Non‐syndromic X‐linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene

Abstract

Three brothers with non-syndromal X-linked mental retardation were found to have a novel missense mutation in FGD1, the gene associated with the Aarskog syndrome. Although the brothers have short stature and small feet, they lack distinct craniofacial, skeletal or genital findings suggestive of Aarskog syndrome. Their mother, the only obligate carrier available for testing, has the FGD1 mutation. The mutation, a C934T base change in exon 4, results in the proline at position 312 to be substituted with a leucine. This missense mutation is predicted to eliminate a beta-turn, creating an extra-long stretch of coiled sequence which may affect the orientations of an SH3 (Src homology 3) binding domain and the first structural conserved region. A new molecular defect associated with non-syndromal X-linked mental retardation affords an opportunity to seek specific diagnosis in males with previously unexplained developmental delays and this opens further predictive tests in families at risk.

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

“…The clinical data of the first reported cases of AAS with FGD1 mutations did not support those observations, as mental retardation did not appear to be part of the phenotype of mutated patients. 6,7 The recent discovery, however, that the FGD1 mutation P312L is associated to nonsyndromic X-linked mental retardation in a family, 8 and the presence of various developmental disabilities and/or behavioural disorders in five of the 12 mutated patients in this study confirms that developmental disabilities may be part of the AAS phenotype. Severe mental retardation, as reported by Lebel et al, 8 was not noted in the present group of mutated patients; 12 of our AAS patients had severe mental retardation, and all 12 were found to be negative for FGD1 mutations.…”

“…8 To avoid confusion, this nomenclature is also applied to the previously reported mutations that are renumbered, while the previously used nomenclature is reported in parantheses. …”

“…11 In addition, it has been reported that some degree of cognitive impairment may be as high as 30% in the AAS subjects, 12 while other studies reject the association with mental handicap. 13 As a further confounding issue, a recent report of nonsyndromic XLMR associated to the P312L FGD1 mutation 8 gives additional evidence that mental impairment may be part of the phenotype, even in the absence of the typical AAS features.…”

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

“…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.…”

“…It is already acknowledged that some patients with pathogenic variants do not have all the typical clinical features. [13][14][15] The clinical sensitivity depends on variable factors such as age or family history. In reporting cases, a general statement to this effect should be given, even if a quantification can only be made case by case.…”