Arterial tortuosity syndrome (ATS) is a rare, highly variable autosomal recessive disorder characterized by severe and extensive tortuosity of the aorta and middle-sized arteries increasing the risk of aneurysms and dissection. ATS can also cause focal and widespread stenosis that can involve aortic and pulmonic arteries. The variability can range from early infant mortality to limited adulthood manifestations, and the prevalence is estimated at less than 1 in 1,000,000 live births. Here we report a child with ATS who was found to be a compound heterozygote for two different SLC2A10 variants.
The patient presented at the age of four years for evaluation of hypotonia, muscle weakness, joint laxity, fatigue, and constipation. She was born at term to a G3P3 29 year old mother. Early development was normal, but after the age of 2 years she began to have gross motor delays, including fatigue and muscle pain. She was reported to have thin, doughy skin, easy bruisability, one shoulder subluxation without dislocations, and an episode of rectal prolapse. Metabolic labs including a CK, lactic acid, acylcarnitine profile, urine organic acids, and pyruvic acid which were normal. Echocardiogram showed a gothic appearing aortic arch with a common brachiocephalic trunk, and a cardiac MRI showed a tortuous aorta and bilateral tortuous carotid arteries.
Whole-Exome sequencing identified that the patient was a compound heterozygote for two variants of uncertain significance in SLC2A10 with a c.727C>A p.Q243K inherited from mother and c.314G>A p.R105H inherited from the father. The in silico tools predicted that both of these mutations are likely disease causing. SLC2A10 encodes for the class III facilitative glucose transporter GLUT10, which regulates the transport of glucose and dehydroascorbic acid across cell membranes. Lack of GLUT10 leads to the abnormal assembly of collagens and elastin, is associated with aberrant TGF-β signaling, and also hypothesized to impact mitochondrial function.
We propose that these two variants of uncertain significance in SLC2A10 are pathogenic. To evaluate our hypothesis we used molecular modeling and in silico mutagenesis that support the pathogenicity of this variant via an impairment in glucose transport. We are also modeling the disease in zebrafish by generating a slc2a10 knockout zebrafish line and introducing the human wild-type gene and the variants, Q243K and R105H, to assess for pathogenicity. Given the rarity of arterial tortuosity syndrome and the specific nature of the hallmark phenotypes that this patient manifests, we are confident of the clinical diagnosis and believe the variants identified in SLC2A10 to be the likely cause of disease.
The proband is a 4 year old female referred for hypotonia, muscle weakness, joint laxity, fatigue, and constipation.
Prenatal: Born to a 29 year old G3P3 heathy mother. Unaffected parents were of European descent.
• Proband was born by induction vaginal delivery at 38 weeks without complications (birth weight: 7 lb. 4 oz.)
• Met milestones at appropriate ages (sitting and walking)
• Physical therapy hypotonia
• Joint laxity: concern for hip dysplasia at birth, but ultrasound revealed "loose" hips, later found hypermobility (Beighton score 5/9)
• Umbilical hernia repair and possibly ripped internal sutures
• Rectal prolapse
• Loose, translucent and “doughy” skin, easy bruisability
• Subluxed shoulder (no dislocation)
• Chronic constipation
• Easy fatigability
• Chronic pain
• Long face
• Muscle biopsy:
• 5% abnormal
• Mitochondrial DNA increased in muscle (228%) – qPCR
• Electron transport chain: Normal to increased
• Mitochondrial DNA-Blood: no common deletions/mutations
• Abnormal EMG: Some myoclonic features with small amplitude MUAP with early recruitment consistent with non-irritable myopathy
• Normal MRI
• Gothic aortic arch with a common brachiocephalic trunk
• Whole exome sequencing was performed identifying 5 variants of uncertain clinical significance (VUS) in disease genes related to her phenotype including 2 compound heterozygous VUSs in SLC2A10.
• Brother who is asymptomatic has a heterozygous variant: c.314G>A
• Sister with a subclavian vascular ring, and no other symptoms: no variants
Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive disorder. There have been approximately 100 reported cases to date, and a majority are infants and children. It is caused by mutations in the SLC2A10 gene that lead to decreased or loss of function, but the mechanism of disease is not fully understood.
Phenotypes and Clinical Features:
• Elongated and twisted (tortuous) arteries: patients are prone to dissection, aneurism, or stenosis and can cause cardiovascular and respiratory complications
• Soft, velvety skin
• Joint hypermobility
• Poor wound healing and abnormal scarring
• Facial features: long face, downslanted palpebral fissures, high arched palate, micrognathia, dental crowding
Zebrafish have been shown to be a good model of SLC2A10. Morphants expressing FLI-GFP (labeling blood vessels) had abnormal vessel structure/development among other phenotypes. To evaluate the pathogenicity of the R105H and Q243K variants identified in the proband, we will:
Generate a knockout slc2a10 zebrafish line using TALENs in FLI-GFP background to label the vessels.
Introduce human SLC2A10 using mini-tol2 transposon system. We will introduce wild-type, R105H, and Q243K variants in the FLI-GFP/slc2a10-null background to assess for phenotypes and knockout phenotype rescue. The construct also contains a heart driver of BFP as an indicator of construct integration.