ABSTRACT
BACKGROUND: Marfan syndrome (MFS) is a multisystem disease with a unique combination of skeletal, cardiovascular and ocular features. Geleophysic/acromicric dysplasias (GPHYSD/ACMICD), characterised by short stature and extremities, are described as 'the mirror image' of MFS. The numerous FBN1 pathogenic variants identified in MFS are located all along the gene and lead to the same final pathogenic sequence. Conversely, in GPHYSD/ACMICD, the 28 known heterozygous FBN1 pathogenic variants all affect exons 41-42 encoding TGFß-binding protein-like domain 5 (TB5). METHODS: Since 1996, more than 5000 consecutive probands have been referred nationwide to our laboratory for molecular diagnosis of suspected MFS. RESULTS: We identified five MFS probands carrying distinct heterozygous pathogenic in-frame variants affecting the TB5 domain of FBN1. The clinical data showed that the probands displayed a classical form of MFS. Strikingly, one missense variant affects an amino acid that was previously involved in GPHYSD. CONCLUSION: Surprisingly, pathogenic variants in the TB5 domain of FBN1 can lead to two opposite phenotypes: GPHYSD/ACMICD and MFS, suggesting the existence of different pathogenic sequences with the involvement of tissue specificity. Further functional studies are ongoing to determine the precise role of this domain in the physiopathology of each disease.
Subject(s)
Bone Diseases, Developmental , Limb Deformities, Congenital , Marfan Syndrome , Humans , Bone Diseases, Developmental/genetics , Fibrillin-1/genetics , Marfan Syndrome/genetics , Marfan Syndrome/pathology , MutationABSTRACT
PURPOSE: Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. METHODS: Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. RESULTS: These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. CONCLUSION: This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.
Subject(s)
Marfan Syndrome , Exons , Fibrillin-1/genetics , Fibrillins , High-Throughput Nucleotide Sequencing , Humans , Marfan Syndrome/diagnosis , Marfan Syndrome/genetics , Mosaicism , MutationABSTRACT
PURPOSE: Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only. METHODS: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations. RESULTS: A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants. CONCLUSION: This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.
Subject(s)
Marfan Syndrome , Cohort Studies , Fibrillin-1/genetics , Fibrillins , Genetic Association Studies , Genotype , Humans , Marfan Syndrome/genetics , Microfilament Proteins/genetics , Mutation , PhenotypeABSTRACT
PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.
Subject(s)
Aortic Aneurysm, Thoracic , Aortic Dissection , ADAM Proteins , Aortic Dissection/genetics , Animals , Aortic Aneurysm, Thoracic/genetics , Exome/genetics , Fibrillin-1/genetics , Humans , MiceABSTRACT
Disease-causing heterozygous variants in the ACTA2 gene cause an autosomal dominant heritable thoracic aortic disease (HTAD) with thoracic aortic aneurysm and dissection as main phenotype, and occasional extravascular abnormalities such as livedo reticularis. ACTA2-HTAD accounts for an important part of non-syndromic HTAD, with detection rates varying between 1.5-21% according to different studies. A consensus statement for the screening and management of patients with pathogenic ACTA2 variants has been recently published by the European reference network for rare vascular diseases (VASCERN). However, management of ACTA2 patients is often challenged by extremely variable inter- and intra-familial clinical courses of the disease. Here we report a family harboring a disease-causing ACTA2 variant. The proband and two siblings presented with acute type A aortic dissection and rupture involving nondilated aortic segments before the age of 30. Their mother died at 49 years-old from type B aortic dissection and rupture. Genetic testing revealed the heterozygous novel p.(Pro335Arg) variant in the ACTA2 gene in the proband and in the affected siblings. The clinical history of this family highlights the difficulty of adopting effective prevention strategies in ACTA2 patients.
Subject(s)
Actins/genetics , Aortic Aneurysm, Thoracic/genetics , Aortic Dissection/genetics , Aortic Rupture/genetics , Genetic Variation , Adult , Aortic Dissection/diagnostic imaging , Aortic Dissection/surgery , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/surgery , Aortic Rupture/diagnostic imaging , Disease Progression , Female , Genetic Predisposition to Disease , Heredity , Heterozygote , Humans , Pedigree , PhenotypeABSTRACT
SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
Subject(s)
Arachnodactyly , Craniosynostoses , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Marfan Syndrome , Mutation , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Adolescent , Adult , Arachnodactyly/diagnosis , Arachnodactyly/genetics , Arachnodactyly/metabolism , Child , Child, Preschool , Craniosynostoses/diagnosis , Craniosynostoses/genetics , Craniosynostoses/metabolism , Female , Humans , Male , Marfan Syndrome/diagnosis , Marfan Syndrome/genetics , Marfan Syndrome/metabolism , Middle Aged , Pathology, MolecularABSTRACT
In this report, we present a new case of mosaic trisomy 13 with prolonged survival, firstly detected by array-CGH analysis which was carried out because of moderate intellectual disability with postaxial hexadactyly, dermatologic features, ventricular septal defect, bicuspid aortic valve, and aortic dystrophy in a 19-year-old male patient. In a subset of 15% of the cells, the patient carried a derivative chromosome 10 generated by a nonreciprocal (10;13) translocation inherited from his healthy mother who carried the translocation in a balanced and homogeneous state. FISH analyses showed interstitial telomeric sequences at the breakpoints. To our knowledge, this is the second report of a patient with trisomy 13 mosaicism displaying a severe aortic root dilatation. We also discuss the mechanisms which could explain the mosaic state, the most likely one being related to the instability of the interstitial telomere.
Subject(s)
Aorta/abnormalities , Marfan Syndrome/etiology , Mosaicism , Trisomy 13 Syndrome/diagnosis , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 13/genetics , Comparative Genomic Hybridization , Humans , In Situ Hybridization, Fluorescence , Male , Translocation, Genetic , Trisomy 13 Syndrome/genetics , Young AdultABSTRACT
Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.
Subject(s)
Arachnodactyly/genetics , Connective Tissue Diseases/genetics , Loeys-Dietz Syndrome/genetics , Transforming Growth Factor beta3/genetics , Adolescent , Adult , Arachnodactyly/pathology , Child , Child, Preschool , Connective Tissue Diseases/pathology , Female , Genetic Predisposition to Disease , Genotype , Heterozygote , Homozygote , Humans , Loeys-Dietz Syndrome/pathology , Male , Middle Aged , Mutation/genetics , Pedigree , Phenotype , Transforming Growth Factor beta3/deficiency , Young AdultABSTRACT
BACKGROUND: Pathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants. METHODS: Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain. RESULTS: Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed. CONCLUSIONS: SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.
Subject(s)
Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Phenotype , Smad3 Protein/genetics , Adolescent , Adult , Aged , Alleles , Amino Acid Substitution , Aortic Aneurysm, Thoracic/complications , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Mutation , Prognosis , Protein Domains/genetics , Risk Factors , Smad3 Protein/chemistryABSTRACT
PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.
Subject(s)
Aortic Aneurysm, Thoracic/genetics , Aortic Dissection/genetics , Fibrillin-1/genetics , Smad3 Protein/genetics , Adolescent , Adult , Aged , Aortic Dissection/diagnosis , Aortic Dissection/physiopathology , Aortic Aneurysm, Thoracic/diagnosis , Child , Codon, Nonsense/genetics , Female , Genetic Predisposition to Disease , Genetic Testing/methods , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Mutation , Pathology, Molecular/methods , Pedigree , Young AdultABSTRACT
PURPOSE: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. METHODS: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. RESULTS: Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK. CONCLUSION: These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.
Subject(s)
Aortic Diseases/genetics , Calcium-Binding Proteins/genetics , Genetic Testing , High-Throughput Nucleotide Sequencing , Myosin-Light-Chain Kinase/genetics , Adult , Aged , Aortic Dissection , Aorta/pathology , Aorta/surgery , Aortic Diseases/pathology , Aortic Diseases/surgery , Female , Heterozygote , Humans , Male , Middle Aged , Pedigree , PregnancyABSTRACT
BACKGROUND: Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. OBJECTIVES: Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. METHODS AND RESULTS: In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. CONCLUSION: Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.
Subject(s)
Fibrillin-1/genetics , Marfan Syndrome/diagnosis , Marfan Syndrome/genetics , Pathology, Molecular , Alleles , Codon, Nonsense , Female , Genetic Predisposition to Disease , Genetic Testing , Heterozygote , Homozygote , Humans , Male , Marfan Syndrome/pathology , Mutation, Missense/genetics , PedigreeABSTRACT
Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene. The disease displays large variability in age of onset or severity and very poor phenotype/genotype correlations have been demonstrated. We investigated the hypothesis that phenotype severity could be related to the variable expression level of fibrillin-1 (FBN1) synthesized from the wild-type (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from 80 Marfan patients with premature termination codons and in skin fibroblasts from 80 controls. Results in controls showed a 3.9-fold variation in FBN1 mRNA synthesis level between subjects. A similar 4.4-fold variation was found in the Marfan population, but the mean level of FBN1 mRNA was a half of the control population. Differential allelic expression analysis in Marfan fibroblasts showed that over 90% of FBN1 mRNA was transcribed from the wild allele and the mutated allele was not detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelic-mRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WT FBN1 mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.
Subject(s)
Marfan Syndrome/genetics , Microfilament Proteins/genetics , Adolescent , Adult , Aged , Alleles , Child , Child, Preschool , Codon, Nonsense , Ectopia Lentis/genetics , Female , Fibrillin-1 , Fibrillins , Gene Expression , Gene Expression Profiling , Humans , Infant , Infant, Newborn , Male , Marfan Syndrome/diagnosis , Middle Aged , Young AdultABSTRACT
Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.
Subject(s)
Aortic Aneurysm, Thoracic/genetics , Aortic Dissection/genetics , Contractile Proteins/genetics , Glycoproteins/genetics , Haploinsufficiency/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , Aortic Dissection/physiopathology , Aortic Aneurysm, Thoracic/physiopathology , Child , Codon, Nonsense , Contractile Proteins/metabolism , Exome/genetics , Female , Fibroblasts , Glycoproteins/metabolism , Humans , Intercellular Signaling Peptides and Proteins , Male , Middle Aged , Pedigree , Sequence Analysis, DNAABSTRACT
High-throughput next-generation sequencing such as whole-exome and whole-genome sequencing are being rapidly integrated into clinical practice. The use of these techniques leads to the identification of secondary variants for which decisions about the reporting or not to the patient need to be made. The American College of Medical Genetics and Genomics recently published recommendations for the reporting of these variants in clinical practice for 56 "actionable" genes. Among these, seven are involved in Marfan Syndrome And Related Disorders (MSARD) resulting from mutations of the FBN1, TGFBR1 and 2, ACTA2, SMAD3, MYH11 and MYLK genes. Here, we show that mutations collected in UMD databases for MSARD genes (UMD-MSARD) are rarely reported, including the most frequent ones, in global scale initiatives for variant annotation such as the NHLBI GO Exome Sequencing Project (ESP), the Exome Aggregation Consortium (ExAC), and ClinVar. The predicted pathogenic mutations reported in global scale initiatives but absent in locus-specific databases (LSDBs) mainly correspond to rare events. UMD-MSARD databases are therefore the only resources providing access to the full spectrum of known pathogenic mutations. They are the most comprehensive resources for clinicians and geneticists to interpret MSARD-related variations not only primary variants but also secondary variants.
Subject(s)
Cardiovascular Diseases/genetics , High-Throughput Nucleotide Sequencing/methods , Mutation , Exome , Genetic Predisposition to Disease , Genome, Human , Genomics/methods , Humans , Knowledge BasesABSTRACT
Supravalvular aortic aneurysms are less frequent than abdominal ones. Among Supravalvular aortic aneurysm aetiologies, we focused on dystrophic lesions as they can be secondary to genetic causes such as elastin anomaly. We report on a familial 7q11.23 triplication - including the ELN gene - segregating with a supravalvular aortic aneurysm. During her first pregnancy, our index patient was diagnosed with tuberous sclerosis and with a Supravalvular aortic aneurysm. The foetus was affected equally. For the second pregnancy, parents applied for preimplantation diagnosis, and a subsequent prenatal diagnosis was offered to the couple, comprising TSC1 molecular analysis, karyotype, and multiplex ligation probe amplification. TSC1 mutation was not found on foetal deoxyribo nucleic acid. Foetal karyotype was normal, but multiplex ligation probe amplification detected a 7q11.23 duplication. Quantitative-polymerase chain reaction and array-comparative genomic hybridisation carried out to further assess this chromosome imbalance subsequently identified a 7q11.23 triplication involving ELN and LIMK1. Foetal heart ultrasound identified a Supravalvular aortic aneurysm. A familial screening was offered for the 7q11.23 triplication and, when found, heart ultrasound was performed. The triplication was diagnosed in our index case as well as in her first child. Of the 17 individuals from this family, 11 have the triplication. Of the 11 individuals with the triplication, 10 were identified to have a supravalvular aortic aneurysm. Of them, two individuals received a medical treatment and one individual needed surgery. We provide evidence of supravalvular aortic aneurysm segregating with 7q11.23 triplication in this family. We would therefore recommend cardiac surveillance for individuals with 7q11.23 triplication. It would also be interesting to offer a quantitative-polymerase chain reaction or an array-comparative genomic hybridisation to a larger cohort of patients presenting with isolated supravalvular aortic aneurysm, as it may provide further information.
Subject(s)
Aortic Aneurysm, Thoracic/genetics , Genetic Predisposition to Disease/genetics , Tuberous Sclerosis/genetics , Adult , Aged , Aortic Aneurysm, Thoracic/complications , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Nucleic Acid Hybridization , Polymerase Chain Reaction , Pregnancy , Prenatal Diagnosis , Tuberous Sclerosis/complications , Ultrasonography, Prenatal , Young AdultABSTRACT
We report on two sibs, a girl, and a boy, with tall stature, long, and triangular faces, prominent foreheads with high frontal hairlines, telecanthus, downward slanting of the palpebral fissures, ptosis of the eyelids, everted lower eyelids, large ears, long noses, full, and everted vermilions, highly arched and narrow palates, tooth crowding, thin and long uvulae, coloboma of the alae, hyperextensible joints, long digits, positive thumb signs, flat feet, slightly diminished muscle strength, myopia, astigmatia, inguinal hernia, and vesical diverticula. Total body X-rays showed the presence of advanced bone age in both sibs and bilateral hallux valgus in the girl. Array-CGH did not reveal any pathological CNV. Molecular analysis of FBN1, FBN2, TGFBR1, TGFBR2, and CHST14 gene was normal, and SNP linkage analysis excluded more candidate genes. Differential diagnoses and the possibility that we might be reporting on a hitherto unreported syndrome are discussed.
Subject(s)
Craniofacial Abnormalities/diagnosis , Face/abnormalities , Marfan Syndrome/diagnosis , Mental Retardation, X-Linked/diagnosis , Osteochondrodysplasias/diagnosis , Comparative Genomic Hybridization , Diagnosis, Differential , Female , Hernia, Inguinal , Humans , Male , Siblings , SyndromeABSTRACT
The thoracic aortic aneurysm corresponds to the dilation of the ascending part of the aorta, which can lead to a dissection (TAAD for Thoracic Aortic Aneurysm and Dissection) or aortic rupture. The etiologies are diverse, but in approximately 20% of cases a genetic origin is found. About thirty genes are reported to be responsible for the development of TAAD. The majority of these genes encode for proteins involved in the extracellular matrix, the contraction of smooth muscle cells or the growth factor TGF-ß signaling pathway. Identifying the pathogenic variant responsible for the aortic disease becomes essential to make a definitive diagnosis, to guide and to personalize the treatment of the patients but also to screen relatives at risk. The availability and access to genetic testing have improved considerably with the development of new sequencing techniques (NGS for Next Generation Sequencing) and the use of gene panels. This review summarizes the main genes associated with TAAD as well as the current diagnostic strategy.
L'anévrisme de l'aorte thoracique correspond à la dilatation de la partie ascendante de l'aorte pouvant aller jusqu'à la dissection (TAAD pour Thoracic Aortic Aneurysm and Dissection), voire la rupture aortique. Les étiologies sont diverses mais dans environ 20 % des cas, l'origine est génétique. Une trentaine de gènes au total ont été rapportés comme étant responsables du développement de TAAD. La majorité de ces gènes codent pour des protéines impliquées dans la matrice extracellulaire, la contraction des cellules musculaires lisses ou la voie de signalisation du facteur de croissance TGF-ß. Identifier le variant pathogène responsable de la maladie aortique permet de poser un diagnostic définitif, d'orienter, voire de personnaliser la prise en charge des patients et permet le dépistage des apparentés à risque. La disponibilité et l'accès aux tests génétiques se sont considérablement améliorés avec le développement de nouvelles techniques de séquençage (NGS pour Next Generation Sequencing) et l'utilisation de panels de gènes. Cette revue résume les principaux gènes associés aux TAAD, ainsi que la stratégie diagnostique actuelle.
Subject(s)
Aortic Aneurysm, Thoracic , Aortic Dissection , Aortic Dissection/diagnosis , Aortic Dissection/genetics , Aortic Dissection/metabolism , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/genetics , Aortic Aneurysm, Thoracic/pathology , Azides , Deoxyglucose/analogs & derivatives , Genetic Testing , HumansABSTRACT
Marfan syndrome is a connective tissue disease that rarely presents first with peripheral aortic aneurysms. We highlight the case of a young man with Marfan syndrome presenting with an abdominal aortic aneurysm due to a heterozygous fibrillin-1 gene mutation.
Subject(s)
Aorta, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/etiology , DNA/genetics , Fibrillin-1/genetics , Marfan Syndrome/complications , Mutation , Adult , Aortic Aneurysm, Abdominal/diagnosis , DNA Mutational Analysis , Fibrillin-1/metabolism , Follow-Up Studies , Humans , Imaging, Three-Dimensional , Male , Marfan Syndrome/diagnosis , Marfan Syndrome/genetics , Patient Acuity , Time Factors , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: While outcome continuously improves after liver transplantation, sepsis remains the leading cause of early postoperative mortality. Diagnosis of infections remains particularly difficult in these patients. This study used plasma profiling coupling Proteinchip array with surface-enhanced laser desorption ionization time-of-fly mass spectrometry to search for biomarkers of postoperative sepsis in patients who underwent liver transplantation. METHODS: Diagnosis of sepsis at day 5 relied on widely accepted clinical signs and positive culture of microbiologic samples. Profiles of day 5 plasma were obtained from SELDI-TOF CM10 chip (BioRad, Marnes-la-Coquette, France) analysis. Mean peak intensity of proteins was compared between septic and nonseptic plasma by U test followed by analysis of the area under the receiver-operating characteristic for the significant peaks. Diagnostic performance of significant proteins was established in a derivation set and in a validation set. RESULTS: In the derivation set of 31 patients with and 30 without infection, 23 plasma protein peaks were differentially expressed between patients with and without sepsis. Combination of five peaks allowed sepsis diagnosis with a positive likelihood ratio of 12.5 and a C-statistics of 0.72, 95% CI 0.57-0.85. In the validation set of 31 patients with infection and 34 without infection, the five peaks were differentially expressed as well and allowed day 5 sepsis diagnosis with a positive likelihood ratio of 5.1 and C-statistics of 0.74 (0.58-0.85). CONCLUSION: A combination of five plasma protein peaks may provide material for useful diagnostic biomarkers of postoperative sepsis in patients undergoing liver transplantation. However, these proteins remain to be identified.