Clinical characteristics.

The autosomal dominant TRPV4-related disorders include two principal types: neuromuscular disorders and skeletal dysplasias. Affected individuals typically have either neuromuscular or skeletal manifestations, although overlapping phenotypes can occur. There is a wide range of phenotypic severity. In the mildest of the autosomal dominant TRPV4-related disorders life span is normal; in the most severe it is shortened.

The three clinically recognized autosomal dominant neuromuscular disorders are Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Clinical overlap between these phenotypes does occur. These neuromuscular disorders are characterized by a motor-predominant, non-length-dependent peripheral neuropathy or motor neuronopathy with a wide range in age of onset, from congenital to late adult. Additional common features include laryngeal dysfunction (i.e., vocal fold paresis causing voice change and/or inspiratory stridor), diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural hearing loss, and joint contractures.

The five autosomal dominant skeletal dysplasias are (from mildest to most severe) familial digital arthropathy with brachydactyly, brachyolmia, spondylometaphyseal dysplasia (Kozlowski type), spondyloepimetaphyseal dysplasia (Maroteaux type), and metatropic dysplasia. All TRPV4-related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis.

Diagnosis/testing.

The diagnosis of an autosomal dominant TRPV4-related disorder is established in a proband who has characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that may include neurologists, physiatrists, orthopedic surgeons, otologists/audiologists, laryngologists, pulmonologists, geneticists, and physical and occupational therapists. This multidisciplinary team will determine the best treatment options for supportive care, prevention of obesity, and management of pain and depression.

For neuromuscular disorders, additional treatment includes special shoes with good ankle support, shoe orthotics, ankle-foot orthoses / knee-ankle-foot orthoses, surgery for severe foot deformities, mobility devices, and exercise as tolerated; management of kyphoscoliosis per orthopedist; management of tethered spinal cord per neurosurgeon; laryngeal surgery for vocal cord paresis (in some individuals, vocal fold lateralization or tracheostomy); speech therapy; and respiratory therapy including noninvasive ventilatory support as needed.

For skeletal dysplasias, additional treatment includes physical therapy/exercise and heel cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present.

Surveillance: For neuromuscular disorders, annual neurologic examination, physical therapy assessment, otolaryngology evaluation of laryngeal function, dynamic breathing chest radiograph, pulmonary function tests, sleep study, hearing assessment, and musculoskeletal evaluation; assessment of weight, height, and weight-for-height or body composition to diagnose obesity at each visit. For skeletal dysplasias, annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia; annual hearing assessment; and assessment of weight, height, and weight-for-height at each visit.

Agents/circumstances to avoid: Obesity, as it makes walking more difficult. For neuromuscular disorders, avoid diabetes and neurotoxic medications; upper respiratory tract infections can cause vocal fold swelling and worsen upper airway obstruction. For skeletal dysplasias, avoid extreme neck flexion and extension (in those with odontoid hypoplasia); activities that place undue stress on the spine and weight-bearing joints.

Pregnancy management: Ideally a woman with an autosomal dominant TRPV4-related disorder would seek consultation from a high-risk obstetrician or maternal-fetal medicine specialist to evaluate risk associated with pregnancy and delivery.

Genetic counseling.

By definition, autosomal dominant TRPV4-related disorders are inherited in an autosomal dominant manner. Because the most severe TRPV4-related skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes typically have a de novo pathogenic variant and unaffected parents. Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a TRPV4 pathogenic variant inherited from a heterozygous parent (de novo pathogenic variants have also been described in individuals with these phenotypes). Each child of an individual with an autosomal dominant TRPV4-related disorder has a 50% chance of inheriting the TRPV4 pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be accurately predicted because of reduced penetrance and highly variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have a similar overall phenotype as the parent, although the age of onset and severity may be quite distinct. Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of an autosomal dominant TRPV4-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in TRPV4 identified by molecular genetic testing (see Table 3) that is suspected to cause gain of channel function.

Note: TRPV4 pathogenic variant p.Ser94Leu has been associated with autosomal recessive TRPV4-related neuromuscular disease (see Genetically Related Disorders).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous TRPV4 variant of uncertain significance does not establish or rule out the diagnosis.

• Single-gene testing. Sequence analysis of TRPV4 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: (1) Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. (2) To date, a large TRPV4 deletion or duplication has not been reported in an individual with an autosomal dominant TRPV4-related disorder; all pathogenic variants reported are suspected to result in gain of function.
• A multigene panel that includes TRPV4 and other genes of interest (see Differential Diagnosis) can be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

The two groups of disorders and the phenotypes comprising autosomal dominant TRPV4-related disorders are the following:

• Neuromuscular disorders (See Table 1.)
  • Charcot-Marie-Tooth disease type 2, TRPV4-related (CMT2C)
  • Scapuloperoneal spinal muscular atrophy, TRPV4-related (TRPV4-SPSMA)
  • Congenital distal spinal muscular atrophy, TRPV4-related (TRPV4-CDSMA)
• Skeletal dysplasias, listed from mildest to most severe (See Table 2.)
  • Familial digital arthropathy with brachydactyly, TRPV4-related
  • Brachyolmia, TRPV4-related
  • Spondylometaphyseal dysplasia, TRPV4-related (Kozlowski type)
  • Spondyloepimetaphyseal dysplasia, TRPV4-related (Maroteaux type)
  • Metatropic dysplasia, TRPV4-related

The phenotypic spectra within both neuromuscular and skeletal groups are broad and overlapping, and the phenotypes of both groups can in rare instances overlap as well [Taga et al 2022].

Genotype-Phenotype Correlations

In general, specific sets of TRPV4 pathogenic variants have been associated with either neuromuscular disorders or skeletal dysplasias. However, overlap phenotypes may occur [Taga et al 2022], making genotype-phenotype correlations difficult (see Molecular Genetics). Moreover, pathogenic variants associated with TRPV4-related neuromuscular disease can cause any of the recognized subtypes, with different presentations even within families.

Functional studies suggest that TRPV4 pathogenic variants associated with neuromuscular disorders and short-stature skeletal dysplasias cause a gain of channel function [Rock et al 2008, Krakow et al 2009, Nilius & Voets 2013, Sullivan et al 2015, Woolums et al 2020, Sullivan et al 2024, Berth et al 2025], whereas there are reports of both loss-of-function and gain-of-function features in pathogenic variants associated with familial digital arthropathy with brachydactyly [Lamandé et al 2011, Berth et al 2025].

TRPV4-related neuromuscular disorders. Several studies suggest that most TRPV4 pathogenic variants associated with a neuromuscular phenotype cluster on the highly positively charged convex surface of the ankyrin repeat domain and target arginine residues that are strictly conserved throughout 27 available TRPV4 orthologs [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Sullivan et al 2015, Kosmanopoulos et al 2025]. These surface pathogenic variants are located in three consecutive finger loops of the protein, a distinct region of the TRPV4 ankyrin repeat domain [Kwon et al 2023, Nadezhdin et al 2023]. The most commonly reported and best validated pathogenic TRPV4 variants are p.Arg186Gln, p.Arg232Cys, p.Arg269Cys, p.Arg269His, p.Arg315Trp, p.Arg316Cys, and p.Arg316His, although several other pathogenic or likely pathogenic variants have been reported [Kosmanopoulos et al 2025]. Pathogenic variants in the N-terminal intrinsically disordered region (p.Ser93Phe, p.Pro97Arg) have also been reported [Fiorillo et al 2012, Berth et al 2025]. Variable phenotypes have been reported, even among members of the same family [Landouré et al 2010].

Note: TRPV4 pathogenic variant p.Ser94Leu has been associated with autosomal recessive TRPV4-related neuromuscular disease (see Genetically Related Disorders).

TRPV4-related skeletal dysplasias. In total, more than 50 pathogenic variants in TRPV4 have been reported to cause brachyolmias. While the pathogenic variants are spread throughout the gene, two hot spots have been observed at residues Pro799 in exon 15 and Arg594 in exon 11 [Nishimura et al 2012], which localize to the channel pore region [Kwon et al 2023, Nadezhdin et al 2023].

The familial digital arthropathy with brachydactyly-causing pathogenic variants are restricted to finger 3 of the ankyrin repeats domain (pathogenic variants p.Gly270Val, p.Arg271Pro, p.Phe273Leu) [Nilius & Voets 2013].

Overlap of TRPV4-related neuromuscular disorders and skeletal dysplasias. At least 19 pathogenic variants have been associated with both neuromuscular disease and skeletal dysplasia [Taga et al 2022], with the most common implicated variants being p.Arg269His, p.Ser542Tyr, and p.Trp785Cys.

Penetrance

Autosomal dominant TRPV4-related neuromuscular disorders. Penetrance is reduced with the neuromuscular disease-associated pathogenic variants.

Autosomal dominant TRPV4-related skeletal dysplasias. In contrast, penetrance of the skeletal dysplasia phenotype appears to be high; however, intra- and interfamilial variability is significant [Dai et al 2010].

Nomenclature

Charcot-Marie-Tooth neuropathy type 2C is also referred to as hereditary motor and sensory neuropathy type 2C.

Spondyloepimetaphyseal dysplasia (SEMD), TRPV4-related (Maroteaux type), was previously referred to as pseudo-Morquio syndrome type 2.

Parastremmatic dysplasia is now considered part of the SEMD, Maroteaux type, phenotype.

Prevalence

The prevalence of the autosomal dominant TRPV4-related neuromuscular and skeletal dysplasias has not been well studied, with estimates ranging from ~1% to 3.5% of Charcot-Marie-Tooth neuropathy type 2 (CMT2) / hereditary motor neuropathy (HMN) [Fawcett et al 2012, Deng et al 2020, Record et al 2024].

Fawcett et al [2012] determined that 13 (<1%) of 422 individuals with a CMT2 (axonal CMT) phenotype were heterozygous for a TRPV4 pathogenic variant, and Record et al [2024] found TRPV4 pathogenic variants in 1.1% of 443 individuals with CMT2/HMN. The detection of a TRPV4 pathogenic variant increased to between 9% and 16% in those with a CMT2 phenotype with additional unusual features (e.g., vocal fold weakness, diaphragmatic paresis, skeletal dysplasia) [Echaniz-Laguna et al 2014].

Autosomal Dominant TRPV4-Related Neuromuscular Disorders

Autosomal dominant TRPV4-related neuromuscular disorders resemble several other disorders (see Table 4).

Note: See Charcot-Marie-Tooth Hereditary Neuropathy Overview for a general overview of CMT2.

Autosomal Dominant TRPV4-Related Skeletal Dysplasias

Autosomal dominant TRPV4-related skeletal dysplasias have a broad phenotypic spectrum and, thus, there are many skeletal dysplasias to consider in the differential diagnosis.

The differential diagnosis of mild TRPV4-related skeletal dysplasias (familial digital arthropathy with brachydactyly) includes reactive arthropathy, diabetic arthropathy, and other forms of brachydactyly [Horta-Baas et al 2017, Ürel-Demir et al 2021].

The differential diagnosis of intermediate TRPV4-related skeletal dysplasias (brachyolmia, spondylometaphyseal dysplasia [Kozlowski type], and spondyloepimetaphyseal dysplasia [Maroteaux type]) and severe TRPV4-related skeletal dysplasia (metatropic dysplasia) is summarized in Table 5.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4-related neuromuscular disorder, the evaluations summarized in Table 6a (if not performed as part of the evaluation that led to the diagnosis) are recommended.

To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4-related skeletal dysplasia, the evaluations summarized in Table 6b (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, otologists/audiologists, laryngologists, pulmonologists, geneticists, and physical and occupational therapists.

Surveillance

Agents/Circumstances to Avoid

In general, obesity is to be avoided because it makes walking more difficult for individuals with neuropathy, skeletal dysplasia, or both.

For neuromuscular disorders

• Preventive health care to avoid diabetes-related complications is recommended.
• Neurotoxic medications should be avoided. Medications that are toxic or potentially toxic to persons with Charcot-Marie-Tooth disease (CMT) comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. See also the Inherited Neuropathy Consortium website for additional information.
• Upper respiratory tract infections can cause vocal fold swelling and worsen upper airway obstruction.

For skeletal dysplasias

• In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.
• Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no registry or data regarding the frequency or outcome of pregnancies in women with an autosomal dominant TRPV4-related disorder; however, the following general information may be reasonable to consider. Ideally a woman with an autosomal dominant TRPV4-related disorder would seek consultation from a high-risk obstetrician or maternal-fetal medicine specialist to evaluate her risks for pregnancy and delivery. Increased risk of ectopic pregnancy has been reported [Li et al 2019].

Autosomal dominant TRPV4-related neuromuscular disorders. Results of an Italian registry observed higher rates of placenta previa, abnormal presentations, and preterm deliveries in all forms of CMT, but pregnancy outcome and newborn weight and health were similar to those of the reference populations [Pisciotta et al 2020]. Additionally, a retrospective review in European pregnancies for inherited neuromuscular disorders demonstrated common complications such as polyhydramnios, preterm labor, miscarriages, and cesarean sections. Specifically, CMT and limb-girdle muscular dystrophy were associated with preterm labor and cesarean deliveries [Ahmed et al 2025]. Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMT. About 50% of women with CMT described increased weakness during pregnancy that usually resolved post partum [Rudnik-Schöneborn et al 1993]. Operative deliveries were reported more commonly in women with CMT in Norway [Hoff et al 2005]. Greenwood & Scott [2007] described the obstetric approach to women with mild and severe forms of CMT. Brock et al [2009] describe use of anesthesia during delivery in a single case study, indicating that regional management is the preferred and safer method, compared to general anesthesia. A German study reviewed 63 pregnancies in 33 women with CMT [Awater et al 2012] and found no increase in the frequency of cesarean section, forceps delivery, premature birth, or neonatal problems. About one third of mothers felt a worsening of CMT symptoms during pregnancy; in one fifth of mothers the changes were felt to be persistent [Pisciotta et al 2020].

Autosomal dominant TRPV4-related skeletal dysplasias. In autosomal dominant TRPV4-related skeletal dysplasias, the degree of pulmonary compromise (from the short trunk and decreased lung capacity) may affect the ability to carry a pregnancy to term. Thus, it is unlikely that a woman with metatropic dysplasia could carry a pregnancy. Pregnant women with a TRPV4-related skeletal dysplasia generally undergo cesarean section delivery because of the small size of the pelvis. Best practice guidelines for prenatal evaluation and delivery of women with skeletal dysplasia have been published [Savarirayan et al 2018].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

De Grado et al [2025] have reviewed the future of therapeutic options in CMT.

Preclinical studies in knock-in mouse models of TRPV4-related neuromuscular disease have shown that small-molecule TRPV4 (transient receptor potential cation channel subfamily V member 4) ion channel antagonists result in improvement in disease phenotypes [Sullivan et al 2024]. Based on these studies and the known mechanism of disease, TRPV4-specific ion channel antagonists are under study as a potential therapy for TRPV4-related neuromuscular disease.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Career and employment choices may be influenced by persistent weakness of hands and/or feet and orthopedic involvement.

Mode of Inheritance

By definition, autosomal dominant TRPV4-related disorders are inherited in an autosomal dominant manner.

• Clinically recognized autosomal dominant TRPV4-related neuromuscular disorders are Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy.
• Clinically recognized autosomal dominant TRPV4-related skeletal dysplasias are familial digital arthropathy with brachydactyly, brachyolmia, spondylometaphyseal dysplasia (Kozlowski type), spondyloepimetaphyseal dysplasia (Maroteaux type), and metatropic dysplasia.

Note: The TRPV4 pathogenic variant p.Ser94Leu has been associated with autosomal recessive TRPV4-related neuromuscular disease (see Genetically Related Disorders).

Risk to Family Members

Parents of a proband

• Because the most severe TRPV4-related skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes typically have a de novo pathogenic variant and unaffected parents.
• Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a TRPV4 pathogenic variant inherited from a heterozygous parent. (Note: A heterozygous parent may appear asymptomatic or have more or less severe clinical manifestations than the proband; see Penetrance and Genotype-Phenotype Correlations.) De novo pathogenic variants have also been described in individuals with these phenotypes.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype (possibly associated with parental mosaicism) or reduced penetrance in the parent with the pathogenic variant. Therefore, de novo occurrence of a TRPV4 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the TRPV4 pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a TRPV4 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the TRPV4 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The specific phenotype, age of onset, and disease severity cannot be predicted accurately in a sib who inherits a familial pathogenic variant because of reduced penetrance and variable expressivity. A heterozygous sib may have the same phenotype as the proband or have less severe or more severe clinical manifestations (see Penetrance and Genotype-Phenotype Correlations).
• If the TRPV4 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the TRPV4 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for a TRPV4-related disorder because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with an autosomal dominant TRPV4-related disorder has a 50% chance of inheriting the TRPV4 pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of reduced penetrance and highly variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have a similar overall phenotype as the parent, although age of onset and severity may be quite distinct.
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with an autosomal dominant TRPV4-related skeletal disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals may be distinct from those of the parents. If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TRPV4 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Genetic counseling is recommended when both parents have a skeletal dysplasia.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the TRPV4 pathogenic variant has been identified in an affected family member. Further clinical evaluation, electromyography / nerve conduction velocity testing, and/or skeletal survey may be appropriate for individuals found to have a familial pathogenic variant. No disease-modifying treatment is available to individuals early in the course of the disease. Thus, such testing is for personal decision making only.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for a condition that may be adult-onset and for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of a TRPV4-related disorder, it is appropriate to consider testing of symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. However, specific phenotype, age of onset, and/or disease severity cannot be reliably predicted based on the results of prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TRPV4 encodes transient receptor potential cation channel subfamily V member 4 (TRPV4), a nonselective Ca2+-permeable cation channel that is predominantly expressed at the plasma membrane [Rosenbaum et al 2020, Toft-Bertelsen & MacAulay 2021]. TRPV4 can be activated by a wide range of stimuli including hypo-osmolarity, heat, and mechanical stretch, as well as numerous endogenous (e.g., endocannabinoid anandamide, arachidonic acid) and synthetic (4α-phorbol-12,13-didecanoate [4αPDD]) compounds [Garcia-Elias et al 2014]. TRPV4 is broadly expressed and has diverse physiologic roles in different tissue types:

• Osmosensation and flow sensing in the kidney [Rosenbaum et al 2020]
• Endothelial barrier function and vascular tone in the cerebral and pulmonary vasculature [Kuppusamy et al 2021, Sonkusare & Laubach 2022, Lambrichts et al 2025]
• Mechanosensation and nociception in the sensory nervous system [Tominaga & Kashio 2024]
• Bladder sensation and function [Wu et al 2021]
• Skin homeostasis and function [Rosenbaum et al 2020]
• Chondrogenesis and bone homeostasis [Toft-Bertelsen & MacAulay 2021, Liu et al 2022, Zhang et al 2022]
• Immune function and inflammation [Michalick & Kuebler 2020]

While the precise mechanisms of pathogenesis in autosomal dominant TRPV4-related disorders are not completely understood, the preponderance of evidence suggests that pathogenic variants cause disease through gain of ion channel function [Nilius & Voets 2013]. TRPV4 is a cell surface-expressed cation channel and principally fluxes calcium. Given the diverse signaling pathways regulated by intracellular calcium influx, many possible downstream pathologic events are conceivable, including activation of calcium-sensitive proteases (such as calpains) or kinases (such as CaMKII), alterations in calcium-sensitive transcriptional programs, and dysregulation of cytoskeletal remodeling. In addition, the downstream consequences of TRPV4 gain of channel function are likely to be dependent on cell type- and tissue-specific factors.

Mechanism of disease causation. Autosomal dominant TRPV4-related disorders are diverse but are likely linked through gain of TRPV4 ion channel function with tissue-specific downstream consequences. Notably, the vast majority of pathogenic variants reported are missense variants.

• Neuromuscular disorders. Gain of ion channel function of multiple pathogenic variants has been demonstrated in vitro and in fly and mouse models of disease [Deng et al 2010, Landouré et al 2010, Klein et al 2011, Sullivan et al 2015, Woolums et al 2020, Sullivan et al 2024, Kosmanopoulos et al 2025]. Notably, Trpv4 knock-in mice develop a severe, rapidly progressive fatal neuromuscular phenotype that can be rescued by pharmacologic inhibition of TRPV4 ion channel activity [Sullivan et al 2024]. In addition, this phenotype is associated with breakdown of blood-brain and blood-spinal cord barriers due to expression of mutated TRPV4 in neural vascular endothelial cells [Sullivan et al 2024]. These findings suggest that disruption of neural vascular barriers could contribute to disease pathogenesis, although such a mechanism has not been demonstrated in affected individuals.
• Skeletal dysplasias. The vast majority of skeletal dysplasia pathogenic variants are missense variants that are believed to cause gain of function, although frameshift and deletion variants have been reported [Dai et al 2010, Nishimura et al 2010]. Like pathogenic variants associated with neuromuscular disorders, skeletal dysplasia-associated variants also generally cause increased basal calcium influx [Loukin et al 2011, Taga et al 2022]. The precise downstream pathogenic events remain unknown, although reduced bone morphogenic protein signaling with resultant impairment in endochondral ossification has been proposed based on in vitro studies and a knock-in mouse model [Leddy et al 2014a, Leddy et al 2014b, Dicks et al 2023, Harissa et al 2025].

Author Notes

Brett A McCray, MD, PhD, is a physician-scientist at the University of Michigan who leads a basic, translational, and clinical research program. His research is focused on furthering the understanding and treatment of hereditary neuropathy with a primary focus on TRPV4-related neuromuscular disease. The lab uses cultured cells and animal models to elucidate pathways important in the pathogenesis of TRPV4-related disease and other forms of neuropathy. The lab is also involved in clinical and translational research efforts to help bring insights from the bench to individuals with TRPV4-related neuromuscular disease.

Charlotte J Sumner, MD, is a physician-scientist at Johns Hopkins University School of Medicine who studies and cares for individuals with genetic motor neuron and peripheral nerve diseases. Her laboratory discovered TRPV4 pathogenic variants that cause neuromuscular disease, developed cell and animal models of disease, and demonstrated that TRPV4 small-molecule antagonists can ameliorate disease features in these models. She is leading ongoing clinical studies of individuals with TRPV4 pathogenic variants at Johns Hopkins University.

Dr McCray (ude.hcimu.dem@yarccmb) and Dr Sumner (ude.imhj@1renmusc) are actively involved in clinical research regarding individuals with TRPV4-related neuromuscular disease. They would be happy to communicate with persons who have any questions regarding diagnosis of TRPV4-related neuromuscular disease or other considerations.

Dr McCray and Dr Sumner are also interested in hearing from clinicians treating families affected by TRPV4-related neuromuscular disease in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr McCray or Dr Sumner to inquire about review of TRPV4 variants of uncertain significance.

Acknowledgments

Research on TRPV4-related neuromuscular diseases has been supported by the Inherited Neuropathies Consortium, NINDS, the Muscular Dystrophy Association, Actio Biosciences, and by individuals and families affected by the condition, particularly the TRPV4 Related Hereditary Neuropathies Facebook group led by Stephanie Carmody.

Revision History

• 4 December 2025 (sw) Comprehensive update posted live
• 17 September 2020 (sw) Comprehensive update posted live
• 15 May 2014 (me) Review posted live
• 30 July 2013 (as) Original submission

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