ClinGen Dosage Sensitivity Curation Page

FGD1

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
17152066 In 2 brothers with Aarskog-Scott syndrome (AAS), Orrico et al. (2006) identified a novel truncating mutation in the FGD1 gene, consisting of a 1 basepair insertion in exon 4 (945insC). This insertion leads to a frameshift with premature termination at codon 319. The resulting protein either lacks all functionally important structural elements or undergoes nonsense-mediated decay, leading to complete absence of a functional protein.
20082460 Orrico et al. (2010) screened 60 European patients with a clinically suspected diagnosis of AAS for mutations in the FGD1 gene. They identified nine novel mutations in 11 patients, including four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC) and the first reported splice site mutation (c.1935?3A>C). See Table 1 for a summary of the mutations.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.