1. ¹Molecular Medicine, Azienda Ospedaliera Universitaria Senese, Siena, Italy
2. ²Medical Genetics, Azienda Ospedaliera 'Cardarelli', Napoli, Italy
3. ³Clinical Genetics, Divisione di Pediatria, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
4. ⁴Center for Human Genetics, University Hospital, Laiden, Belgium
5. ⁵Department of Endocrinology, Our Lady's Hospital for Sick Children, Dublin, Ireland
6. ⁶Medical Genetics, Hospital de Santa Maria, Lisboa, Portugal
7. ⁷Department of Neurosciences, Molecular Medicine Section, Università di Siena, Italy

Correspondence: Dr A Orrico, Molecular Medicine, Azienda Ospedaliera Universitaria Senese, Viale Bracci n. 2, Siena 53100, Italy. Tel.: +39 577 586264; Fax: +39 577 234191; E-mail: a.orrico@ao-siena.toscana.it

Received 27 March 2003; Revised 27 June 2003; Accepted 1 July 2003; Published online 15 October 2003.

Abstract

Faciogenital dysplasia or Aarskog–Scott syndrome (AAS) is a genetically heterogeneous developmental disorder. The X-linked form of AAS has been ascribed to mutations in the FGD1 gene. However, although AAS may be considered as a relatively frequent clinical diagnosis, mutations have been established in few patients. Genetic heterogeneity and the clinical overlap with a number of other syndromes might explain this discrepancy. In this study, we have conducted a single-strand conformation polymorphism (SSCP) analysis of the entire coding region of FGD1 in 46 AAS patients and identified eight novel mutations, including one insertion, four deletions and three missense mutations (19.56% detection rate). One mutation (528insC) was found in two independent families. The mutations are scattered all along the coding sequence. Phenotypically, all affected males present with the characteristic AAS phenotype. FGD1 mutations were not associated with severe mental retardation. However, neuropsychiatric disorders, mainly behavioural and learning problems in childhood, were observed in five out of 12 mutated individuals. The current study provides further evidence that mutations of FGD1 may cause AAS and expands the spectrum of disease-causing mutations. The importance of considering the neuropsychological phenotype of AAS patients is discussed.