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Genetic Testing for Marfan Syndrome, Thoracic Aortic Aneurysms and Dissections, and Related Disorders

Policy Number: MP-580

 Latest Review Date: February 2019

Category:  Laboratory                                                            

Policy Grade:  C

DESCRIPTION OF PROCEDURE OR SERVICE:

Marfan syndrome (MFS) is a systemic connective tissue disease that may have a high degree of clinical variability and overlapping phenotypes with other syndromes and disorders. The diagnosis of most suspected connective tissue disorders can be made based on clinical findings and family history. Some of these disorders are associated with a predisposition to the development of progressive thoracic aortic aneurysms (TAAs) and dissection (TAAD). Accurate diagnosis of one of these syndromes can lead to changes in clinical management, including surveillance of the aorta, and surgical repair of the aorta, when necessary, as well as surveillance for multisystem involvement in syndromic forms of TAAD. Known pathogenic variants are associated with MFS and the other connective tissue disorders that may share clinical features with MFS.

Syndromes associated with thoracic aortic aneurysms may have established clinical criteria with major and minor criteria, e.g., Marfan syndrome (Ghent criteria) and Ehlers-Danlos syndrome Type IV, or may be associated with characteristic clinical findings. While most of these syndromes can be diagnosed based on clinical findings, these syndromes may be associated with variability in clinical presentation and may show overlapping features with each other, and with other disorders. The use of genetic testing to establish a diagnosis in a patient with a suspected connective tissue disorder is most useful in those patients who do not meet sufficient clinical diagnostic criteria at the time of initial examination, in patients who have an atypical phenotype and other connective tissue disorders cannot be ruled out, and in individuals who belong to a family in which a pathogenic variant is known (presymptomatic diagnosis).

Genetic testing has conventionally been used when a definitive diagnosis of one of these conditions cannot be made. More recently, panels using next generation sequencing (NGS), which test for multiple genes simultaneously, have been developed for the syndromes that are associated with thoracic aortic aneurysms and dissections, and other conditions that may have overlapping phenotypes. Although the laboratory-reported sensitivity of these panels is high for some of the conditions on the panel, the analytic validity of these panels is unknown, and the detection rate of variants of uncertain significance (VUS) is unknown.

However, there may be certain clinical scenarios in which focused panel testing may be appropriate to include a narrow list of differential diagnoses of TAAD based on clinical findings.

Connective Tissue Diseases

Individuals suspected of having a systemic connective tissue disorder like MFS usually have multiple features that affect many different organ systems; most of these conditions can be diagnosed using clinical criteria. However, these different syndromes may show shared features, overlapping phenotypes, and similar inheritance patterns, which can cause a diagnostic challenge. Additional difficulties in the diagnosis of one of these syndromes may occur due to the age dependent development of many of the physical manifestations of the syndrome (making the diagnosis more difficult in children), many show variable expression, and many of the features found in many of these syndromes occur in the general population (e.g., pectus excavatum, tall stature, joint hypermobility, mitral valve prolapse, nearsightedness). The identification of the proper syndrome is important to address the manifestations and complications of the specific syndrome, in particular, the risk of aortic aneurysms and dissection.

Thoracic Aortic Aneurysms and Dissection

Most TAAs are degenerative and are often associated with the same risk factors as abdominal aortic aneurysms (e.g., atherosclerosis). TAAs may be associated with a genetic predisposition, which can either be familial or related to defined genetic disorders or syndromes.

Genetic predisposition to TAA is due to a genetic defect that leads to abnormalities in connective tissue metabolism. Genetically-related TAA accounts for approximately 5% of TAA. Some of the genetic syndromes associated with TAA have more aggressive rates of aortic expansion and are more likely to require intervention compared with sporadic TAA. MFS is the most common inherited form of syndromic TAA and TAAD. Other genetic systemic connective tissue disorders associated with a risk of TAAD include Ehlers-Danlos syndrome (EDS) Type IV, Loeys-Dietz syndrome (LDS), and arterial tortuosity syndrome.

Familial TAAD refers to patients with a family history of aneurysmal disease, but who do not meet criterial for a connective tissue syndrome.

Marfan Syndrome

MFS is an autosomal-dominant condition, in which there is a high degree of clinical variability of systemic manifestations, ranging from isolated features of MFS to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. Despite the clinical variability, the principal manifestations involve the skeletal, ocular, and cardiovascular systems. Involvement of the skeletal system is characterized by bone overgrowth and joint laxity, disproportionately long extremities for the size of the trunk (dolichostenomelia), overgrowth of the ribs which can push the sternum in or out (pectus excavatum or carinatum, respectively), and scoliosis which can be mild or severe and progressive. Ocular features include myopia and displacement of the lens from the center of the pupil (ectopic lentis). Ectopia lentis is a hallmark feature of this syndrome and is seen in 60% of affected individuals. Cardiovascular manifestations are the major source of morbidity and mortality. The manifestations include dilation of the aorta at the level of the sinuses of Valsalva, predisposition for aortic tear and rupture, mitral valve prolapse, tricuspid valve prolapse and enlargement of the proximal pulmonary artery. However, with proper management, the life expectancy of someone with MFS can approximate that of the general population.

Diagnosis

The diagnosis of MFS is mainly a clinical one and based on the characteristic findings in multiple organ systems, as well as the family history. The Ghent criteria, revised in 2010, are used for the clinical diagnosis of MFS. The previous Ghent criteria had been criticized for taking an insufficient account of the age-dependent nature of some of the clinical manifestations which made the diagnosis in children more difficult, and for including some nonspecific physical manifestations or poorly validated diagnostic thresholds. The revised criteria are based on clinical characteristics in large published patient cohorts, and expert opinions. The revised criteria have several major changes to the previous diagnostic guidelines as follows. More weight is given to the two cardinal features of MFS, aortic root aneurysm/dissection and ectopic lentis. In the absence of findings that are not expected in MFS, the combination of these two features is sufficient to make the diagnosis. When aortic disease is present, but ectopia lentis is not, all other cardiovascular and ocular manifestations of MFS and findings in other organ systems contribute to a “systemic score” that guides diagnosis. Second, a more prominent role has been given to molecular testing of FBN1 and other relevant genes, allowing for the appropriate use when necessary. Third, some of the less specific manifestations of MFS were removed or made less influential in the diagnostic criteria. Fourth, the revised criteria formalize the concept that additional diagnostic considerations and testing may be required if a patient has findings that satisfy the criteria for MFS but show unexpected findings, particularly if they are suggestive of a specific alternative diagnosis. Particular emphasis is placed on LDS, Shprintzen-Goldberg syndrome (SGS), and EDS vascular type. LDS and SGS may have substantial overlap with MFS, including the potential for similar involvement of the aortic root, skeleton, skin and dura. EDS vascular type occasionally shows overlap with MFS. Each of these conditions has a unique risk profile and management protocol. Given the autosomal-dominant inheritance, the number of physical findings needed to establish a diagnosis for someone with an established family history is reduced.

Genetic Testing

It is estimated that molecular techniques allow the detection of FBN1 pathogenic variants in up to 97% of Marfan patients who fulfil Ghent criteria, suggesting that the current Ghent criteria have excellent specificity.

FBN1 is the only gene in which pathogenic variants are known to cause classic MFS. Approximately 75% of individuals with MFS have an affected parent, and 25% have a de novo pathogenic variant. Over 1000 FBN1 pathogenic variants that cause MFS have been identified. The following findings in FBN1 molecular genetic testing should infer causality in making the diagnosis of MFS: a pathogenic variant previously shown to segregate in families with MFS and de novo pathogenic variants of a certain type (e.g., nonsense, certain missense variants, certain splice site variants, certain deletions and insertions).

Most variants in the FBN1 gene that cause MFS can be identified with sequence analysis (~70% to 93%) and, although the yield of deletion/duplication analysis in patients without a defined coding sequence or splice site by sequence analysis is unknown, it is estimated to be about 30%. The most common testing strategy of a proband suspected of having MFS is sequence analysis followed by deletion/duplication analysis if a pathogenic variant is not identified. However, the use of genetic testing for a diagnosis of MFS has limitations. More than 90% of pathogenic variants that have been described are unique, and most pathogenic variants are not repeated among nongenetically related patients. Therefore, the absence of a known pathogenic variant in a patient in whom MFS is suspected does not exclude the possibility that the patient has MFS. No clear genotype-phenotype correlation exists for MFS and, therefore the severity of the disease cannot be predicted from the type of variant.

Caution should be used in interpreting the identification of a FBN1 variant, as other conditions with overlapping phenotypes with MFS can have an FBN1 variant (e.g., MASS syndrome, familial mitral valve prolapse syndrome, SGS, isolated ectopic lentis).

Treatment

Management of MFS includes both treatment of manifestations and prevention of complications, including surgical repair of the aorta depending on the maximal measurement, the rate of increase of the aortic root diameter, and the presence of progressive and severe aortic regurgitation.

Ehlers-Danlos Syndrome

EDS are a group of disorders that affect connective tissue disorders and share common features characterized by skin hyperelasticity or laxity, abnormal wound healing, and joint hypermobility. The defects in connective tissues can vary from mildly loose joints to life-threatening complications. All types of EDS affect the joints and many affect the skin, but features vary by type.

The different types of EDS include Types I and II (classical type), Type III (hypermobility type), Type IV (vascular type), Type VI (kyphoscoliotic form), all of which are inherited in an autosomal-dominant pattern with the exception of Type VI, which is autosomal recessive. It is estimated that affected individuals with Types I, II or IV may inherit the pathogenic variant from an affected parent 50% of the time, and about 50% have a de novo pathogenic variant.

Most types of EDS are not associated with aortic dilation, with the exception of the vascular type (also known as Type IV), which can involve serious and potentially life-threatening complications. The prevalence of the vascular type may affect about one in 250,000 people. Vascular complications include rupture, aneurysm, and/or dissection of major or minor arteries. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae or dissection, or may occur spontaneously. Such complications are often unexpected and may present as sudden death, stroke, internal bleeding and/or shock. The vascular type is also associated with an increased risk of gastrointestinal perforation or organ rupture, and rupture of the uterus during pregnancy.

Diagnosis

The clinical diagnosis of EDS Type IV can be made from major and minor clinical criteria. The combination of two major criteria (arterial rupture, intestinal rupture, uterine rupture during pregnancy and a family history of EDS Type IV) is highly specific. The presence of one or more minor clinical criteria supports the diagnosis, but is not considered sufficient to make the diagnosis by itself.

Genetic Testing

Pathogenic variants in the COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and TNXB genes cause EDS. The vascular type (Type IV) is caused by pathogenic variants in the COL3A1 gene.

Loeys-Dietz Syndrome

LDS is an autosomal-dominant condition that is characterized by four major groups of clinical findings, including vascular, skeletal, craniofacial, and cutaneous manifestations. Vascular findings include cerebral, thoracic, and abdominal arterial aneurysms and/or dissections. Skeletal findings include pectus excavatum or carinatum, scoliosis, joint laxity, arachnodactyly, and talipes equinovarus. The natural history of LDS is characterized by arterial aneurysms, with a mean age of death of 26 years and a high incidence of pregnancy-related complications, including uterine rupture and death. Treatment considerations take into account that aortic dissection tends to occur at smaller aortic diameters than MFS, and the aorta and its major branches can dissect in the absence of much, if any, dilation. Patients with LDS require echocardiography at frequent intervals, to monitor the status of the ascending aorta, and angiography evaluation to image the entire arterial tree.

Genetic Testing

LDS is caused by pathogenic variants in the TGFBR1, TGFBR2, TGFB2, and SMAD3 genes.

Arterial Tortuosity Syndrome

Arterial tortuosity syndrome is inherited in an autosomal recessive pattern and is characterized by tortuosity of the aorta and/or large- and middle-sized arteries throughout the body. Aortic root dilation, stenosis and aneurysms of large arteries are common. Other features of the syndrome include joint laxity and hyperextensible skin.

Genetic Testing

The syndrome is caused by pathogenic variants in the SLC2A10 gene.

Familial TAAD

Approximately 80% of familial TAA and TAAD is inherited in an autosomal-dominant manner and may be associated with variable expression and decreased penetrance of the disease-associated variant.

The major cardiovascular manifestations of familial TAAD (fTAAD) include dilatation of the ascending thoracic aorta at the level of the sinuses of Valsalva or ascending aorta or both and dissections of the thoracic aorta involving either the ascending or descending aorta. In the absence of surgical repair of the ascending aorta, affected individuals have progressive enlargement of the ascending aorta, leading to acute aortic dissection. Presentation of the aortic disease and the age of onset are highly variable.

Diagnosis

Familial TAAD is diagnosed based on the presence of thoracic aorta pathology, absence of clinical features of MFS, LDS, or vascular EDS, and a positive family history of TAAD.

Genetic Testing

Familial TAAD is associated with pathogenic variants in TGFBR2, TGFBR1, MYH11, ACTA2, MYLK, SMAD3, and two loci on other chromosomes, AAT1 and AAT2. Rarely, fTAAD can also be caused by FBN1 pathogenic variants. To date, only about 20% of fTAAD is accounted for by variants in known genes. Early prophylactic repair should be considered in individuals with confirmed pathogenic variants in TGFBR2 and TGFBR1 and/or a family history of aortic dissection with minimal aortic enlargement.

Other Syndromes and Disorders

The following syndromes and conditions may share some of the features of these connective tissue syndromes, but do not share the risk of TAAD.

Congenital Contractural Arachnodactyly (Beal Syndrome)

Congenital contractural arachnodactyly (CCA) is an autosomal-dominant condition characterized by a Marfan-like appearance and long, slender toes and fingers. Other features may include “crumpled” ears, contractures of the knees and ankles at birth with improvement over time, camptodactyly, hip contractures, and progressive kyphoscoliosis. Mild dilatation of the aorta is rarely present. CCA is caused by pathogenic variants in the FBN2 gene.

MED12-Related Disorders

The phenotypic spectrum of MED12-related disorders is still being defined, but includes Lujan syndrome (LS) and FG syndrome Type 1 (FGS1). LS and FGS1 share the clinical findings of hypotonia, cognitive impairment and abnormalities of the corpus callosum. Individuals with LS share some physical features with MFS, in that they have Marfanoid features including tall and thin habitus, long hands and fingers, pectus excavatum, narrow palate and joint hypermobility. MED12-related disorders are inherited in an X-linked manner, with males being affected and carrier females not usually being affected.

Shprintzen-Goldberg Syndrome

SGS is an autosomal-dominant condition that is characterized by a combination of major characteristics which include craniosynostosis, craniofacial findings, skeletal findings, cardiovascular findings, neurologic and brain anomalies, certain radiographic findings, and other findings. SK1 is the only gene in which pathogenic variants are known to cause SGS.

Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency

Homocystinuria is a rare metabolic disorder, inherited in an autosomal recessive manner, which is characterized by an increased concentration in the blood and urine, of homocysteine, a sulfur-containing amino acid. The classical type is due to a deficiency of cystathionine beta synthase (CBS). Affected individuals appear normal at birth but develop serious complications in early childhood, usually by age three to four years. Heterozygous carriers (1/70 of the general population) have hyperhomocysteinemia without homocystinuria, however, their risk for premature cardiovascular disease is increased.

Overlap with MFS can be extensive and includes a Marfanoid habitus with normal to tall stature, pectus deformity, scoliosis, and ectopia lentis. Central nervous system manifestations include mental retardation, seizures, cerebrovascular events, and psychiatric disorders. Patients have a tendency for intravascular thrombosis and thromboembolic events, which can be life-threatening. Early diagnosis and prophylactic medical and dietary care can decrease and even reverse some of the complications. The diagnosis depends on measurement of CBS activity in tissue (e.g., liver biopsy, skin biopsy).

POLICY:

Individual genetic testing for the diagnosis of Marfan syndrome, other syndromes associated with thoracic aortic aneurysms and dissections, and related disorders, and panels comprised entirely of focused genetic testing limited to the following genes: FBN1 and MYH11 (CPT code 81408) and ACTA2, TGFBR1, and TGFBR2 (CPT code 81405), may be considered medically necessary when signs and symptoms of a connective tissue disorder are present, but a definitive diagnosis cannot be made using established clinical diagnostic criteria.

Individual, targeted familial variant testing for Marfan syndrome, other syndromes associated with thoracic aortic aneurysms and dissections, and related disorders, for assessing future risk of disease in an asymptomatic individual, may be considered medically necessary when there is a known pathogenic variant in the family.

Genetic testing panels for Marfan syndrome, other syndromes associated with thoracic aortic aneurysms and dissections, and related disorders that are not limited to focused genetic testing as defined by CPT codes 81405 and 81408 are considered not medically necessary and investigational.

KEY POINTS:

The most recent literature review was updated through December 14, 2018.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Testing Patients with Signs and/or Symptoms of a Connective Tissue Disease

Clinical Context and Test Purpose

The purpose of genetic testing of patients who have signs and/or symptoms of connective tissue disease linked to thoracic aortic aneurysms and diagnosis cannot be made clinically is to confirm a diagnosis and inform management decisions such increased surveillance of the aorta, and surgical repair of the aorta, when necessary, as well as surveillance for multisystem involvement in syndromic forms of thoracic aortic aneurysms and dissection (TAAD).

The question addressed in this evidence review is: Does genetic testing improve health outcomes in individuals with signs and/or symptoms of connective tissue disorder linked to thoracic aortic aneurysms?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients with clinical signs and/or symptoms of a connective tissue disorder linked to thoracic aortic aneurysms and diagnosis cannot be made clinically.

Interventions

The relevant intervention of interest is genetic testing for genes associated with connective tissue disorders.

Comparators

The following practice is being used to diagnose CTDs associated with TAAs: standard clinical management without genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be improvement in OS and disease-specific survival and decreased morbid events. Increased surveillance of the aorta, and surgical repair of the aorta, when necessary, as well as surveillance for multisystem involvement in syndromic forms of thoracic aortic aneurysms and dissection (TAAD) is initiated to detect and treat aortic aneurysms and dissections prior to rupture or dissection.

The potential harmful outcomes are those resulting from a false-positive or false-negative test result. False-positive test results can lead to initiation of unnecessary surveillance of the aorta and surgical repair of the aorta. False-negative test results can lead to lack of surveillance of the aorta that allows for development and subsequent rupture of aortic aneurysms or dissection.

Time

The primary outcomes of interest would be related to the frequency of surveillance and the short-term and long-term survival after surgical repair of the aorta.

Setting

Patients may be referred from primary care to a cardiologist or medical geneticist for investigation and management of connective tissue disorders related to TAAD. Referral for genetic counseling is important for explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Simplifying Test Terms

There are 3 core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:

  • Technically reliable

  • Clinically valid

  • Clinically useful.

Because different specialties may use different terms for the same concept, we are highlighting the core characteristics. The core characteristics also apply to different uses of tests, such as diagnosis, prognosis, and monitoring treatment.

Diagnostic tests detect presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.

Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or to predicting a response to therapy.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review, and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test may detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Single Gene Testing

Sequencing analysis for Marfan syndrome (MFS) has been reported to detect 70% to 93% of pathogenic variants in probands with MFS. This is influenced by the accuracy of the clinical diagnosis and the variant type. The yield of deletion/duplication analysis in individuals with MFS is unknown.

Sequencing analysis for variant detection in Ehlers-Danlos syndrome (EDS) Type IV is greater than 95% and deletion/duplication analysis is approximately 2%.

Panel Testing

NGS technology cannot detect large deletions or insertions, and therefore, samples from patients with a high clinical suspicion of a thoracic aortic aneurysm disorder without identified pathogenic variants after sequencing should be evaluated by other testing methodologies (e.g., MLPA: multiplex ligation-dependent probe amplification).

Marfan Syndrome

Sequence analysis of all exons in the FBN1 gene is expected to identify a pathogenic variant in 70% to 93% of individuals with a clinical suspicion of MFS, with the variant detection rate approaching 93% in individuals fulfilling a clinical diagnosis of MFS based on the Ghent nosology; the test sensitivity significantly decreases for individuals who do not meet Ghent criteria for MFS. Large deletions have been detected in approximately 2% of individuals who did not have a variant identified by sequencing.

Loeys-Dietz Syndrome

The pathogenic variant detection rate for sequence analysis of all exons in the TGFBR1 and TGFBR2 genes in patients with LDS has not been well established but may be as high as 87% in patients with a strong clinical suspicion of LDS. Of patients with LDS with an identifiable pathogenic variant, 70% have a pathogenic variant in the TGFBR2 gene, 20% have a pathogenic variant in the TGFBR1 gene, 5% in SMAD3, and approximately 1% in the TGFB2 gene.

Familial TAAD

Sequence analysis of all exons in the ACTA2 gene is expected to identify a pathogenic variant in up to 15% of cases of familial TAAD (fTAAD), the TGFBR1 and TGFBR2 genes are expected to identify pathogenic variants in 1% and 4%, respectively, of individuals with TAAD, and pathogenic variants reported in SMAD3 account for about 2% of individuals with TAAD. Rarely, TAAD has been associated with pathogenic variants in the nine other genes on the panel.

In a 2017 study conducted in China, 70 TAAD patients were screened by NGS coupled with DNA target capture for 11 known causative genes of TAAD that included ACTA2, Col3A1, Col5A2, FBN1, MSTN, MYH11, MYLK, SLC2A10, SMAD3, TGFBR1, and TGFBR2. The study identified 40 variants in 36 (51%) patients. Among all variants, 12 pathogenic/likely pathogenic variants were in the FBN1 gene, one likely pathogenic variant was in the ACTA2 gene, and the other 27 VUS presented in eight genes.

Ambry Genetics states that TAADNext identifies greater than 96% of described pathogenic variants in the genes included in their NGS panel and that up to 93% of patients with MFS will have a pathogenic variant in the FBN1 gene, testing of COL3A1 will detect a pathogenic variant in over 95% of patients with EDS Type IV, and that 30% to 40% of patients with fTAAD will have a pathogenic variant detected by TAADNext.

Baetens et al (2011) described the validation of a variant discovery strategy using multiplex polymerase chain reaction (PCR) followed by NGS. The pilot stage involved the analysis of the DNA from five patients with MFS or Loeys-Dietz syndrome (LDS) and pathogenic variants and/or benign variants in FBN1, TGFBR1, and TGFBR2 genes previously identified by Sanger sequencing; all expected variants were identified. NGS was then validated on 87 samples from patients with MFS fulfilling the Ghent criteria. Seventy-five FBN1 pathogenic variants were identified, 67 of which were unique. Because sequencing methods cannot detect larger deletions or insertions, multiplex ligation-dependent probe amplification (MLPA) analysis was performed on the negative samples and identified four large deletions/duplications. The authors concluded that their technique of multiplex PCR followed by NGS analysis coupled with MLPA, is a robust strategy for time- and cost-effective identification of pathogenic variants in MFS and LDS.

Campens et al (2015) performed NGS based screening on 264 consecutive samples from unrelated probands referred for heritable thoracic aortic disorders. Patients presenting with marfanoid features, LDS features and/or vascular EDS features were considered as syndromic patients. Panel testing was performed whenever overlapping and/or insufficient clinical features were present, or when patients fulfilled the criteria for MFS but targeted FBN1 sequencing and duplication/deletion testing were negative. The panels were focused and included the seven genes associated with the most commonly occurring and phenotypically overlapping syndromic and nonsydromic hereditary thoracic aortic disorders: FBN1 (MFS), TGFBR1/2, TGFB2, SMAD3 (LDS), ACTA2 (fTAAD) and COL3A1 (EDS Type IV). A causal variant was identified in 34 patients (13%), 12 of which were FBN1, one TGFBR2, two TGFRBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1. Six VUS in FBN1 were identified. Pathogenic variants in FBN1 (n=3), TGFBR2 (n=1) and COL3A1 (n=2) were identified in patients without characteristic clinical features of a syndromal hereditary thoracic aortic disorder. Six patients with a SMAD3, and one patient with a TGFB2 pathogenic variant fulfilled diagnostic clinical criteria for MFS.

Wooderchak-Donahue et al (2015) reported the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories using NGS and CGH array to detect variants in 10 genes that cause thoracic aortic aneurysms. The majority of patients referred had aortic findings (dilation, dissection, rupture) and a positive family history. Pathogenic variants on the panel were identified in FBN1, FBN2, TGFBR1/2, SMAD3, ACTA2, COL3A1, MYH11, MYLK and SLC2A10, comprising fTAAD, EDS Type IV, MFS, CCA, TAAD-patent ductus arteriosus, arterial tortuosity and LDS. Of the 175 individuals, 18 had a pathogenic variant and 32 had a VUS. Most of the pathogenic variants (72%) were identified in FBN1. The most frequently identified disorders were fTAAD (11 variants, two of which were pathogenic and nine VUS), LDS (12 variants, three of which were pathogenic and nine VUS) and MFS (21 variants, 13 of which were pathogenic and eight VUS).

Section Summary: Clinical Valid

Evidence from multiple studies indicates that the clinical sensitivity of genetic testing for connective tissue disorders related to TAAD may be highly variable. This may reflect the phenotypic heterogeneity of the associated syndromes and the silent, indolent nature of TAAD development. The true clinical specificity is uncertain because different connective tissue disorders are defined by specific disease-associated variants.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

No literature on the direct impact of genetic testing for CTDs addressed in the evidence review was identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Establishing a definitive diagnosis can lead to:

  • treatment of manifestations of a specific syndrome,

  • prevention of primary manifestations,

  • prevention of secondary complications,

  • impact on surveillance,

  • counseling on agents and circumstances to avoid,

  • evaluation of relatives at risk, including whether or not to follow a relative who does or does not have the familial variant,

  • pregnancy management,

  • future reproductive decision making

Most of the time, a diagnosis of one of the connective tissue syndromes that predisposes to TAAD, or of one of the syndromes that may not predispose to TAAD but has overlapping phenotypic features of one of the syndromes associated with TAAD, can be made based on clinical criteria and evidence of an autosomal-dominant inheritance pattern by family history. However, there are cases in which the diagnosis cannot be made clinically because the patient does not fulfill necessary clinical criteria, the patient has an atypical presentation and other connective tissue diseases cannot be excluded, or in a child with a family history in whom certain age-dependent manifestations of the disease have not yet developed. In these circumstances, the clinical differential diagnosis is narrow, and single gene testing or focused panel testing, may be warranted, establishing the clinical utility of these types of tests. However, the incremental benefit of expanded NGS panel testing in these situations is unknown, and the VUS rate with the use of these NGS panels is also unknown. In addition, the more disorders that are tested in a panel, the higher the VUS rate is expected to be.

Section Summary: Clinically Useful

Direct evidence of the clinical usefulness of genetic testing for connective tissue orders related to TAAD is lacking. However, genetic testing can confirm the diagnosis in patients with clinical signs and symptoms of a connective tissue disorder associated with TAAD who do not meet clinical diagnostic criteria. Management changes include increased surveillance of the aorta and surgical repair of the aorta.

Targeted Familial Variant Testing of Asymptomatic Individuals with a Known Familial Pathogenic Variant Associated with TAAD

Clinical Context and Purpose

The purpose of familial variant testing of asymptomatic individuals with a first-degree relative with a connective tissue disorder related to TAAD is to screen for the family-specific pathogenic variant to inform management decisions such increased cancer surveillance or to exclude asymptomatic individuals from increased surveillance of the aorta.

The question addressed in this evidence review is: Does genetic testing improve health outcomes in asymptomatic individuals with a first-degree relative with a connective tissue disorder related to TAAD?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is asymptomatic individuals with a first-degree relative with a connective tissue disorder related to TAAD.

Interventions

The relevant population of interest is targeted genetic testing for a familial variant related to TAAD.

Comparators

The following practice is being used for targeted testing of asymptomatic individuals with a first-degree relative who has a CTD related to TAAD: standard clinical management without targeted genetic testing for a familial variant related to TAAD.

Outcomes

The potentially beneficial outcomes of primary interest would be improvement in OS and disease-specific survival and decreased morbid events. Increased surveillance of the aorta, and surgical repair of the aorta, when necessary, as well as surveillance for multisystem involvement in syndromic forms of thoracic aortic aneurysms and dissection (TAAD) is initiated to monitor the development of aortic aneurysms and dissection and potentially repair prior to rupture or dissection. If targeted genetic testing for a familial variant is negative, the asymptomatic individual can be excluded from increased cancer surveillance.

The potentially harmful outcomes are those resulting from a false-positive or false-negative test results. False-positive test results can lead to unnecessary surveillance and surgical repair of the aorta. False-negative test results can lead to lack of surveillance of the aorta that allows for development and subsequent rupture of aortic aneurysms or dissection.

Time

The primary outcomes of interest would be related to the frequency of surveillance and the short-term and long-term survival after surgical repair of the aorta.

Setting

Asymptomatic individuals may be referred from primary care to a cardiologist or medical geneticist if a familial variant related to TAAD is identified. Referral for genetic counseling is important for explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review, and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Same as the discussion in the previous Clinically Valid section for patients with sign and/or symptoms of a CTD associated with TAAD.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Preferred evidence comes from randomized controlled trials. No such trials were identified.

No literature on the direct impact of genetic testing for CTDs addressed in the evidence review was identified.

Chain of Evidence

A chain of evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

When a disease-associated variant for a connective tissue disorder associated with TAAD has been identified in a proband, testing of first-degree relatives can identify those who also have the familial variant and may develop TAAD. These individuals need initial evaluation and ongoing surveillance of the aorta. Alternatively, first-degree relatives who test negative for the familial variant could potentially be excluded from ongoing surveillance of the aorta.

Section Summary: Clinically Useful

Direct evidence of the clinical utility of familial variant testing in asymptomatic individuals is lacking. However, for first-degree relatives of individuals affected individuals with a connective tissue disorder associated with TAAD, a positive test for a familial variant confirms the diagnosis of the TAAD-associated disorder and results in ongoing surveillance of the aorta while a negative test for a familial variant potentially reduces the need for ongoing surveillance of the aorta.

Summary of Evidence

For individuals who have signs or symptoms of a connective tissue disorders associated with thoracic aortic aneurysms who received testing for genes associated with CTDs, the evidence includes mainly of clinical validity data. Relevant outcomes are overall survival, disease-specific survival, test accuracy, test validity, symptoms and morbid events. Sequencing analysis for MFS has been reported to detect 70% to 93% of pathogenic variants in probands with MFS, and greater than 95% in Ehlers-Danlos syndrome Type IV. Direct evidence of clinical utility is lacking, however, confirming a diagnosis leads to changes in clinical management which improve health outcomes. These changes in management include treatment of manifestations of a specific syndrome, prevention of primary manifestations and secondary complications, impact on surveillance, and counselling on agents/circumstances to avoid. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who are asymptomatic with a known pathogenic variant associated with thoracic aortic aneurysms and dissections who receive targeted familial variant testing, the evidence is generally lacking. Relevant outcomes are overall survival, disease-specific survival, test accuracy, test validity, symptoms and morbid events. Direct evidence of clinical usefulness is lacking, however, confirming a diagnosis leads to changes in clinical management which improve health outcomes, similar to those in the proband. In addition, the test results will determine whether or not to follow a relative who does or does not have the familial variant. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

The American College of Medical Genetics and Genomics

The American College of Medical Genetics and Genomics issued guidelines (2012) on the evaluation of the adolescent or adult with some features of Marfan Syndrome (MFS). The guidelines recommend the following:

“If there is no family history of MFS, then the subject has the condition under any of the following four situations:

· A dilated aortic root (defined as greater than or equal to two standard deviations above the mean for age, sex, and body surface area…) and ectopia lentis;

· A dilated aortic root and a mutation [variant] in FBN1 that is clearly pathologic;

· A dilated aortic root and multiple systemic features … ; or

· Ectopia lentis and a mutation [variant] in FBN1 that has previously been associated with aortic disease.”

“If there is a positive family history of MFS (independently ascertained with these criteria), then the subject has the condition under any of the following three situations:

· Ectopia lentis;

· Multiple systemic features … ; or

· A dilated aortic root (if over 20 years, greater than two standard deviations; if younger than 20, greater than three standard deviations).”

The systemic features are weighted by a scoring system.

American College of Cardiology Foundation et al

Joint evidence-based guidelines (2010) from the American College of Cardiology Foundation and 9 other medical associations for the diagnosis and management of thoracic aortic disease include MFS. Genetic testing for MFS was addressed in the following guidelines statements:

  • "If the mutant gene (FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) associated with aortic aneurysm and/or dissection is identified in a patient, first-degree relatives should undergo counseling and testing. Then, only the relatives with the genetic mutation [pathogenic variant] should undergo aortic imaging.” [class 1, level of evidence C. Recommendation that procedure or treatment is useful/effective. It is based on very limited populations evaluated and only expert opinion, case studies, or standard of care.]

  • "The criteria for Marfan syndrome is based primarily on clinical findings in the various organ systems affected in the Marfan syndrome, along with family history and FBN1 mutations [pathogenic variants] status."

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Marfan Syndrome, Thoracic Aortic Aneurysm, TAA, Thoracic Aortic Aneurysm Dissection, TAAD, Ehlers-Danlos Syndrome, Loeys-Dietz Syndrome, Arterial Tortuosity Syndrome, Familial TAAD, fTAAD, genetic testing, Beal Syndrome, Congenital Contractural ArachnodactylyMED12-Related Disorders, Shprintzen-Goldberg Syndrome, Homocystinuria, Cystathionine Beta-Synthase Deficiency

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Several commercial laboratories currently offer targeted genetic testing, as well as NGS panels that simultaneously analyze multiple genes associated with MFS, TAADs, and related disorders. NGS technology cannot detect large deletions or insertions, and therefore samples that are variant-negative after sequencing should be evaluated by other testing methodologies.

Ambry Genetics offers “TAADNEXT,” an NGS panel which simultaneously analyzes 22 genes that are associated with TAADs, MFS and related disorders. The panel detects variants in all coding domains and splice junctions of ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1, and TGFBR2. Deletion/duplication analysis is performed for all genes on the panel except CBS, COL5A1, FLNA, SMAD4, and TGFB3.

Prevention Genetics offers targeted familial variants testing, as well as panel testing “Marfan syndrome and related aortopathies next generation sequencing [NGS] panel,” which includes 14 genes: ACTA2, COL3A1, COL5A1, COL5A2, FBN1, FBN2, MYH11, MYLK, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1, and TGFBR2.

GeneDx offers panel testing “Marfan/TAAD sequencing panel” and “Marfan/TAAD deletion/duplication panel,” which include variant testing for ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1, and TGFBR2.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

81401

-MED12 (mediator complex subunit 12) (e.g., FG syndrome Type 1, Lujan syndrome), common variants (e.g., R961W, N1007S)

81405

  -ACTA2 (actin, alpha 2, smooth muscle, aorta) (e.g., thoracic aortic aneurysms and aortic dissections), full gene sequence

-TGFBR1 (transforming growth factor, beta receptor 1) (e.g., Marfan syndrome), full gene sequence

-TGFBR2 (transforming growth factor, beta receptor 2) (e.g., Marfan syndrome), full gene sequence

81408

-FBN1 (fibrillin 1) (e.g., Marfan syndrome), full gene sequence

-MYH11 (myosin, heavy chain 11, smooth muscle) (e.g., thoracic aortic aneurysms and aortic dissections), full gene sequence

        

For genetic testing of genes that have not been codified by CPT, the unlisted molecular pathology code 81479 would be used.

 

Panel Testing

       There are specific CPT codes for the panel testing:

81410

Aortic dysfunction or dilation (e.g., Marfan syndrome, Loeys Dietz syndrome, Ehlers-Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, and MYLK

81411

duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1

 

(Refer to Appendix 1)

 

REFERENCES:

  1. Baetens M, Van Laer L, De Leeneer K, et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. Sep 2011;32(9):1053-1062.

  2. Beridze N, Frishman WH. Vascular Ehlers-Danlos syndrome: pathophysiology, diagnosis, and prevention and treatment of its complications. Cardiol Rev. Jan-Feb 2012; 20(1):4-7.

  3. Campens L, Callewaert B, Muino Mosquera L, et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis. 2015; 10:9.

  4. Dietz HC. Marfan Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA) 1993.

  5. Fang M, Yu C, Chen S, et al. Identification of novel clinically relevant variants in 70 Southern Chinese patients with thoracic aortic aneurysm and dissection by next-generation sequencing. Sci Rep. Aug 30 2017;7(1):1003

  6. Greally MT. Shprintzen-Goldberg Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA) 1993.

  7. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine. J Am Coll Cardiol. Apr 6 2010;55(14):e27-e129.

  8. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. Jul 2010; 47(7):476-485.

  9. Lyons MJ. MED12-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA) 1993.

  10. Milewicz DM, Regalado E. Thoracic Aortic Aneurysms and Aortic Dissections. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA) 1993.

  11. Pepin MG, Byers PH. Ehlers-Danlos Syndrome Type IV. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA) 1993.

  12. Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. Jan 2012; 14(1):171-177.

  13. Woo YJ. Epidemiology, risk factors, pathogenesis and natural history of thoracic aortic aneurysm. In: UpToDate, ed. UpToDate. Waltham, MD2014.

  14. Wooderchak-Donahue W, VanSant-Webb C, Tvrdik T, et al. Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A. Aug 2015; 167A(8):1747-1757.

POLICY HISTORY:

Medical Policy Panel, February 2015

Medical Policy Group, January 2016 (3): Newly adopted policy; the panel testing for these syndromes (CPT codes 81410 and 81411) were already on our investigational listing; this new policy allows coverage for individual mutation testing when certain criteria are met; panel testing remains investigational

Medical Policy Administration Committee, February 2016

Available for comment February 5 through March 20, 2016

Medical Policy Panel, February 2016

Medical Policy Group, March 2016 (3): 2016 Updates to Description, Key Points, & References; added Appendix 1; no change in policy statement, remains investigational

Medical Policy Panel, February 2017

Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points, Approved by Governing Bodies & Appendix 1; No new References added; Policy statement revised with updated genetics nomenclature; No change in policy statement intent.

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (4): Updates to Description, Key Points and References.

Medical Policy Panel, February 2019

Medical Polilcy Group, March 2019 (9): Updates to Description, Key Points, Appendix. No change in policy statement intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.

Appendix (1)

Individual Gene Testing

For individual gene testing, the following codes may be used:

Disease

Associated Gene

Percentage of Probands With a Pathogenic Variant Detected by Method

CPT Codes

Diseases associated with TAAD

Marfan syndrome

FBN1

  • Sequence analysis detects 70%-93%

  • Deletion/duplication analysis detection rate unknown

FBN1

81408

81411

EDS Type IV (vascular

type)

COL3A1

  • Sequence analysis detects >95%

  • Deletion/duplication analysis detects ≈2%

COL3A1

81410

81411

LDS

TGFBR1

TGFBR2

SMAD3

TGFB2

  • Percentage of LDS attributed to pathogenic variants in following genes by sequence analysis:

TGFBR1: 20%

TGFBR2: 70%

SMAD3: 5%

TGFB2: 1%

  • In general, variants detected in LDS by deletion/duplication analysis are not associated with aortic aneurysms

TGFBR1

TGFBR2

SMAD3,

TGFB2

81405

81405

81410

81479

Familial TAAD

TGFBR1

TGFBR2

MYH11

ACTA2

FBN1

MYLK

SMAD3

  • Percentage of familial TAAD attributed to pathogenic variants in following genes by sequence and deletion/duplication analysis:

TGFBR1: 1%

TGFBR2: 4%

MYH11: 1%

ACTA2: 10%-14%

FBN1: unknown

  • Sequence analysis:

MYLK: 1%

SMAD3: 2%

TGFBR1

TGFBR2

MYH11

ACTA25

FBN1

MYLK,

SMAD3

81411

81405

81405

81408

81405

81408

81410

81410

Arterial tortuosity

syndrome

SLC2A10

  • Sequence analysis detects ≈86%

  • Deletion/duplication analysis detects ≈7%

SLC2A10

81410

81411

Diseases not associated with TAAD

MED12-related

disorders (FS

syndrome Type 1 and

Lujan syndrome)

MED12

Pathogenic variant detection frequency unknown

MED12

81401

Shprintzen-Goldberg

syndrome

SK1

Sequence analysis and deletion/duplication analysis rates of detection have not been reported

SK1

Unlisted 81479

EDS classic type (EDS

I and II)

COL5A1

COL5A2

Percentage of EDS classic type attributed to pathogenic variants in following genes by sequence analysis:

COL5A1: 46%

COL5A2: 4%

COL5A1,

COL5A2

Unlisted 81479

EDS kyphoscoliotic

form (EDS Type VI)

PLOD1

  • Pathogenic variant detection frequency by sequence analysis is unknown

  • Deletions/duplications have been detected with a frequency of 18%

PLOD1

Unlisted 81479

Periventricular

heterotopia, EDS

variant

FLNA

  • Sequence analysis 100% in those with family history and

     26% in simplex females

  • Detection by deletion/duplication analysis is unknown

FLNA

Unlisted 81479

Congenital contractural

arachnodactyly

FBN2

  • Sequence analysis has been reported to detect 27%-75% of pathogenic variants

  • Pathogenic variant detection by deletion/duplication analysis is unknown

FBN2

Unlisted 81479

EDS: Ehlers-Danlos syndrome; LDS: Loeys-Dietz syndrome; TAAD: thoracic aortic aneurysms and dissection.