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FAT4
FAT atypical cadherin 4
The FAT4 gene provides instructions for a protein critical in brain, kidney, heart, and lymphatic system development, influencing cell positioning and potentially acting as a tumour suppressor. The FAT4 gene encodes a protein that plays a key role in the formation and function of multiple organ systems, including the brain, kidneys, heart, and lymphatic system.
FAT4 is located on the long (q) arm of chromosome 4, at band 4q28.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The FAT4 gene, also known as FAT atypical cadherin 4, is integral to various developmental processes in the human body. The protein produced from this gene is involved in the proper development of key organs such as the brain, kidneys, and heart. It also contributes significantly to the formation and function of the lymphatic system, a vital network for immune response and fluid balance.
Beyond organ development, the FAT4 protein helps determine the precise positioning of cells and their internal components within different tissues. This organised arrangement is crucial for cells to coordinate their activities effectively and for tissues to develop their characteristic structure and function. Furthermore, research suggests the FAT4 protein may act as a tumour suppressor, helping to regulate cell growth and division.
What the gene does
The FAT4 gene provides instructions for the FAT4 protein, which is believed to be involved in cell-to-cell adhesion and signalling pathways crucial for tissue development. This protein influences the placement and organisation of cells, allowing them to communicate and collaborate effectively to form complex structures like organs and the lymphatic system. In the brain, kidneys, and heart, FAT4 plays a role in their proper formation during development. Within the lymphatic system, the FAT4 protein is important for the normal structure and function of lymphatic vessels, which transport immune cells, nutrients, and fluids throughout the body. Additionally, the FAT4 protein may contribute to maintaining cellular control by inhibiting excessive cell proliferation, suggesting a potential function as a tumour suppressor.
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Chromosome location
The FAT4 gene is located on chromosome 4 at position 4q28.1. This specific location refers to the long arm (q) of chromosome 4, within region 28, band 1.
Protein structure
The FAT4 protein is a large protein, composed of 4981 amino acids. It features an extensive array of cadherin domains, which are typically involved in cell adhesion. These include Cadherin 1 (amino acids 43-135), Cadherin 2 (amino acids 136-250), Cadherin 3 (amino acids 251-353), Cadherin 4 (amino acids 359-475), Cadherin 5 (amino acids 476-582), Cadherin 6 (amino acids 584-689), Cadherin 7 (amino acids 690-793), Cadherin 8 (amino acids 794-893), Cadherin 9 (amino acids 894-996), Cadherin 10 (amino acids 997-1100), Cadherin 11 (amino acids 1101-1210), Cadherin 12 (amino acids 1211-1315), Cadherin 13 (amino acids 1316-1420), Cadherin 14 (amino acids 1421-1529), and Cadherin 15 (amino acids 1529-1629).
Key variants
Variants in the FAT4 gene can affect its ability to produce a functional protein, which may disrupt its roles in development and cell organisation. These genetic changes, sometimes referred to as pathogenic variants, can lead to altered protein structure or function, potentially impacting various bodily systems. The clinical significance of a FAT4 variant is assessed based on its specific nature and location within the gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.13588C>T | p.Gln4530Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hennekam lymphangiectasia-lymphedema syndrome 2 |
c.5704C>T | p.Arg1902Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hennekam lymphangiectasia-lymphedema syndrome 2 |
c.6700C>T | p.Arg2234Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Van Maldergem syndrome |
c.7504G>T | p.Glu2502Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive FAT4-related disorders |
c.10730_10731del | p.Glu3577fs | Pathogenic | ★☆☆☆ | not provided |
c.108del | p.Gln37fs | Pathogenic | ★☆☆☆ | not provided |
c.3032_3033dup | p.Asn1012Ter | Pathogenic | ★☆☆☆ | not provided |
c.6887C>A | p.Ser2296Ter | Pathogenic | ★☆☆☆ | not provided |
c.775dup | p.Val259fs | Pathogenic | ★☆☆☆ | not provided |
c.7787T>A | p.Leu2596Ter | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Genetic changes in the FAT4 gene are associated with specific inherited conditions. Pathogenic variants in FAT4 have been identified as a cause of Hennekam syndrome, a disorder characterised by abnormalities of the lymphatic system, often including dilated lymphatic vessels and fluid accumulation. Additionally, FAT4 variants have been found in individuals with van Maldergem syndrome, a condition featuring intellectual disabilities, hearing loss, skeletal abnormalities, and a brain malformation known as periventricular heterotopia.
No disease links recorded for this gene in our reference set.
UK clinical status
The FAT4 gene is currently listed on several NHS Genomic Medicine Service clinical panels, indicating its relevance in diagnostic testing within the UK. It is a 'green' gene for conditions such as COVID-19 research, Developmental Disorders (DDG2P), Foetal anomalies (R21), Intellectual disability, Intestinal failure or congenital diarrhoea (R331), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), and Primary lymphoedema (R136).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the FAT4 gene?
The FAT4 gene primarily provides instructions for a protein crucial for the proper development of the brain, kidneys, heart, and lymphatic system. It is also involved in organising cells within tissues and may function as a tumour suppressor.
Which conditions are associated with changes in the FAT4 gene?
Pathogenic variants in the FAT4 gene are associated with Hennekam syndrome, characterised by lymphatic system abnormalities, and van Maldergem syndrome, which involves intellectual disabilities, hearing loss, skeletal issues, and a specific brain malformation.
How does the FAT4 protein contribute to tissue structure?
The FAT4 protein helps determine the precise positioning of cells and their internal components within various tissues. This organised arrangement is essential for cells to coordinate their activities and for tissues to achieve their characteristic structure and function.
References
- Alders M, Al-Gazali L, Cordeiro I. Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Human genetics. 2014. PMID: 24913602