Phenotypic and molecular characterisation of the Aarskog–Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients

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.

Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

“…These comprise 32 missense variants, 16 frameshift variants, 6 nonsense variants, 4 splice site variants, 1 in-frame deletion and 2 gross deletions. [2][3][4][5][6][7][8][9][10] In addition, a large duplication (exon 2-12) and a branch-point variant, both leading to a premature stop codon, have been described in affected families. 11,12 Germline mosaicism has been reported.…”

“…11,12 Germline mosaicism has been reported. 6 No definite genotype-phenotype correlation is apparent from comparison of patients with different variants; 2,10 however, affected members of one family with a c.1341G4A; p.(Trp447Ter) variant in exon 6 all presented with additional signs of myopathy and distal arthropathy. 8 …”

“…These approaches will facilitate the distinction of pathogenic variants from polymorphisms, especially in the cases of missense variants 1.8 Estimated frequency of the disease (incidence at birth ('birth prevalence') or population prevalence) Only 35 molecularly proven cases have been published worldwide. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] The majority of patients with a clinical diagnosis where details were published before the advent of molecular testing have not undergone subsequent molecular testing. Experience in Leuven (Prof. JP Fryns: personal communication), a typical-sized clinical genetics unit, suggests that two to three new patients with a proven variant in the FGD1 gene will be identified per year, a similar number as for Angelman and Prader-Willi syndrome.…”

Management of Children with Intellectual and Developmental Disability in an African Setting

“…Only a minority of the clinically diagnosed patients carries a mutation in the faciogenital dysplasia 1 gene. The diagnosis of the X-linked Aarskog syndrome needs to be made with care as the spectrum of clinical signs overlaps with that of many different disease entities and, although the phenotype may be impressive, many alternative diagnoses have to be considered (Orrico et al, 2004). We got two cases of mucopolysaccharidosis type I that is also called Hurler syndrome with a severe intellectual disability.…”

Association of FGD1 polymorphisms with early-onset breast cancer

“…Polymorphisms in the FGD1 gene have been associated with a rare X-linked disorder known as faciogenital dysplasia or Aarskog-Scott syndrome (3). This disorder is characterized by short stature and congenital anomalies of the face, skeleton and genitals (11)(12)(13). Malformations are consistent with a loss of cellular migration during embryonic development (14).…”