• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
FGD1 (HGNC:3663) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
FYVE, RhoGEF and PH domain containing 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
FGDY
Alias symbols
ZFYVE3
%HI
18.2(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.2(Read more about gnomAD LOEUF score)
Cytoband
Xp11.22
Genomic Coordinates
GRCh37/hg19: chrX:54471887-54522667 NCBI Ensembl UCSC
GRCh38/hg38: chrX:54445454-54496234 NCBI Ensembl UCSC
MANE Select Transcript
NM_004463.3 ENST00000375135.4 (Read more about MANE Select)
Function
Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Plays a role in regulating the actin cytoskeleton and cell shape. {ECO:0000269|PubMed:8969170}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-26106
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
05/26/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Aarskog-Scott syndrome, X-linked Monarch
HI Evidence:
  • PUBMED: 17152066
    In 2 Argentinian brothers with Aarskog-Scott syndrome (AAS), Orrico et al. (2006) identified a novel truncating variant in the FGD1 gene, consisting of a 1 basepair insertion in exon 4 of 18 (c.945insC, p.Ala316fs). AAS is characterized mainly by short stature, hypertelorism, brachydactyly and genital anomalies. This phenotype was more typical in the one of the brothers while the older sibling had craniofacial features that were more severe and atypical of AAS. The mother of the probands and her sister were also carriers of the same variant with random X-inactivation patterns. This insertion leads to a frameshift with premature termination at codon 319. The resulting protein was predicted to lack all functionally important structural elements or undergo nonsense-mediated decay, leading to complete absence of a functional protein.
  • PUBMED: 20082460
    Orrico et al. (2010) screened 60 European patients with a clinically suspected diagnosis of AAS for variants in the FGD1 gene. They identified nine novel variants in 11 patients, including four truncating variants (p.Y530X; p.R656X; c.806delC; c.1620delC) and the first reported splice site variant (c.1935þ3A>C). See Table 1 for a summary of the variants.
  • PUBMED: 16353258
    Shalev et al. (2006): A 2189delA variant causing a frameshift in exon 15 of the FDG1 gene in a large Arabic family was detected. The affected individuals in this family demonstrated clinical variability in AAS phenotype.
  • PUBMED: 19110080
    Bedoyan et al. (2009): A male was born at term after an uneventful pregnancy. At 15 months, he was noted to have ocular hypertelorism, downslanting palpebral fissures, small upturned nose, high arched palate, bilateral camptodactyly, and mild shawl scrotum. Given the clinical suspicion of AAS, further molecular testing was performed and initial testing for the FGD1 gene failed to generate PCR amplicons for all coding exons. This was also noted on repeat testing, suggesting a whole gene deletion within this region. For confirmation, chromosome X exon-specific oligonucleotide microarray (OGT) analysis confirmed a FGD1 deletion. Minimum and maximum deletion breakpoints at chrX:54,488,150–54,514,890 and chrX:54,487,830–54,537,940 were identified (hg18) with the max deletion spanning 50kb. The mother declined testing.
  • PUBMED: 28103835
    Hamzeh et al 2017 in BMC Pediatrics reports on two affected brothers from UAE who presented with a number of primary features of AAS, including; hypertelorism, short stature, short nose, anteverted nostrils, interdigital webbing and bilateral fifth finger clinodactyly. On clinical suspension, they were identified with a novel hemizygous variant in FGD1 c.53del (p.Pro18Argfs*106) by PCR amplification and direct sequencing of the entire coding region of FGD1. The parents of siblings were first half cousins and mother was identified as a heterozygous carrier . This frameshift deletion is close to the N-terminus of FGD1 and is predicted to shift the reading frame.
  • PUBMED: 33067218
    Bae et al. (2020) report a 31-month-old Korean boy and his cousin as initially believed to have Noonan syndrome. Subsequent targeted gene panel sequencing revealed a novel hemizygous splice variant c.1192-1 G>A in FGD1 in both the proband and his cousin.
HI Evidence Comments:
Additional frameshift, nonsense variants, and partial deletions in FGD1: https://pubmed.ncbi.nlm.nih.gov/14560308/ Orrico et al. (2004): Orrico et al. (2004) performed SSCP analysis of the FGD1 gene in 46 male patients with a clinical diagnosis of AAS. Eight novel variants, including a frameshift due to a c.528insC was found in 2 independent families. Those with variants presented with a fuller clinical spectrum of the AAS phenotype. https://pubmed.ncbi.nlm.nih.gov/24770546/ Völter et al. (2014): The authors describe a pathogenic variant, p.Q490*, in the index patient, leading to a stop codon in the highly conserved RhoGEF gene domain. The mother and maternal grandmother also found to be heterozygous for this FGD1 variant. https://pubmed.ncbi.nlm.nih.gov/23169394/ Aten et al. (2013): The authors describe a c.2016-35delA branch point variant leading to skipping of exon 13 detected by whole-exome sequencing in two patients with Aarskog-Scott syndrome. https://pubmed.ncbi.nlm.nih.gov/26029706/ Pérez-Coria et al. (2015): The authors describe four unrelated families of Mexican origin with an AAS phenotype, in whom FGD1 sequencing was performed. This analysis identified two stop gain variants not previously reported in the literature: p.Gln664* and p.Glu380*. https://pubmed.ncbi.nlm.nih.gov/27544718/ Parıltay et al. (2016): The authors describe poradic Aarskog syndrome reported in a male (PMID: 25258334, 2014) in which FGD1 (in addition to other genes FAM120C and PHF8) was deleted. Another sporadic case from Germany (PMID: 11093277 2000) describes an intragenic deletion of 3 exons of FGD1 in a male. Of note, the FGD1 protein is considered essential for normal embryogenesis in mammals; with an important role in skeletal development and morphogenesis. The majority of AAS cases are yet to be characterized molecularly, with FGD1 variants being established in about 20% of cases (PMID: 28103835).
NOTE:

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.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
No focal duplications of FGD1 have been reported to date. There has been one reported case of a duplication involving both the FGD1 gene and the HSD17B10 gene by chromosomal microarray (PMID: 33067218); however, because more than one gene is involved, it is not being utilized as evidence for this triplosensitivity evaluation.
NOTE:

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.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)