FGD1 – Aarskog-Scott syndrome

Aarskog-Scott syndrome (ASS) is a rare X-linked recessive disorder characterised by disproportionate short stature, craniofacial, limb, and genitourinary anomalies. Mutations in FGD1 (FYVE, RhoGEF, and PH domain-containing protein 1) underlie the X-linked form of ASS, encoding a Rho/Rac guanine nucleotide exchange factor crucial for embryonic morphogenesis.

The FGD1 gene was first implicated in ASS by identification of a hemizygous c.1829G>A (p.Arg610Gln) variant in exon 10 in a proband, which segregated with phenotype in affected males and carrier females from a multigenerational Italian family (n = 13 patients; 1 variant) (PMID:10930571). Subsequent screening of 46 independent ASS patients revealed eight additional FGD1 variants including insertions, deletions, and missense changes distributed across the coding sequence, confirming genetic heterogeneity and recurrent mutational events (19.56% detection rate) (PMID:14560308).

Expanded case series and family studies have identified over 30 pathogenic variants in FGD1 from more than 20 unrelated families, encompassing missense changes (e.g., c.527dup (p.Leu177fs)), nonsense mutations (e.g., c.1468C>T (p.Gln490Ter)), splice-site and large exon deletions, and the first branch-point intronic variant disrupting exon 13 splicing (PMID:23169394). Maternal germline mosaicism has also been documented, demonstrating de novo mutational events and highlighting genetic counselling considerations (PMID:21739585).

Functional assays reveal that Fgd1 directly interacts with actin-regulatory proteins cortactin and mAbp1 via its SH3-binding domain, and that disease-associated mutations impair these interactions leading to actin cytoskeletal defects (PMID:12913069). In osteoblast models, FGD1 activates CDC42, which engages MLK3 to stimulate ERK and p38 MAPK signaling and Runx2-driven bone mineralization; FGD1 mutations ablate MLK3 activation and recapitulate skeletal anomalies in Mlk3-deficient mice (PMID:21965325).

Integrating genetic and experimental data over two decades supports a Definitive FGD1–ASS association. Genetic evidence is strong—FGD1 variants in >30 probands from >15 families with clear X-linked recessions and segregation of at least 19 affected relatives. Functional data are concordant with haploinsufficiency and disrupted CDC42 signaling. These insights enable molecular diagnosis, inform genetic counselling, and suggest MAPK modulation as a potential therapeutic avenue.

Key Take-home: FGD1 genetic testing should be prioritized for males presenting with ASS phenotypes, with targeted sequencing and copy-number analysis coupled with functional assays to confirm pathogenicity.

References

• FEBS Letters • 2000 • A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome). PMID:10930571
• European Journal of Human Genetics • 2004 • Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. PMID:14560308
• Human Mutation • 2013 • Exome sequencing identifies a branch point variant in Aarskog-Scott syndrome. PMID:23169394
• American Journal of Medical Genetics Part A • 2011 • Fraternal twins with Aarskog-Scott syndrome due to maternal germline mosaicism. PMID:21739585
• Human Molecular Genetics • 2003 • Fgd1, the Cdc42 GEF responsible for Faciogenital Dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape. PMID:12913069
• Journal of Clinical Investigation • 2011 • MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. PMID:21965325

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