with an overall frequency of 6%. DSD phenotypes in individuals with neurodevelopmental delay. The 370 patients had a total of 447 DSD phenotypes, the majority, 420 (94%) abnormalities of the external genitalia. Of the male external genitalia abnormalities, 212 (54%) were testicular, 74 (19%) were hypospadias, 57 (15%) were penile and 47 (12%) were other abnormalities. Testicular abnormalities included unilateral cryptorchidism, bilateral cryptorchidisms, hydrocele and other phenotypes. Causative mutations were found in 14 genes already listed on the Developmental Disorders Genotype To Phenotype (DDG2P) database (, confirming a range of syndromic diagnoses with associated DSD, including: KBG syndrome, Meier-Gorlin syndrome, (α – thalassemia/mental retardation syndrome, Kabuki syndrome and Donnai-Barrow syndrome. Of these likely pathogenic mutations, 6 of 14 (43%) were found in DDG2P genes not previously associated with DSD.

Conclusion: The association of DSD with learning difficulties is not uncommon and a range of DSD phenotypes may be encountered. Recognition of these associations should not be overlooked in the management of patients with complex conditions. Exomic sequencing through projects like DDD increases diagnostic yield and the identification of mutations in developmental genes may improve our understanding about the pathogenesis of DSD.

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