RESUMO
Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.
Assuntos
Opacidade da Córnea , Anormalidades do Olho , Segmento Anterior do Olho/anormalidades , Hibridização Genômica Comparativa , Opacidade da Córnea/diagnóstico , Opacidade da Córnea/genética , Opacidade da Córnea/patologia , Variações do Número de Cópias de DNA/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Humanos , Mutação/genética , Fatores de Transcrição SOXB1/genéticaRESUMO
Usher syndrome is an autosomal recessive disorder characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia. Three clinical subtypes are distinguished, and MYO7A and USH2A represent the two major causal genes involved in Usher type I, the most severe form, and type II, the most frequent form, respectively. Massively parallel sequencing was performed on a cohort of patients in the context of a molecular diagnosis to confirm clinical suspicion of Usher syndrome. We report here 231 pathogenic MYO7A and USH2A genotypes identified in 73 Usher type I and 158 Usher type II patients. Furthermore, we present the ACMG classification of the variants, which comprise all types. Among them, 68 have not been previously reported in the literature, including 12 missense and 16 splice variants. We also report a new deep intronic variant in USH2A. Despite the important number of molecular studies published on these two genes, we show that during the course of routine genetic diagnosis, undescribed variants continue to be identified at a high rate. This is particularly pertinent in the current era, where therapeutic strategies based on DNA or RNA technologies are being developed.
Assuntos
Proteínas da Matriz Extracelular/genética , Genótipo , Mutação de Sentido Incorreto , Miosina VIIa/genética , Sítios de Splice de RNA , Síndromes de Usher , Adulto , Feminino , França , Humanos , Masculino , Síndromes de Usher/classificação , Síndromes de Usher/genéticaRESUMO
BACKGROUND: Brugada syndrome (BrS) is sometimes diagnosed because of chest pain. Prevalence and characteristics of such BrS patients are unknown. METHODS: A total of 200 BrS probands were retrospectively included. BrS diagnosis made because of chest pain (n = 34, 17%) was compared to the other ones. RESULTS: BrS probands with diagnosis because of chest pain had significantly more often smoker habits, increased body mass index, and familial history of coronary artery disease but less frequently previous resuscitated sudden death/syncope or atrial fibrillation. Presence of coronary spasm and familial coronary artery disease were independently associated with BrS diagnosed because of chest pain. They presented more often with spontaneous type 1 ST elevation (59% vs 26%, P = .0004) and higher ST elevation during the episode of chest pain compared to other patients or compared to baseline electrocardiogram after chest pain resumption. ST elevation during chest pain was lower compared to ajmaline test. A total of 20% of them had significant coronary artery disease and four (11%) had coronary spasm, and they experienced more often recurrent chest pain episodes (24% vs 5%, P = .0002). Presence of chest pain at BrS diagnosis was not correlated to future arrhythmic events in univariate analysis. Only previous sudden cardiac death (SD)/syncope and familial SD were still significantly associated with outcome in multivariate analysis. CONCLUSION: Chest pain is a common cause for BrS diagnosis, although major part is not apparently explained by ischemic heart disease. Mechanisms leading to chest main remain unknown in the other ones. ST elevation is higher in this situation but does not seem to carry poor prognosis.
Assuntos
Síndrome de Brugada/complicações , Síndrome de Brugada/epidemiologia , Dor no Peito/etiologia , Adulto , Angina Pectoris/complicações , Síndrome de Brugada/diagnóstico , Doença da Artéria Coronariana/complicações , Vasoespasmo Coronário/complicações , Correlação de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos RetrospectivosRESUMO
Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.
Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Filaminas/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Alelos , Cardiomiopatias/epidemiologia , Ecocardiografia , Eletrocardiografia , Feminino , Testes Genéticos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Linhagem , Fenótipo , Prevalência , Análise de Sequência de DNARESUMO
Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.
Assuntos
Surdez/genética , Predisposição Genética para Doença/genética , Síndrome de Kallmann/genética , Neuroglia/patologia , Condutos Olfatórios/patologia , Fatores de Transcrição SOXE/genética , Animais , Análise Mutacional de DNA , Surdez/patologia , Feminino , França , Galactosídeos , Células HeLa , Humanos , Indóis , Síndrome de Kallmann/patologia , Masculino , Camundongos , Mutação/genética , Plasmídeos/genéticaRESUMO
BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.
Assuntos
Cardiomiopatias , Cardiomiopatia Dilatada , Cardiomiopatia Hipertrófica , Morte Súbita do Lactente , Fibrilação Ventricular , Masculino , Lactente , Humanos , Adulto , Pessoa de Meia-Idade , Cardiomiopatia Dilatada/genética , Prevalência , Cardiomiopatias/diagnóstico , Fenótipo , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/complicações , Morte Súbita Cardíaca/etiologia , Prognóstico , Proteínas dos Microfilamentos/genéticaRESUMO
BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes, or pleiotropy, which have not been systematically described. Additionally, the involvement of SCN5A in dilated cardiomyopathies (DCM) remains controversial. OBJECTIVE: We aimed to (1) evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and (2) determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced using a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. RESULTS: The study included 170 P/LP variants found in 495 patients. Among them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, six with progressive cardiac conduction disease, four with multifocal ectopic Purkinje-related premature contraction, and three with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes and/or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Among those, eight were carried by eight patients presenting with DCM with a debatable causative genotype/phenotype link. CONCLUSION: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960), if not questionable.
RESUMO
The preparation of a prenatal diagnosis in a family of North-African origin in which a child received a bone marrow transplant for ß-thalassemia major (ß-TM), prompted us to make the molecular diagnosis in the parents and siblings. Molecular and phenotype assays were carried on blood samples from the parents and the proband's sister. The father, a 45-year-old man, was found to be heterozygous for a rare mutation in exon 2 [codon 46 (+A), HBB:c.138_139insA] creating a frameshift, while the mother and sister were found to be carriers of the common codon 39 (C>T) stop mutation (HBB:c.118C>T). Because of the bone marrow transplant, proband genotyping was done from a buccal swab and revealed that he is a compound heterozygote for both the codon 46 and codon 39 mutations. In the parents and sister, hematological parameters were those of a thalassemia minor in agreement with the two ß(0) mutations found in the family.
Assuntos
Códon/genética , Mutação da Fase de Leitura/genética , Mutagênese Insercional/genética , Globinas beta/genética , Adulto , Sequência de Bases , Criança , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Mutação Puntual/genética , Talassemia beta/diagnóstico , Talassemia beta/genéticaRESUMO
AIMS: To phenotype patients referred to a tertiary centre for the exploration of a left ventricular hypertrophy (LVH) starting from 12 mm of left ventricular wall thickness (LVWT). METHODS AND RESULTS: Consecutive patients referred for aetiological workup of LVH, beginning at 12 mm of LVWT were retrospectively included in this tertiary single-centred observational study. Patients presenting with severe aortic stenosis were excluded. Aetiological workup was reviewed for each subject and aetiologies were adjudicated by expert consensus.Among 591 patients referred for LVH aetiological workup, 41% had a maximal LVWT below 15 mm. LVH aetiologies were led by cardiac amyloidosis (CA, 34.3%), followed by sarcomeric hypertrophic cardiomyopathy (S-HCM, 32.1%), hypertensive cardiomyopathy (21.7%), unknown aetiology (7.6%) and other (4.2%), including Anderson-Fabry's disease (1.7%). CA and S-HCM affected over 50% of patients with mild LVH (12-14 mm); the prevalence of these aetiologies rose with LVH severity. Among patients with Anderson-Fabry's disease, 4 (40%) had a maximal LVWT <15 mm. CONCLUSIONS: Mild LVH (ie, 12-14 mm) conceals multiple aetiologies that can lead to specific treatment, cascade family screening and specific follow-up. Overall, CA is nowadays the leading cause of LVH in tertiary centers.
Assuntos
Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Imagem Cinética por Ressonância Magnética/métodos , Centros de Atenção Terciária , Função Ventricular Esquerda/fisiologia , Idoso , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Predictive genetic testing (PGT) is offered to asymptomatic relatives at risk of hereditary heart disease, but the impact of result disclosure has been little studied. We evaluated the psychosocial impacts of PGT in hereditary heart disease, using self-report questionnaires (including the State-Trait Anxiety Inventory) in 517 adults, administered three times to the prospective cohort (PCo: n = 264) and once to the retrospective cohort (RCo: n = 253). The main motivations for undergoing PGT were "to remove doubt" and "for their children". The level of anxiety increased between pre-test and result appointments (p <0.0001), returned to baseline after the result (PCo), and was moderately elevated at 4.4 years (RCo). Subjects with a history of depression or with high baseline anxiety were more likely to develop anxiety after PGT result (p = 0.004 and p <0.0001, respectively), whatever it was. Unfavourable changes in professional and/or family life were observed in 12.4% (PCo) and 18.7% (RCo) of subjects. Few regrets about PGT were expressed (0.8% RCo, 2.3% PCo). Medical benefit was not the main motivation, which emphasises the role of pre/post-test counselling. When PGT was performed by expert teams, the negative impact was modest, but careful management is required in specific categories of subjects, whatever the genetic test result.
RESUMO
Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.