TNXB-Related Classical-Like Ehlers-Danlos Syndrome

Clinical characteristics.

The clinical features of TNXB-related classical-like Ehlers-Danlos syndrome (clEDS) strongly resemble those seen in classic EDS (cEDS). Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising, but do not have atrophic scarring, as is seen in cEDS. There are also several other distinguishing clinical findings including anomalies of feet and hands, edema in the legs in the absence of cardiac failure, mild proximal and distal muscle weakness, and axonal polyneuropathy. Vaginal, uterine, and/or rectal prolapse can also occur. Tissue fragility with resulting rupture of the trachea, esophagus, and small and large bowel has been reported. Vascular fragility causing a major event occurs in a minority of individuals. Significant variability in the severity of musculoskeletal symptoms and their effect on day-to-day function between unrelated affected individuals as well as among affected individuals in the same family has been reported. Fatigue has been reported in more than half of affected individuals. The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound as a result of severe and painful foot deformities and fatigue.

Diagnosis/testing.

The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing.

Management.

Treatment of manifestations: Non-weight-bearing exercise, physical therapy, and careful selection of analgesic medication to address joint pain; if pain is severe or debilitating, consider referral to a pain management specialist or clinic. The use of opioid medication should be avoided for chronic pain, as this does not lead to long-term pain relief and has the potential for addiction issues. Long-term chronic pain may result in the need for mental health services. Prompt assessment and management in a tertiary center is required for bowel rupture, arterial rupture, or organ rupture. Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the key characteristics of skin hyperextensibility and joint hypermobility. DDAVP^® (deamino-delta-D-arginine vasopressin) may also be useful to normalize bleeding time in those with easy bruising. Standard treatment is applicable for joint dislocations, subjective muscle weakness, and cardiac abnormalities.

Prevention of primary manifestations: Maintenance of a health body weight; low threshold for referral to gastroenterologist for evaluation of gastrointestinal symptoms; special attention during general anesthesia in order to provide adequate positioning and support as well as being aware of tissue fragility, which has been reported after intubation. Avoid invasive procedures unless absolutely medically necessary; consider carrying medical information or wearing jewelry denoting an increased risk of tissue fragility.

Surveillance: Routine follow up ideally with rheumatologist, pain management clinic, and/or specialized EDS services, if available.

Agents/circumstances to avoid: Sports with heavy joint strain, as well as contact sports; invasive procedures unless they are absolutely medically necessary; acetylsalicylate (aspirin) and long-term use of NSAIDS; use of opioid medication for chronic pain.

Pregnancy management: It is important that the obstetrician and midwives are made aware of the diagnosis of clEDS during a pregnancy. Reported pregnancy and postpartum issues in affected women include miscarriage, premature rupture of membranes, post- or peripartum hemorrhage, and prolapse of the rectum, vagina, and/or uterus. Specialist delivery is strongly advised in view of reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe.

Genetic counseling.

TNXB-related clED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TNXB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the TNXB pathogenic variants have been identified in an affected family member, carrier testing and prenatal/preimplantation genetic testing are theoretically possible.

Suggestive Findings

TNXB-related clEDS should be suspected in individuals with a combination of the following major, minor, and family history criteria [Malfait et al 2017].

Major criteria

• Skin hyperextensibility with velvety skin texture and absence of atrophic scarring (See Figure 1.)
  • Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
  • For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
• Generalized joint hypermobility with or without recurrent dislocations (most commonly shoulder and ankle)
  • Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome, Table 1; Malfait et al [2017]).
  • A score of ≥5 at some point in life is considered positive.
• Easy or spontaneous bruising of the skin

Figure 1.

Hyperextensible skin at the elbow

Minor criteria

• Hand anomalies including:
  • Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
  • Mallet finger(s) (See Figure 2.)
  • Clinodactyly
  • Brachydactyly
• Atrophy of the muscles in the hands and feet
• Foot anomalies including:
  • Broad/plump forefoot
  • Brachydactyly with excessive skin
  • Pes planus
  • Hallux valgus (See Figure 3.)
  • Piezogenic papules
• Edema in the legs in the absence of cardiac failure
• Mild proximal and distal muscle weakness
• Axonal polyneuropathy
• Vaginal, uterus, and/or rectal prolapse
• Predisposition to tissue fragility, particularly of the gastrointestinal tract (a feature usually suggestive of vascular Ehlers-Danlos syndrome; see Differential Diagnosis.)
  Note: This finding was proposed as an additional important feature of TNXB-related clEDS by Green et al [2020] but was not included in the 2017 revised Ehlers-Danlos syndrome nosology [Malfait et al 2017].

Figure 2.

Mallet finger (digit 5)

Figure 3.

Flat, broad feet with left hallux valgus and bilateral hammer toes of digits 2-4

Family history is compatible with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis [Malfait et al 2017].

Establishing the Diagnosis

The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic (or likely pathogenic) variants in TNXB identified by molecular genetic testing (see Table 1). See Molecular Genetics for more information about the technical challenges related to genetic testing for this gene.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic TNXB variants of uncertain significance (or identification of one known TNXB pathogenic variant and one TNXB variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of TNXB-related clEDS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by connective tissue findings, comprehensive genomic testing may be considered.

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in TNXB-Related Classical-Like Ehlers-Danlos Syndrome

Other laboratory findings. In the past, detection of tenascin-X in serum was performed and reported to be absent in individuals with TNXB-related clEDS [Schalkwijk et al 2001]. However, no diagnostic laboratory currently offers this test.

Clinical Description

TNXB-related classical-like Ehlers-Danlos syndrome (clEDS) was first reported in 1997 [Burch et al 1997]. It was noted that the clinical features of these individuals strongly resembled classic EDS (cEDS) because of hyperextensible skin and generalized hypermobility, with two key differences: (1) absence of atrophic scarring and (2) autosomal recessive inheritance. Due to the clinical resemblance with cEDS, updated nosology has renamed the condition classical-like EDS (clEDS) [Malfait et al 2017]. Since the first publications, other features have been reported in individuals with clEDS that are more specific to clEDS [Brady et al 2017, Demirdas et al 2017]. These are reflected in the minor criteria for clEDS and include broad feet and hands, brachydactyly, edema in the legs in the absence of cardiac failure, and predisposition to tissue fragility, particularly of the gastrointestinal tract [Green et al 2020].

To date, 56 individuals from 44 families have been identified with TNXB-related clEDS [Burch et al 1997, Schalkwijk et al 2001, Lindor & Bristow 2005, Voermans et al 2007, Voermans et al 2009, Besselink-Lobanova et al 2010, O'Connell et al 2010, Hendriks et al 2012, Pénisson-Besnier et al 2013, Sakiyama et al 2015, Demirdas et al 2017, Micale et al 2019, Rymen et al 2019, Brisset et al 2020, Green et al 2020, Watanabe et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports. It is important to note that the majority of affected individuals were diagnosed in adulthood.

Table 2.

TNXB-Related Classical-Like Ehlers-Danlos Syndrome: Frequency of Select Features

Skin. People with TNXB-related clEDS invariably have hyperextensible skin.

• Although absence of atrophic scarring is one of the features that distinguishes TNXB-related clEDS from cEDS, mild atrophic scarring (not including cigarette paper scarring and hemosiderosis) has been reported in seven affected individuals.
• Easy bruising is reported in the majority of affected individuals. In one individual a suspicion of nonaccidental injury had been raised due to excessive bruising.
• Hematomas are frequently encountered.

Musculoskeletal. Generalized joint hypermobility is always present in affected individuals, and many have recurrent joint (sub)luxations. Foot deformities (listed in Suggestive Findings) are present in the majority; hand abnormalities (acrogeric hands, mallet finger[s], clinodactyly, and brachydactyly) are less frequently reported [Demirdas et al 2017, Green et al 2020].

• Significant variability between both unrelated and related affected individuals in the severity of musculoskeletal symptoms and their effect on day-to-day function has been reported.
• The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound due to severe and painful foot deformities, joint dislocations, and fatigue [Green et al 2020].
• More than half of affected individuals reported fatigue as an important feature (e.g., Demirdas et al [2017]: 14/17 individuals; Green et al [2020]: 14/20 individuals).
• Edema of the ankles and/or feet has been described in 14 of 56 individuals and could not be attributed to a cardiac etiology.

Cardiovascular

• Vascular fragility has been reported in 15 of 56 (27%) affected individuals, with three of 56 (5%) experiencing major medical events due to vascular fragility.
  • Ten individuals experienced frequent subconjunctival hemorrhages.
  • Rupture of a right brachial vein was reported in a woman age 26 years [Micale et al 2019].
  • A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [Demirdas et al 2017].
  • An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [Demirdas et al 2017].
  • One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [Green et al 2020].
  • One individual developed a spontaneous left-calf hematoma that had to be drained surgically [Green et al 2020].
    This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
    She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
• Valvular anomalies. Mild valvular abnormalities, often involving the mitral valve, have been reported in nine of 56 (16%) of affected individuals.
• Cardiomyopathy was detected in three of 56 (5%) individuals (postpartum, dilated, and unspecified, respectively). It remains unclear if this represents rare co-occurrences of cardiomyopathy with TNXB-related clEDS or if cardiomyopathy is a rare feature of TNXB-related clEDS.

Neuromuscular

• Subjective muscle weakness has been reported in about one third of affected individuals. Based partially on physiologic studies in affected individuals, a dose-effect relation of TNX levels and degree of neuromuscular involvement has been suggested [Castori & Voermans 2014].
  The most elaborate study included ten individuals with TNXB-related clEDS among a group of 40 individuals with EDS of varying types [Voermans et al 2009].
  Those with TNXB-related clEDS generally had moderate neuromuscular complaints, mild reduced sensation, muscle weakness, and functional impairment on physical examination.
  • Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
  • Muscle ultrasound demonstrated increased echo intensity.
  • Muscle biopsy showed mild myopathic changes in some affected individuals.
  • It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [Castori & Voermans 2014].
• Atrophy of the muscles in the hands and feet has been reported in 4% of affected individuals, although this feature was not assessed by Green et al [2020] in their cohort of 20 affected individuals. It is unclear whether this is a characteristic feature of TNXB-related clEDS.

Gastrointestinal

• Rupture. Nine affected individuals have been reported with gastrointestinal fragility leading to a total of 14 gastrointestinal events. Four of these individuals had more than one gastrointestinal event in different locations, and four had a gastrointestinal event during an invasive procedure. One of these latter four had three events, two of which occurred after an invasive procedure. Age at which first gastrointestinal complications occurred varied from 36 years to 59 years. These findings imply a degree of tissue fragility with complications resulting from invasive procedures. The nine affected individuals and their respective events were as follows:
  • A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [Lindor & Bristow 2005]
  • A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [Hendriks et al 2012]
  • A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [Sakiyama et al 2015]
  • An individual age 48 years who had a bowel perforation as a result of diverticulitis [Demirdas et al 2017]
  • An individual age 38 years with a colonic perforation during a colonoscopy [Brisset et al 2020]
  • A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [Rymen et al 2019]
  • Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [Green et al 2020]
  • Jejunal perforation at age 40 years [Green et al 2020]
  • Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [Green et al 2020]
  Note: Demirdas et al [2017] reported death as a result of infection following bowel perforation of an individual in the sixth decade as unpublished data (not included in the cross-sectional analysis of 17 individuals represented in the publication).
• Diverticular disease has been noted in ten of 56 affected individuals. It is hypothesized that affected individuals may be more prone to structural defects along the walls of the gastrointestinal tract, which can predispose to diffuse diverticulosis, diverticulitis, and resulting bowel perforation as well as to perforation during invasive procedures and spontaneous perforation [Green et al 2020].
• Gastrointestinal bleeding has been reported in three of 56 affected individuals. It was not specified whether this occurred spontaneously or due to another gastrointestinal issue.

Other tissue fragility. Tracheal rupture possibly due to intubation has been reported in a woman age 41 years [Besselink-Lobanova et al 2010]. A woman age 47 years had extensive surgical emphysema within the subcutaneous tissues of her face and computed tomography (CT) scans of the sinuses revealed a defect of the left nasal cartilages anteriorly, allowing air to track into the soft tissues. It was felt that vigorous nose blowing had most likely been the cause of the emphysema. This may also point to tissue fragility in individuals with TNXB-related clEDS [Green et al 2020].

Organ prolapse. As in other types of EDS, vaginal/uterus/rectal prolapse are more frequently encountered and have been reported in 21% of individuals with TNXB-related clEDS.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

Outdated terms for TNXB-related clEDS include tenascin-X deficient type of Ehlers-Danlos syndrome and tenascin-X deficiency.

Prevalence

The prevalence of TNXB-related clEDS is unknown; 56 individuals from 44 families have been described in the literature. Two additional affected individuals were referenced by Demirdas et al [2017] as "unpublished data."

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TNXB-related clEDS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with TNXB-Related Classical-Like Ehlers-Danlos Syndrome

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with TNXB-Related Classical-Like Ehlers-Danlos Syndrome

Prevention of Primary Manifestations

For recommendations on prevention of primary manifestations of joint laxity and dislocations as well as joint pain, see Hypermobile Ehlers-Danlos Syndrome, Prevention of Primary Manifestations.

Table 6.

Prevention of Primary Manifestations in Individuals with TNXB-Related Classical-Like Ehlers-Danlos Syndrome

Surveillance

Table 7.

Recommended Surveillance for Individuals with TNXB-Related Classical-Like Ehlers-Danlos Syndrome

Agents/Circumstances to Avoid

The following should be avoided:

• Sports with heavy joint strain (e.g., contact sports, fighting sports, football, running)
• Invasive procedures such as intubation, endoscopy, and/or colonoscopy unless essential because of reported tissue fragility of the trachea, esophagus, and small and large bowels
• Acetylsalicylate (aspirin) and long-term use of nonsteroidal anti-inflammatory drugs because of elevated risks of diverticulitis and diverticular bleeding
• The use of opioid medication for chronic pain, which does not lead to long-term pain relief and has the potential for addiction issues

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

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

Pregnancy Management

It is important that the obstetrician and midwives be made aware of the diagnosis of TNXB-related clEDS during a pregnancy. Reported pregnancy and postpartum issues in affected women include miscarriage, premature rupture of membranes, post- or peripartum hemorrhage, and prolapse of the rectum, vagina, and/or uterus [Green et al 2020].

Gynecologic follow up during pregnancy can be considered. Specialist delivery is strongly advised in view of the reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe. These complications emphasize the need for careful handling of pregnant women with TNXB-related clEDS, especially in emergency situations [Brady et al 2017].

Therapies Under Investigation

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.

Mode of Inheritance

TNXB-related classical-like Ehlers-Danlos syndrome (clEDS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one TNXB pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TNXB pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes may or may not be asymptomatic. Zweers et al [2003] investigated 20 heterozygous family members. All had significantly reduced serum TNX levels (compatible with heterozygote status). Clinical examination revealed generalized joint hypermobility and recurring joint dislocations and chronic joint pain in the majority of heterozygous females (nine of 14). Further investigations are needed to elucidate a possible role of reduced TNX levels and joint hypermobility. Skin hyperextensibility and easy bruising were absent in heterozygotes; heterozygotes as such do not fulfill the major criteria for TNXB-related clEDS and are not at risk of developing TNXB-related clEDS.

Sibs of a proband

• If both parents are known to be heterozygous for a TNXB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Although sibs with biallelic TNXB pathogenic variants are expected to fulfill the major criteria for TNXB-related clEDS, intrafamilial variability has been observed and the severity of related manifestations (e.g., musculoskeletal problems) can be variable.
• Heterozygotes may or may not be asymptomatic (see Parents of a proband).

Offspring of a proband. The offspring of an individual with TNXB-related clEDS are obligate heterozygotes (carriers) for a pathogenic variant in TNXB.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TNXB pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the TNXB pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the TNXB pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

TNXB encodes tenascin-X (TN-X), a glycoprotein of the extracellular matrix. Biallelic pathogenic variants result in a loss of the functional protein product and the characteristic clinical features. Pathogenic splice site or nonsense TNXB variants can lead to nonsense-mediated decay of the mutated RNA and result in complete absence of TN-X. Pathogenic missense variants may result in misfolding of the protein. Individuals with a molecularly confirmed diagnosis of TNXB-related classical-like Ehler-Danlos syndrome (clEDS) can have (1) intragenic pathogenic variants, (2) TNXB whole-gene or small deletions, or (3) contiguous deletions of TNXB and CYP21A2.

TNXB and CYP21A2 (associated with congenital adrenal hyperplasia) are located within the human leukocyte antigen histocompatibility complex at 6p23.1 alongside their homologous pseudogenes, TNXA and CYP21A1P. This region is prone to meiotic nonhomologous recombination resulting in gene conversions (exchange of DNA sequences between gene and pseudogene). Three types of TNXA/TNXB gene conversions have been identified [Morissette et al 2015]: (1) CAH-X chimera 1 (CH-1) has TNXB exons 35-44 replaced with TNXA and is characterized by the c.11435_11524+30del variant; (2) CAH-X chimera 2 (CH-2) has TNXB exons 40-44 replaced with TNXA and is characterized by the TNXA-derived c.12174C>G (p.Cys4058Trp) variant; (3) CAH-X chimera 3 (CH-3) has TNXB exons 41-44 replaced by TNXA and is characterized by three TNXA-derived missense variants. The exact pathogenic mechanism of the c.12174C>G (p.Cys4058Trp) variant is unknown, but the variant affects a cysteine residue that is predicted to form a disulfide bond, stabilizing tertiary protein structure [Demirdas et al 2017]. TNXB-related clEDS is often caused by gene conversion events, which are the most common recurrent mechanism of pathogenicity [Green et al 2020].

Mechanism of disease causation. Loss of function

TNXB-specific laboratory technical considerations. Molecular genetic testing may be complicated by the presence of pseudogene TNXA, which has greater than 97% homology to the 3' end (exons 32-44) of TNXB. As such, exon and intron sequences are (almost) identical in the gene and pseudogene [Demirdas et al 2017].

Table 8.

Notable TNXB Pathogenic Variants

Revision History

• 15 September 2022 (ma) Review posted live
• 24 September 2021 (fvd) Original submission

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