Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical utility gene card for: Arterial tortuosity syndrome



1.1 Name of the disease (synonyms)

Arterial tortuosity syndrome (arterial tortuosity).

1.2 OMIM# of the disease


1.3 Name of the analysed genes or DNA/chromosome segments

SLC2A10, also named GLUT10, located in 20q13.12 chromosomal segment.

1.4 OMIM# of the gene(s)


1.5 Mutational spectrum

To date, <30 mutations have been described, approximately one-third of them are present in the public SLC2A10 variants database (

The mutation spectrum comprises transitions, transversions, large (exonic) deletions, small deletions and splice-site mutations.


frameshift, missense, nonsense, splice-site, haploinsufficiency by mRNA decay.


The collection of variants in a shared database is of great importance, particularly in the case of very rare disorders like ATS, as it improves the diagnosis in laboratories by helping analysis and interpretation of these rare variants. All published and unpublished case with identified SLC2A10 pathogenic variant(s) should be submitted in an open-access database.

1.6 Analytical methods

Sequencing of both strands is necessary. This can be completed if needed by a semi-quantitative technique seeking for partial or complete deletions of the gene, as described.1 As this disorder is recessive and frequently caused by homozygous mutations, denaturation-based screening techniques can be performed on equimolar mixtures of patient and control DNA.

1.7 Analytical validation

Mutations are responsible for a loss-of-function of the corresponding allele. Analytical validation should systematically integrate conservation analysis of the mutant nucleotide(s) and aminoacid(s), as well as the surrounding sequence(s). The variation(s) should systematically be searched in databases of polymorphisms and pathogenic variations.

1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence’) or population prevalence. If known to be variable between ethnic groups, please report)

The incidence is extremely low although no accurate data exist. Estimates vary between 1/100 000 to 1/500 000 live births. The frequency does not seem to vary between different ethnical backgrounds, although in some populations a high level of consanguinity possibly favours the occurrence of new cases).2

1.9 Diagnostic setting


A first comment must be made concerning differential diagnostics:

One main differential diagnosis has to be considered in the classical neonatal or infantile form of the disease. This syndromic condition, named Autosomal Recessive Cutis Laxa Type 1 (ARCL1b) is caused by mutations in FBLN4 gene encoding fibuline 4. ARCL1b associates diffuse arterial tortuosity combining stenosis and aneurysms with severe to mild cutis laxa, inconstant diaphragmatic and inguinal hernias and facial dysmorphism.3, 4, 5 Differential diagnosis between those two conditions can be considered on the basis of slight dysmorphic differences of the face, a tendency to more generalised and severe cutis laxa in ARCL1b patients.4

In cases when the ATS is revealed by late childhood or adulthood cardiovascular complications, the differential diagnosis includes connective tissue disorders affecting the arterial system as Loeys–Dietz syndromes (LDS),6 and Ehlers–Danlos syndromes (EDS), particularly the vascular form. All differential diagnoses of ATS are available for diagnostic testing and should be explored in case of negativity of SLC2A10 screening (see 2.3).

A second comment is necessary concerning prenatal diagnosis: ATS severity is variable and its outcome is currently unpredictable. As early severe morbidity and early demise have frequently been reported, prenatal diagnosis can be offered for this disease when the mutations have been identified.

2. Test characteristics

2.1 Analytical sensitivity

(proportion of positive tests if the genotype is present)

Almost 100%. When only one mutation has been identified by sequencing, the test should be completed by a semi-quantitative technique, allowing the detection of loss or gains of one or more exons of the gene. In these conditions the AS is close to 100%. When two heterozygous mutations are found, parental testing should always be performed to confirm compound heterozygosity.

2.2 Analytical specificity

(proportion of negative tests if the genotype is not present)

100%. As this is a recessive disorder, two loss-of-function mutations are expected, and false-positive results with two unknown variants in a patient’s SLC2A10 genomic sequence are not to be expected.

2.3 Clinical sensitivity

(proportion of positive tests if the disease is present)

The clinical sensibility can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.

When the clinical diagnosis has correctly been established, very few false negative patients are expected. The high level of global arterial tortuosity, associated with arterial stenosis (mostly of the pulmonary circulation) and specific dysmorphic features in infancy are generally sufficient to propose the diagnosis of ATS. However, as mentioned in 1.9, differential diagnoses can be proposed in infancy or in adulthood.9

Molecular screening of genomic sequences of FBLN4 (for ARCL1b), COL3A1, COL5A1 and COL5A2 (for EDS) and TGFB2, TGFBR1/2 and SMAD3 (for LDS) can be performed depending on the clinical presentation of the patient, in case of negativity of SLC2A10 screening.

2.4 Clinical specificity

(proportion of negative tests if the disease is not present)

The clinical specificity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.

Same comment as for 2.3.

2.5 Positive clinical predictive value

(life time risk to develop the disease if the test is positive).

100% if a prenatal diagnosis is performed. Not applicable in adulthood as this condition is a recessive childhood disorder.

2.6 Negative clinical predictive value

(probability of developing the disease if the test is negative).

Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.

Index case in that family had been tested:


Index case in that family had not been tested:

Assuming the clinical diagnosis is right, 100%. In case of erroneous diagnosis, it depends on the differential diagnosis, which can either correspond to recessive or dominant conditions. All differential diagnoses corresponding to adult-onset, dominant disorders should be cautiously kept in mind as penetrance is highly variable depending on families and age of the patients.

3. Clinical utility

3.1 (Differential) diagnostics: the tested person is clinically affected

(To be answered if in 1.9 ‘A’ was marked)

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

In classical cases, clinical diagnosis can be strongly suggested by combining family history, physical examination, echocardiography and arterial imaging like angioMRI or CT.1

Patients are often born from consanguineous marriages. They generally present at birth with facial dysmorphism including beaked nose, blepharophimosis, hypertelorism, downslanting palpebral fissures and a small mouth with retrognathism. A hyperextensible skin or mild cutis laxa can exist. Fingers are long and thin. Inguinal hernias are frequent, but diaphragmatic hernias rarely occur.1, 6

Infants with ATS may develop dyspnoea revealing pulmonary hypertension, due to stenoses of the pulmonary arteries or branches, which can be confirmed by cardiovascular imaging (ultrasound, catheterisation, angioCT or angioMRI) showing truncal or branch stenosis of the pulmonary arteries followed by a dilated segment.

Generalised severe arterial tortuosity is present, and can be associated with venous tortuosity.7 The aortic arch often shows elongation and tortuosity, followed by a stenotic prediaphragmatic aortic segment.7, 8

All medium-sized arteries are highly tortuous,9 and may show localised aneurysms and stenoses. This high level of tortuosity may result in functional stenosis at multiple levels.

This typical presentation allows clinicians to make the diagnosis of ATS.

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

Clinical and imaging methods are actually used to get an accurate clinical evaluation of the patients, which is necessary for their long-term follow-up, particularly concerning interventional or surgical treatment.

When a genetic test is available, it should always be performed to propose familial screening and genetic counselling of carriers and prenatal diagnosis, if necessary.

3.1.4 Will disease management be influenced by the result of a genetic test?


Catheter interventions (balloon dilatation±stenting), cardiovascular surgery of aneurysms and stenoses, associated with medical treatment of general and/or pulmonary hypertension, are the therapeutic cornerstones of the disorder. There is no modification of the treatment to expect after genotyping.

3.2 Predictive setting: the tested person is clinically unaffected but carries an increased risk based on family history

(To be answered if in 1.9 ‘B’ was marked)

3.2.1 Will the result of a genetic test influence lifestyle and prevention?

If the test result is positive (please describe)

Not applicable.

If the test result is negative (please describe)

Not applicable.

3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done (please describe)?

Not applicable.

3.3 Genetic risk assessment in family members of a diseased person

(To be answered if in 1.9 ‘C’ was marked)

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?

Not applicable.

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

Not applicable.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?

Not applicable.

3.4 Prenatal diagnosis

(To be answered if in 1.9 ‘D’ was marked)

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnosis?

Yes, prenatal diagnosis can be performed in foetuses of parents having an affected child. It might also be proposed in the offspring of an affected adult and a carrier partner.

4. If applicable, further consequences of testing

Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe)

In populations where consanguineous marriages occur frequently, heterozygous carrier identification might be useful in a patient’s relative, if prenatal diagnosis for the offspring is considered.2


  1. 1

    Callewaert BL, Willaert A, Kerstjens-Frederikse WS et al: Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat 2008; 29: 150–158.

    CAS  Article  Google Scholar 

  2. 2

    Faiyaz-Ul-Haque M, Zaidi SH, Wahab AA et al: Identification of a p.Ser81Arg encoding mutation in SLC2A10 gene of arterial tortuosity syndrome patients from 10 Qatari families. Clin Genet 2008; 74: 189–193.

    CAS  Article  Google Scholar 

  3. 3

    Sawyer SL, Dicke F, Kirton A et al: Longer term survival of a child with autosomal recessive cutis laxa due to a mutation in FBLN4. Am J Med Genet A 2013; 161A: 1148–1153.

    Article  Google Scholar 

  4. 4

    Kappanayil M, Nampoothiri S, Kannan R et al: Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis. Orphanet J Rare Dis 2012; 7: 61.

    Article  Google Scholar 

  5. 5

    Renard M, Holm T, Veith R et al: Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. Eur J Hum Genet 2010; 18: 895–901.

    CAS  Article  Google Scholar 

  6. 6

    Coucke PJ, Willaert A, Wessels MW et al: Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet 2006; 38: 452–457.

    CAS  Article  Google Scholar 

  7. 7

    Moceri P, Albuisson J, Saint-Faust M et al: Arterial tortuosity syndrome: early diagnosis and association with venous tortuosity. J Am Coll Cardiol 2013; 61: 783.

    Article  Google Scholar 

  8. 8

    Kalfa D, Gronier C, Ly M, Le Bret E, Roussin R, Belli E : Giant aortic aneurysm in an infant with arterial tortuosity syndrome. Ann Thorac Surg 2012; 94: e51.

    Article  Google Scholar 

  9. 9

    Castori M, Ritelli M, Zoppi N et al: Adult presentation of arterial tortuosity syndrome in a 51-year-old woman with a novel homozygous c.1411+1G&gt;A mutation in the SLC2A10 gene. Am J Med Genet A 2012; 158A: 1164–1169.

    Article  Google Scholar 

Download references


This work was supported by EuroGentest2 (Unit 2: ‘Genetic testing as part of health care’), a Coordination Action under FP7 (Grant agreement Number 261469), the European Society of Human Genetics and the Centre de Référence des Maladies Vasculaires Rares.

Author information



Corresponding author

Correspondence to Juliette Albuisson.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Albuisson, J., Moceri, P., Flori, E. et al. Clinical utility gene card for: Arterial tortuosity syndrome. Eur J Hum Genet 23, 1432 (2015).

Download citation


Quick links