Hereditary connective tissue disorders in unselected patients with spontaneous cervical artery dissection: a targeted next generation sequencing approach and systematic review.
Corradi L, Ferraro C, et al. • Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2026
Systematic search for rare disease-causing variants should not be recommended in all sCeAD cases but should be limited to selected individuals with a high pre-test probability to harbor a monogenic disease.
Key Findings
Results
In an unselected cohort of 183 sCeAD patients, only 2 (1.1%) carried clinically relevant disease-causing genetic variants.
The cohort consisted of 183 patients (males, 51.3%; mean age, 42.0 ± 11.3 years) with apparently sporadic sCeAD consecutively referred to one comprehensive stroke center from August 2020 to December 2025.
One disease-causing variant was identified in COL3A1 (NM_000090.4:c.2959G > A:p.Gly987Ser) and one in ABCC6 (NM_001351800.1:c.3071G > A:p.Arg1024Gln).
These 2 carriers represented 1.1% of the total screened population.
The study used a targeted next-generation sequencing (NGS) panel designed to identify variants in 38 candidate genes associated with arterial dissection or aneurysm.
Results
Variants of uncertain significance (VUS) were identified in 13.6% of unselected sCeAD patients.
30 VUS were identified in 25 patients, representing 13.6% of the 183-patient cohort.
VUS were described as 'pertinent variants of uncertain significance' in the context of hereditary connective tissue disorders.
The panel screened 38 candidate genes associated with arterial dissection or aneurysm.
The clinical significance of these VUS remains uncertain by definition.
Results
The systematic review of 14 studies revealed that the prevalence of disease-causing variant carriers in sCeAD ranges widely depending on patient selection criteria.
The systematic review analyzed 330 patients across 14 studies evaluating prevalence of monogenic disorders among sCeAD patients up to December 2025.
Prevalence of carriers of disease-causing variants ranged between 0.4% in series of unselected patients and 23.4% in patients with familial history of CeAD.
This wide range (0.4% to 23.4%) underscores the strong influence of pre-test probability and patient selection on genetic yield.
The review covered studies published up to December 2025.
Background
Spontaneous cervical artery dissection (sCeAD) is the leading cause of ischemic stroke in young adults, and whether it represents a manifestation of unrecognized hereditary connective tissue disorders (HCTDs) has been a matter of ongoing debate.
The study framed sCeAD as 'the leading cause of ischemic stroke in young adults.'
The relationship between sCeAD and HCTDs was described as 'a matter of ongoing debate.'
A high-throughput sequencing panel targeting 38 candidate genes was designed specifically to address this question in an unselected population.
Prior to this study, the frequency of clinically relevant genetic variants in unselected sCeAD patients had not been definitively established.
Conclusions
Routine genetic screening for rare disease-causing variants is not recommended for all sCeAD patients, but should be reserved for individuals with high pre-test probability of harboring a monogenic disease.
This recommendation was based on the low yield (1.1%) of disease-causing variants found in unselected patients.
High pre-test probability factors implied by the data include familial history of CeAD, where prevalence reached 23.4% in the systematic review.
The authors concluded that 'systematic search for rare disease-causing variants should not be recommended in all sCeAD cases.'
The recommendation aligns with the systematic review finding that prevalence is as low as 0.4% in unselected series.
What This Means
This research suggests that hereditary connective tissue disorders — genetic conditions that affect the body's structural proteins — are relatively uncommon causes of spontaneous cervical artery dissection (sCeAD), which is the most common cause of stroke in young adults. In a carefully studied group of 183 unselected patients with sCeAD, only 2 people (about 1%) were found to carry a confirmed disease-causing genetic mutation, both in genes known to affect connective tissue (COL3A1 and ABCC6). An additional 13.6% of patients carried genetic variants of uncertain significance, meaning changes in genes that might be relevant but whose role in causing disease is not yet proven.
The researchers also reviewed 14 previous studies on this topic, finding that the proportion of sCeAD patients with identified disease-causing genetic variants varied enormously — from as low as 0.4% in studies of general sCeAD patients to as high as 23.4% in patients who had a family history of the condition. This wide variation shows that genetic testing is far more likely to find meaningful results in patients who already have other clues suggesting a hereditary condition.
This research suggests that genetic screening for hereditary connective tissue disorders should not be performed routinely in every person who experiences a spontaneous cervical artery dissection. Instead, such testing is more likely to be useful and cost-effective when focused on individuals who have a higher likelihood of carrying a genetic cause — for example, those with a family history of arterial dissection or other features suggesting a connective tissue disorder. This finding has practical implications for how clinicians decide which patients to refer for specialized genetic evaluation after a sCeAD event.
Corradi L, Ferraro C, Tesi F, Abrignani G, Castellini P, Latte L, et al.. (2026). Hereditary connective tissue disorders in unselected patients with spontaneous cervical artery dissection: a targeted next generation sequencing approach and systematic review.. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. https://doi.org/10.1007/s10072-026-09308-6