Absence Of Syndromic Features Research Articles

The genetics of left ventricular noncompaction.

This article summarises current understanding of the genetic architecture underpinning left ventricular noncompaction (LVNC) and highlights the difficulty in differentiating LVNC from hypertrabeculation seen in normal, healthy individuals, that caused by physiological adaptation or that seen in association with cardiomyopathy phenotypes. Progress has been made in better defining the LVNC phenotype and those patients who may benefit from genetic testing. Yield of diagnostic genetic testing may be low in the absence of syndromic features, systolic dysfunction and a family history of cardiomyopathy. Sarcomeric gene variants are most commonly identified but a wide-range of genes are implicated, emphasising the high degree of heterogeneity of studied cohorts. More accurate phenotyping and genotype-phenotype correlation are required to better characterise the genetic architecture of LVNC.

Rare variants of the 3’-5’ DNA exonuclease TREX1 in early onset small vessel stroke

Background: Monoallelic and biallelic mutations in the exonuclease TREX1 cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of TREX1 in small vessel stroke is warranted. Methods: We sequenced the TREX1 gene in an exploratory cohort of patients with lacunar stroke (Edinburgh Stroke Study, n=290 lacunar stroke cases). We subsequently performed a fully blinded case-control study of early onset MRI-confirmed small vessel stroke within the UK Young Lacunar Stroke Resource (990 cases, 939 controls). Results: No patients with canonical disease-causing mutations of TREX1 were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of TREX1 and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of TREX1 in a larger and MRI-confirmed patient cohort, the UK Young Lacunar Stroke Resource, identified heterozygous rare variants in 2.1% of cases and 2.3% of controls. No association was observed with stroke risk (odds ratio = 0.90; 95% confidence interval, 0.49-1.65 p=0.74). Similarly no association was seen with rare TREX1 variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91). Conclusions: No patients with early-onset lacunar stroke had genetic evidence of a TREX1-associated monogenic microangiopathy. These results show no evidence of association between rare variants of TREX1 and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the TREX1 gene in patients with early onset lacunar stroke is therefore unlikely to be of diagnostic utility, in the absence of syndromic features or family history.

Rare variants of the 3'-5' DNA exonuclease TREX1 in early onset small vessel stroke.

Background: Monoallelic and biallelic mutations in the exonuclease TREX1 cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of TREX1 in small vessel stroke is warranted. Methods: We sequenced the TREX1 gene in an exploratory cohort of patients with lacunar stroke (Edinburgh Stroke Study, n=290 lacunar stroke cases). We subsequently performed a fully blinded case-control study of early onset MRI-confirmed small vessel stroke within the UK Young Lacunar Stroke Resource (990 cases, 939 controls). Results: No patients with canonical disease-causing mutations of TREX1 were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of TREX1 and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of TREX1 in a larger and MRI-confirmed patient cohort, the UK Young Lacunar Stroke Resource, identified heterozygous rare variants in 2.1% of cases and 2.3% of controls. No association was observed with stroke risk (odds ratio = 0.90; 95% confidence interval, 0.49-1.65 p=0.74). Similarly no association was seen with rare TREX1 variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91). Conclusions: No patients with early-onset lacunar stroke had genetic evidence of a TREX1-associated monogenic microangiopathy. These results show no evidence of association between rare variants of TREX1 and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the TREX1 gene in patients with early onset lacunar stroke is therefore unlikely to be of diagnostic utility, in the absence of syndromic features or family history.

Mendelian Genes and Risk of Intracerebral Hemorrhage and Small-Vessel Ischemic Stroke in Sporadic Cases.

Mendelian strokes are rare genetic disorders characterized by early-onset small-vessel stroke. Although extensively studied among families with syndromic features, whether these genes affect risk among sporadic cases is unknown. We sequenced 8 genes responsible for Mendelian stroke in a case-control study of sporadic stroke cases (≤70 years). Participants included 1251 primary stroke cases of small-vessel pathology (637 intracerebral hemorrhage and 614 small-vessel ischemic stroke cases) and 1716 controls from the INTERSTROKE study (Study of the Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World). Overall, the prevalence of canonical disease-causing mutations was 0.56% in cases and 0.23% in controls (odds ratio=1.89; 95% confidence interval, 0.54-7.57; P=0.33). CADASIL (Cerebral Autosomal Dominant Arteriopathies with Subcortical Infarcts and Leukoencephalopathies) mutations were more frequent among cases (0.48%) than controls (0.23%) but were not significantly associated with stroke risk (odds ratio=2.03; 95% confidence interval, 0.58-8.02; P=0.27). Next, we included all rare nonsynonymous mutations to investigate whether other types of mutations may contribute to stroke risk. Overall, 13.5% of cases and 14.2% of controls were carriers of at least one rare nonsynonymous mutation among the 8 Mendelian stroke genes. Mutation carriers were not at elevated risk of stroke (odds ratio=0.93; 95% confidence interval, 0.75-1.16; P=0.55). In the absence of syndromic features and family history of stroke, screening for Mendelian mutations among small-vessel stroke patients is unlikely to have high diagnostic utility.

Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.

Marfan syndrome (MFS) due to mutations in FBN1 is a known cause of thoracic aortic aneurysms and acute aortic dissections (TAAD) associated with pleiotropic manifestations. Genetic predisposition to TAAD can also be inherited in families in the absence of syndromic features, termed familial TAAD (FTAAD), and several causative genes have been identified to date. FBN1 mutations can also be identified in FTAAD families, but the frequency of these mutations has not been established. We performed exome sequencing of 183 FTAAD families and identified pathogenic FBN1 variants in five (2.7%) of these families. We also identified eight additional FBN1 rare variants that could not be unequivocally classified as disease-causing in six families. FBN1 sequencing should be considered in individuals with FTAAD even without significant systemic features of MFS.

Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review.

The presence of germline mutations in sporadic pheochromocytomas and paragangliomas (SPPs) may change the clinical management of both index patients and their family members. However, the frequency of germline mutations in SPPs is unknown. To describe the frequency of germline mutations in SPPs and to determine the value of testing index patients and their family members for these mutations. We searched databases through June 2012 for observational studies of patients with SPPs who underwent germline genetic testing. The criteria used to define sporadic tumours were (i) the absence of a family history of PCC/PG, (ii) the absence of syndromic features, (iii) the absence of bilateral disease and (iv) the absence of metastatic disease. We included 31 studies including 5031 patients (mean age 44). These patients received tests for any of these ten mutations: SDHAF2, RET, SDHD, SDHB, SDHC, VHL, TMEM127, MAX, Isocitrate Dehydrogenase Mutation (IDH) and NF1. The overall frequency of germline mutation in SPP was 551 of 5031 or 11%; when studies with patients fulfilling four criteria for sporadic tumours were used, the frequency was 171 of 1332 or 13%. The most common germline mutation was SDHB 167 of 3611 (4·6%). Little outcome data were available to assess the benefits of genetic testing in index cases and family members. The frequency of germline mutations in SPPs is approximately 11-13% and the most common mutations affect less than 1 in 20 patients. The value of testing for germline mutations in patients with SPPs and their family members is unknown, as the balance of potential benefits and harms remains unclear.

Genetic Basis of Thoracic Aortic Aneurysms and Dissections: Focus on Smooth Muscle Cell Contractile Dysfunction

Thoracic aortic aneurysms leading to type A dissections (TAAD) can be inherited in isolation or in association with genetic syndromes, such as Marfan syndrome and Loeys-Dietz syndrome. When TAAD occurs in the absence of syndromic features, it is inherited in an autosomal dominant manner with decreased penetrance and variable expression, the disease is referred to as familial TAAD. Familial TAAD exhibits significant clinical and genetic heterogeneity. The first genes identified to cause TAAD were FBN1, TGFBR2, and TGFBR1. The identification and characterization of these genes suggested that increased TGF-beta signaling plays a role in pathogenesis. The recent discovery that mutations in the vascular smooth muscle cell (SMC)-specific beta-myosin (MYH11) and alpha-actin (ACTA2) can also cause this disorder has focused attention on the importance of the maintenance of SMC contractile function in preserving aortic structure and preventing TAAD.

Genetic Basis of Thoracic Aortic Aneurysms and Dissections

Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) have long been known to occur in association with a genetic syndrome such as Marfan syndrome (MFS). More recently, TAAD has also been demonstrated to occur as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified TAAD loci at 5q13-14 (TAAD1), 11q23 (FAA1), 3p24-25 (TAAD2), and 16p12.2-13.13. The genetic heterogeneity of TAAD is reflected by variation in disease in terms of the age of onset, progression, penetrance, and association with additional cardiac and vascular features. The underlying genetic heterogeneity of TAAD is reflected in the phenotypic variation associated with familial TAAD with respect to age of onset, progression, penetrance, and association with additional cardiac and vascular features. Mutations in the TGFBR2 gene have been identified as the cause of disease linked to the 3p24-25 locus, implicating dysregulation of TGF-beta signaling in TAAD. Mutations in myosin heavy chain (MYH11), a smooth muscle cell-specific contractile protein, have been identified in familial TAAD associated with patent ductus arteriosus (PDA) linked to 16p12.2-12.13. The identification of these novel disease pathways has led to new directions for future research addressing the pathology and treatment of TAAD.

Genetic basis of thoracic aortic aneurysms and aortic dissections

Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) can occur in association with a genetic syndrome, such as Marfan syndrome (MFS), or as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified three TAAD loci at 5q13-14 (TAAD1), 11q23 (FAA1), and 3p24-25 (TAAD2). The underlying genetic heterogeneity of TAAD is reflected in the phenotypic variation associated with familial TAAD with respect to age of onset, progression, penetrance, and association with additional cardiac and vascular features. Recently, mutations in the TGFBR2 gene have been identified as the cause of disease linked to the TAAD2 locus, supporting the hypothesis that dysregulation of TGFbeta signaling is a mechanism leading to aneurysms and dissections. The recent identification of the TGFbeta pathway as a key target in the molecular pathogenesis of TAAD has opened new avenues for future genetic and therapeutic research.