FGD1 |
- 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
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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)
Haploinsufficiency (HI) Score Details
- Aarskog-Scott syndrome, X-linked Monarch
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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.
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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.
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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.
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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.
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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.
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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.
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
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.