On this page
WAC
WW domain containing adaptor with coiled-coil
WAC encodes an adaptor protein involved in cellular protein regulation, with variants linked to neurodevelopmental disorders. The WAC gene provides instructions for making a protein that functions as a cellular adaptor, helping to coordinate protein interactions and regulate various cellular processes.
WAC is located on the short (p) arm of chromosome 10, at band 10p12.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 10 in the library →Overview
The WAC gene, located on chromosome 10, encodes a protein of 647 amino acids known as WW domain containing adaptor with coiled-coil. This adaptor protein plays a role in coordinating protein-to-protein interactions within cells, contributing to the regulation of various cellular pathways. The gene's name reflects two key structural features: a WW domain that mediates binding to other proteins, and a coiled-coil region that facilitates protein assembly.
Pathogenic changes in WAC have been recognised in clinical genetics practice, particularly in relation to neurodevelopmental presentations. The gene is included in UK NHS genomic medicine panels for intellectual disability and neurodevelopmental disorders, reflecting its clinical relevance. Understanding WAC function helps explain how disruptions to cellular protein networks can affect neurological development and function.
What the gene does
The WAC protein functions primarily as a molecular adaptor, bringing together different proteins to enable specific cellular processes. The WW domain within the protein recognises and binds to proline-rich sequences in partner proteins, whilst the coiled-coil region facilitates the formation of larger protein complexes. This architecture allows WAC to act as a scaffold, coordinating interactions between multiple proteins simultaneously.
WAC participates in several cellular pathways, including those involved in transcriptional regulation and ubiquitin-mediated protein degradation. By serving as a bridge between different signalling molecules, the protein helps cells respond appropriately to developmental cues and environmental changes. The protein's adaptor function appears particularly important in neuronal cells, where precise coordination of protein networks supports normal brain development and function.
The protein's role extends to maintaining proper cellular organisation and protein turnover. Through its interactions with other regulatory proteins, WAC contributes to quality control mechanisms that ensure cellular proteins are correctly folded, localised, and degraded when no longer needed. Disruption of these processes can have cascading effects on cellular health, particularly in tissues with high metabolic demands such as the developing nervous system.
Video: Genetics 101
Chromosome location
WAC is located on the short arm of chromosome 10 at position 10p12.1. This chromosomal region contains numerous genes involved in development and cellular regulation. The gene's position on chromosome 10 places it within a genomic neighbourhood that has been studied in relation to various neurodevelopmental phenotypes.
The precise genomic context of WAC includes both regulatory elements that control when and where the gene is expressed, and structural features that influence how the chromosome is organised within the cell nucleus. Understanding the gene's chromosomal location can be relevant for interpreting certain genetic findings, particularly those involving larger chromosomal rearrangements.
Protein structure
The WAC protein, in its canonical form, comprises 647 amino acids and exhibits a modular architecture with distinct functional regions distributed across its sequence. The N-terminal region, spanning amino acids 1 to 138, is classified as disordered, meaning it lacks a fixed three-dimensional structure. Such disordered regions often provide flexibility and enable the protein to interact with multiple different binding partners.
The signature WW domain occupies amino acids 129 to 162, representing the primary protein-binding module. This compact domain recognises proline-rich motifs in partner proteins, facilitating specific molecular interactions. Additional disordered regions are found at amino acids 168 to 353 and 428 to 549, interspersed with more structured segments. These intrinsically disordered regions may allow the protein to undergo conformational changes in response to binding events.
Near the C-terminus, a coiled-coil structure extends from amino acid 618 to 644. Coiled coils are elongated structures formed by intertwining alpha helices, commonly involved in protein oligomerisation and the assembly of multiprotein complexes. This domain likely enables WAC to form stable associations with other proteins, contributing to its function as a molecular scaffold within cells. Note that alternative isoforms may exist with different lengths; the information provided here describes the canonical isoform.
Key variants
Genetic variants in WAC range from single nucleotide changes to larger deletions affecting the gene's coding sequence. Pathogenic variants typically disrupt the protein's ability to interact with its binding partners or alter its stability within cells. Loss-of-function variants, which severely reduce or eliminate functional protein, have been particularly associated with clinical presentations.
The variant landscape includes missense changes that affect critical residues within the WW domain, as well as nonsense and frameshift variants that result in truncated proteins. Variants affecting the coiled-coil region may disrupt protein complex formation, whilst those in disordered regions can alter the protein's regulatory properties. The majority of pathogenic WAC variants identified in affected individuals occur de novo (as new changes not inherited from parents), though familial cases with autosomal dominant inheritance have been documented. The clinical features appear to result from haploinsufficiency, where a single functional copy of the gene is insufficient for normal development.
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.1161_1164del | p.Asn387fs | Pathogenic | ★★☆☆ | not provided |
c.1198C>T | p.Gln400Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1346C>G | p.Ser449Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.139C>T | p.Arg47Ter | Pathogenic | ★★☆☆ | DeSanto-Shinawi syndrome due to WAC point mutation |
c.1437+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | DeSanto-Shinawi syndrome due to WAC point mutation |
c.1537C>T | p.Arg513Ter | Pathogenic | ★★☆☆ | DeSanto-Shinawi syndrome due to WAC point mutation |
c.1648C>T | p.Arg550Ter | Pathogenic | ★★☆☆ | DeSanto-Shinawi syndrome due to WAC point mutation |
c.1746+2T>C | - | Pathogenic | ★★☆☆ | Neurodevelopmental delay |
c.1837C>T | p.Arg613Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1864C>T | p.Arg622Ter | Pathogenic/Likely pathogenic | ★★☆☆ | DeSanto-Shinawi syndrome due to WAC point mutation |
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
Pathogenic variants in WAC have been associated with neurodevelopmental disorders characterised by intellectual disability and related features. Affected individuals may present with developmental delay, learning difficulties, and various neurological manifestations. The spectrum of clinical presentations can vary, reflecting both the nature of specific genetic changes and additional genetic and environmental factors.
Commonly reported features in individuals with pathogenic WAC variants include hypotonia (reduced muscle tone), behavioural characteristics, and in some cases seizures, though the specific combination and severity of features varies between individuals. The gene's inclusion in UK clinical genomics panels for intellectual disability and neurodevelopmental genetics reflects its recognised role in these conditions. The phenotypic variability associated with WAC variants continues to be characterised through ongoing clinical research.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic WAC variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
Within the UK National Health Service Genomic Medicine Service, WAC is included on clinical gene panels used to investigate neurodevelopmental conditions. The gene holds a green classification on the Developmental Disorders Genotype to Phenotype (DDG2P) panel, indicating strong evidence for its role in developmental disorders. This classification reflects robust data linking WAC variants to clinical phenotypes and supports its use in diagnostic genomic testing.
WAC is also included on the Intellectual Disability panel with green status and relevance code R29 (intellectual disability), denoting its established role in this clinical domain. These panel memberships guide NHS genomic laboratories in determining when to include WAC in genetic testing strategies for patients presenting with relevant clinical features. Panel statuses should be verified against current PanelApp versions prior to use, as these can change with updates to the evidence base. The green classification ensures that variants identified in WAC receive appropriate clinical interpretation and genetic counselling support.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For conditions associated with WAC variants, general principles of neurodevelopmental support apply. Research in broader neurodevelopmental contexts suggests that structured environments, early educational interventions, and therapies tailored to individual needs may support optimal development. However, no specific dietary modifications or lifestyle interventions have been established specifically for individuals with WAC-related conditions.
Maintaining overall health through balanced nutrition, regular physical activity appropriate to individual abilities, and good sleep hygiene represents sensible general practice for neurodevelopmental conditions. Families are encouraged to work closely with multidisciplinary healthcare teams who can provide personalised guidance based on the individual's specific needs and clinical presentation.
Supplement considerations
Currently, there is no evidence that specific nutritional supplements prevent or modify the course of conditions associated with WAC variants. Whilst various supplements have been explored in broader neurodevelopmental research contexts, none have been demonstrated to specifically address the underlying cellular mechanisms disrupted by WAC dysfunction.
Individuals and families considering any supplementation should discuss this with their healthcare providers. A doctor or clinical geneticist can provide personalised advice taking into account the individual's overall health status, other medications, and specific clinical needs. Self-directed supplementation without medical guidance is not recommended.
Frequently asked questions
What does the WAC gene do?
WAC encodes an adaptor protein that coordinates interactions between different cellular proteins, particularly through its WW domain and coiled-coil regions. This scaffolding function supports various cellular processes including protein regulation and transcriptional control, with particular importance in developing neuronal cells.
How are WAC variants inherited?
WAC-related conditions follow an autosomal dominant inheritance pattern, meaning a variant in one copy of the gene can lead to clinical features. Each child of an affected parent has a 50% chance of inheriting the variant, though many cases arise from new (de novo) variants not present in either parent.
Is WAC included in NHS genetic testing?
Yes, WAC is included on UK NHS genomic medicine panels for intellectual disability and developmental disorders with green classification. This means the gene is routinely analysed when genetic testing is requested for patients presenting with relevant neurodevelopmental features.
What conditions are linked to WAC variants?
Pathogenic variants in WAC are associated with neurodevelopmental disorders, particularly those involving intellectual disability. The clinical spectrum can include developmental delay, learning difficulties, and various neurological features, with variability in presentation between affected individuals.
Can lifestyle changes help with WAC-related conditions?
No specific lifestyle interventions have been proven to modify WAC-related conditions. However, general neurodevelopmental support strategies may benefit affected individuals, including early educational interventions, structured therapeutic support, and maintaining overall health through balanced nutrition and activity appropriate to individual capabilities.