A novel, putatively null, FGD1 variant leading to Aarskog-Scott syndrome in a family from UAE

Abstract

BackgroundThe X-linked condition “Aarskog-Scott syndrome (AAS)” causes a characteristic combination of short stature, facial, genital and skeletal anomalies. Studies elucidated a causative link between AAS and mutations in the FGD1 gene, which encodes a Rho/Rac guanine exchange factor. FGD1 is involved in regulating signaling pathways that control cytoskeleton organization and embryogenesis.Case presentationFGD1 was studied in an Emirati family with two cases of AAS using PCR amplification and direct sequencing of the entire coding region of the gene. Various in silico tools were also used to predict the functional consequences of FGD1 mutations. In the reported family, two brothers harbor a novel hemizygous mutation in FGD1 c.53del (p.Pro18Argfs*106) for which the mother is heterozygous. This frameshift deletion, being close to N-terminus of FGD1, is predicted to shift the reading frame in a way that it translates to 105 erroneous amino acids followed by a premature stop codon at position 106. Full molecular and clinical accounts about the variant are given so as to expand molecular and phenotypical knowledge about this disorder.ConclusionsA novel variant in FGD1 was found in an Emirati family with two brothers suffering from AAS. The variant is predicted to be a null mutation, and this is the first report of its kind from the United Arab Emirates.Electronic supplementary materialThe online version of this article (doi:10.1186/s12887-017-0781-4) contains supplementary material, which is available to authorized users.

FGD1 Variant Associated With Aarskog–Scott Syndrome

“…Intriguingly, his mother and sister also carried the same FGD1 variant, who only presented with mild short stature. This was also observed in other female carriers ( 2 , 17 , 30 ). Alternatively, clinical phenotypes of female patients with AAS, in general, seemed relatively mild, which may be associated with X chromosome inactivation ( 31 , 32 ).…”

“…Children with AAS have heterogeneous clinical manifestations. Short stature, craniofacial, genital, and skeletal anomalies are the classically characteristic combination ( 2 ). With respect to short stature, the most common symptom in the disease; it is disproportionate, with an increased upper-to-lower segment ratio and shortened distal extremities ( 3 , 4 ).…”

Identification of TAF1, SAT1, and ARHGEF9 as DNA methylation biomarkers for hepatocellular carcinoma

“…The guanine nucleotide exchange factor FGD1 could activate Rho GTPase cell division cycle 42. Reports showed that FGD1 was a critical gene marker to the diagnosis of Aarskog‐Scott syndrome (Griffin, Farley, Antonellis, & Keegan, ; Hamzeh et al, ) and breast cancer (Beasley, Buckhaults, Pedigo, & Farrell, ), implying its important role in the development of cancer. Collectively, these genes we found in our study might play an important role in the development of HCC.…”