Thoracic Aortic Aneurysm and Dissection (TAAD) via the LOX Gene

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease affecting the aorta and is the 15th leading cause of death in the United States (Hoyert et al. 2001. PubMed ID: 11591077). The age of onset ranges from 11 to 62 years (Guo et al. 2016. PubMed ID: 26838787). Aortic dissections most commonly originate in the ascending aorta above the aortic valve (Stanford type A), but can also occur in the descending aorta (Stanford type B). Aneurysms in the cerebral and peripheral artery and abdominal aorta have also been observed (Milewicz and Regalado. 2017. PubMed ID: 20301299). An intense sharp pain in the chest is the most common symptom of aortic dissection. Familial TAAD is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta using imaging studies (MRI, echocardiography, CT), the absence of syndromic conditions that have clinical features that overlap with familial TAAD, and a positive family history. Syndromic forms of TAAD include Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, Shprintzen-Golberg syndrome, congenital contractural arachnodactyly, aneurysms-osteoarthritis syndrome, multisystemic smooth muscle dysfunction syndrome, Ehlers-Danlos syndrome (vascular type, classic type, and kyphoscoliosis form), and periventricular nodular heterotopia.

Autosomal dominant familial thoracic aortic aneurysm 10 (AAT10) is characterized by aneurysm of aortic root and ascending thoracic aorta, resulting in aortic dissections. Additional features may include bicuspid aortic valve, pectus excavatum, joint hypermobility, dural ectasia, striae distensae, and tall stature. Less common and more variable phenotypes include mitral regurgitation, coronary artery disease, left ventricular hypertrophy, hepatic artery aneurysm, abdominal aortic aneurysm, and abdominal hernia (Guo et al. 2016. PubMed ID: 26838787; Lee et al. 2016. PubMed ID: 27432961). Some patients with AAT10 exhibit features of Marfan syndrome but do not meet diagnostic criteria for Marfan syndrome (Guo et al. 2016. PubMed ID: 26838787). Incomplete penetrance, variable expressivity, and variable age of aortic ruptures have been documented even among family members who carry the same variant (Guo et al. 2016. PubMed ID: 26838787; Lee et al. 2016. PubMed ID: 27432961).

Advantages of genetic testing for TAAD include confirmation of diagnosis, identification of other health risks associated with TAAD, and targeted testing of other family members. An early diagnosis of TAAD followed by prophylactic surgical repair and early medical treatment has been demonstrated to reduce the mortality rate (Mody et al. 2014. PubMed ID: 25336626).

AAT10 is an autosomal dominant disorder that results from heterozygous pathogenic variants in LOX. To date, about ten variants have been reported in patients with AAT10 (Guo et al. 2016. PubMed ID: 26838787; Lee et al. 2016. PubMed ID: 27432961; Kwartler et al. 2018. PubMed ID: 29961567; Wolford et al. 2019. PubMed ID: 31211624). Pathogenic LOX alteration types include missense, nonsense, and frameshift variants. Pathogenic missense variants were found to cluster at a highly conserved LOX catalytic domain and functional studies of these missense variants showed lower LOX enzyme activity (Guo et al. 2016. PubMed ID: 26838787), supporting a haploinsufficiency disease mechanism. These variants have not been reported in population databases or have been reported at very low frequencies. To our knowledge, de novo variants have not been reported for LOX and no gross deletion or duplication events have been documented as disease-causing. Of note, one biallelic missense variant in LOX has been observed in a case of unexplained intrauterine fetal demise (Aggarwal et al. 2020. PubMed ID: 31742715); however, this variant was also reported in one homozygote in a large population database. The autosomal recessive inheritance in LOX has not been supported by other studies.

A study which conducted molecular screenings on 410 index cases with TAAD identified five variants (two nonsense and three missense) that segregated with disease in families (Guo et al. 2016. PubMed ID: 26838787). The study estimated that disease-causing LOX variants are responsible for ~1% of TAAD with decreased penetrance.

The LOX gene encodes an extracellular copper enzyme that initiates crosslinking of collagens and elastin. Studies in homozygous knockout mice showed aortic aneurysms, aortic tortuosity, aortic rupture, and perinatal death. While heterozygotes appeared grossly normal, careful examination showed longer ascending aortas with fragmented elastic fiber (Mäki et al. 2002. PubMed ID: 12417550; Lee et al. 2016. PubMed ID: 27432961). Similar defects in aortic aneurysm and dissection were recapitulated in a knockin mouse model, which harbored a pathogenic missense variant reported in TAAD patients (Lee et al. 2016. PubMed ID: 27432961). In vitro studies of missense variants showed decreased enzyme activity as a result of aberrant LOX protein function (Guo et al. 2016. PubMed ID: 26838787; Lee et al. 2016. PubMed ID: 27432961; Kwartler et al. 2018. PubMed ID: 29961567). LOX has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). LOX is relatively intolerant to loss of function variants (Genome Aggregation Database).

This test is estimated to detect causative variants in LOX in 1% of patients with familial TAAD (Guo et al. 2016. PubMed ID: 26838787). Analytical sensitivity should be high as all reported pathogenic variants are detectable by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the LOX gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.