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Intellectual and developmental disabilities result from abnormal nervous system development. Over a 1,000 genes have been associated with intellectual and developmental disabilities, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants in CC2D1A in a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, including Xenopus, Drosophila, and patient-derived fibroblasts. Our experiments revealed that cc2d1a is expressed explicitly in a spectrum of ciliated tissues, including the left-right organizer, epidermis, pronephric duct, nephrostomes, and ventricular zone of the brain. In line with this expression pattern, loss of cc2d1a led to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development, mutant tadpoles showed abnormal CSF circulation only in the midbrain region, suggesting abnormal local CSF flow. Furthermore, our analysis of the patient-derived fibroblasts confirmed defective ciliogenesis, further supporting our observations. In summary, we revealed novel insight into the role of CC2D1A by establishing its new critical role in ciliogenesis and CSF circulation.
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Cílios , Ciliopatias , Deficiência Intelectual , Humanos , Animais , Deficiência Intelectual/genética , Masculino , Cílios/metabolismo , Feminino , Ciliopatias/genética , Ciliopatias/metabolismo , Fibroblastos/metabolismo , Mutação , Rim/metabolismo , Encéfalo/metabolismo , Linhagem , Xenopus , Líquido Cefalorraquidiano/metabolismoRESUMO
Artificial intelligence (AI) platforms have emerged as pivotal tools in genetics and molecular medicine, as in many other fields. The growth in patient data, identification of new diseases and phenotypes, discovery of new intracellular pathways, availability of greater sets of omics data, and the need to continuously analyse them have led to the development of new AI platforms. AI continues to weave its way into the fabric of genetics with the potential to unlock new discoveries and enhance patient care. This technology is setting the stage for breakthroughs across various domains, including dysmorphology, rare hereditary diseases, cancers, clinical microbiomics, the investigation of zoonotic diseases, omics studies in all medical disciplines. AI's role in facilitating a deeper understanding of these areas heralds a new era of personalised medicine, where treatments and diagnoses are tailored to the individual's molecular features, offering a more precise approach to combating genetic or acquired disorders. The significance of these AI platforms is growing as they assist healthcare professionals in the diagnostic and treatment processes, marking a pivotal shift towards more informed, efficient, and effective medical practice. In this review, we will explore the range of AI tools available and show how they have become vital in various sectors of genomic research supporting clinical decisions.
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Inteligência Artificial , Medicina Molecular , Humanos , Medicina Molecular/métodos , Genética Médica/tendências , Genética Médica/métodos , Medicina de Precisão/métodos , Genômica/métodosRESUMO
Osteogenesis imperfecta (OI) is the most common inherited connective tissue disease of the bone, characterized by recurrent fractures and deformities. In patients displaying the OI phenotype, genotype-phenotype correlation is used to screen multiple genes swiftly, identify new variants, and distinguish between differential diagnoses and mild subtypes. This study evaluated variants identified through next-generation sequencing in 58 patients with clinical characteristics indicative of OI. The cohort included 18 adults, 37 children, and 3 fetuses. Clinical classification revealed 25 patients as OI type I, three patients as OI type II, 18 as OI type III, and 10 as OI type IV. Fifteen variants in COL1A1 were detected in 19 patients, 9 variants in COL1A2 (n = 19), 5 variants in LEPRE1/P3H1 (n = 7), 3 variants in FKBP10 (n = 4), 3 variants in SERPINH1 (n = 2), 1 variant in IFITM5 (n = 1), and 1 variant in PLS3 (n = 1). In total, 37 variants (18 pathogenic, 14 likely pathogenic, and 5 variants of uncertain significance), including 16 novel variants, were identified in 43 (37 probands, 6 family members) of the 58 patients analyzed. This study highlights the efficacy of panel testing in the molecular diagnosis of OI, the significance of the next-generation sequencing technique, and the importance of genotype-phenotype correlation.
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PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases. METHODS: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6KozakGAL4 allele to assess the expression pattern of dYkt6. RESULTS: Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, developmental delay, and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] and exhibited neurodevelopmental disorders and optic atrophy. Fly dYkt6 is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type genomic rescue constructs can rescue the lethality and autophagic flux defects, whereas the variants are less efficient in rescuing the phenotypes. CONCLUSION: The YKT6 variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).
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Carcinoma Hepatocelular , Deficiências do Desenvolvimento , Homozigoto , Neoplasias Hepáticas , Mutação com Perda de Função , Mutação de Sentido Incorreto , Animais , Feminino , Humanos , Lactente , Masculino , Alelos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Drosophila/genética , Proteínas de Drosophila/genética , Predisposição Genética para Doença , Hepatopatias/genética , Hepatopatias/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mutação de Sentido Incorreto/genética , Fenótipo , Proteínas de Transporte Vesicular/genéticaRESUMO
Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43 _ c.1000+2T>C splice site mutation and the SCN5A _ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4 , RANGRF , A KAP9 , KCND3 , KCNE1 , DSG2 , CASQ1 , and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.
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Canalopatias , Humanos , Autopsia , Canalopatias/diagnóstico , Canalopatias/genética , Canalopatias/complicações , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/patologia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/complicações , MutaçãoRESUMO
BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.
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Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Genes BRCA2 , Predisposição Genética para Doença , Células Germinativas/patologia , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias Ovarianas/genética , TurquiaRESUMO
STAT3 plays an important role in various complex and sometimes contradictory pathways such as proliferation, differentiation, migration, inflammation, and apoptosis. The transcriptional activity of the STAT3 gene is controlled by a transcription factor called ZNF341. There is insufficient data on radiation sensitivity and post-radiation DNA repair in STAT3- loss-of-function (LOF) patients. We aimed to investigate the radiosensitivity in patients with STAT3-LOF and ZNF341 deficiency. Twelve patients with STAT3-LOF and four ZNF341-deficiency patients were recruited from three clinical immunology centers in Turkey and evaluated for radiosensitivity by the Comet assay, comparing to 14 age- and sex-matched healthy controls. The tail length (TL) (µm), percentage of DNA in the tail (TDNA%), and olive tail moment (OTM) (arbitrary units) were evaluated at the same time for baseline (spontaneous), initial (immediately after 2 Gy irradiation), and recovery (2 h after irradiation) periods by using a computerized image-analysis system, estimating DNA damage. Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups. During the recovery period of irradiation, TL, TDNA%, and OTM values of healthy controls decreased rapidly toward the baseline, while these values of patients with STAT3-LOF and ZNF341 deficiency continued to increase, implying impaired DNA repair mechanisms. Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation.
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Reparo do DNA , Tolerância a Radiação , Fator de Transcrição STAT3 , Fatores de Transcrição , Ensaio Cometa , Dano ao DNA/genética , Reparo do DNA/genética , Regulação da Expressão Gênica , Humanos , Mutação com Perda de Função , Tolerância a Radiação/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genéticaRESUMO
PURPOSE: SARS-CoV-2-infected individuals may be asymptomatic, and therefore, the virus is highly contagious. We aimed to develop an agent to control viral replication in the upper respiratory tract and to prevent progression of the disease into the lower airways as well as inter-individual transmission. For this purpose, we investigated the antibacterial and antiviral activities of our novel nanobubble ozonated hyaluronic acid-decorated liposomal (NOHAL) solution, developed by using nanotechnology. METHODS: The MIC levels of NOHAL solution were determined on blood agar cultures of Staphylococcus aureus (ATCC 6538), Streptococcus pneumoniae (ATCC 49619) and Escherichia coli (ATCC 25922). The in vitro anti-viral activity of NOHAL solution was studied using recombinant SARS-CoV-2 copies of the original virus, grown in Vero cells generated by reverse genetic technology. Human primary lung epithelial cells obtained by bronchoscopy or lung resection were used for cell viability tests using flow cytometry analysis. The cytotoxicity testing was performed using the BALB/c 3T3 (CCL-163) cell line. Skin, oral, nasal and ocular irritation tests were performed using New Zealand albino rabbits, Syrian hamsters, BALB c mice and New Zealand albino rabbits of both sexes. RESULTS: Bacterial growth was prevented by NOHAL solution in a time-/dose-dependent manner. In vivo or in vitro experiments did not show any toxicity of NOHAL solution. No cytotoxicity was recorded on cell viability. No skin, oral, nasal or ocular toxicities were recorded. In addition, in a SARS-CoV-2 mouse infection model, NOHAL solution diminished the viral RNA levels effectively in nasopharyngeal and lung samples after its prophylactic intranasal application. CONCLUSION: NOHAL solution has the potential to reduce or prevent the spread of SARS-CoV-2 through the nose and/or oral cavity. The clinical efficacy of this solution needs to be tested in order to determine its efficacy in the early phase of COVID-19.
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COVID-19 , Ozônio , Animais , Antibacterianos/farmacologia , Chlorocebus aethiops , Cricetinae , Feminino , Humanos , Ácido Hialurônico , Lipossomos , Masculino , Camundongos , Coelhos , SARS-CoV-2 , Células VeroRESUMO
T cell receptor excision circles (TRECs) and kappa-deleting excision circles (KRECs) are DNA fragments potentially indicative of T and B cell development, respectively. Recent thymic emigrants (RTEs) are a subset of peripheral cells that may also represent thymic function. Here, we investigated TREC/KREC copy numbers by quantitative real-time PCR in the peripheral blood of patients with primary immunodeficiencies (PIDs, n = 145) and that of healthy controls (HCs, n = 86) and assessed the correlation between RTEs and TREC copy numbers. We found that TREC copy numbers were significantly lower in children and adults with PIDs (P < .0001 and P < .002, respectively) as compared with their respective age-matched HCs. A moderate correlation was observed between TREC copies and RTE numbers among children with PID (r = .5114, P < .01), whereas no significant correlation was detected between RTE values and TREC content in the HCs (r = .0205, P = .9208). Additionally, we determined TREC and KREC copy numbers in DNA isolated from the Guthrie cards of 200 newborns and showed that this method is applicable to DNA isolated from both peripheral blood samples and dried blood spots, with the two sample types showing comparable TREC and KREC values. We further showed that RTE values are not always reliable markers of T cell output. Although additional confirmatory studies with larger cohorts are needed, our results provide thresholds for TREC/KREC copy numbers for different age groups.
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Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , DNA/genética , DNA/imunologia , Feminino , Hematopoese/genética , Hematopoese/imunologia , Humanos , Lactente , Recém-Nascido , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Triagem Neonatal/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptores de Antígenos de Linfócitos T/genética , Imunodeficiência Combinada Severa/genética , Adulto JovemRESUMO
Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report a 17-year-old male whose main clinical findings are oculomotor apraxia and truncal ataxia. Magnetic resonance imaging revealed the characteristic molar tooth sign of Joubert syndrome. He also has obsessive-compulsive disorder concomitantly, which is not a known feature of Joubert syndrome. Molecular genetic analysis revealed a homozygous c.2106G>A (p.(Thr702=)) variation in the Abelson helper integration 1 (AHI1) gene and another homozygous c.1739C>T (p.Thr580Ile) variation in the coiled-coil and C2 domain-containing protein 1A (CC2D1A) gene. Even though certain AHI1 variations were previously associated with Joubert syndrome (JS), c.2106G>A (p.(Thr702=)) was only reported in one patient in trans with another known pathogenic JS variant. The CC2D1A c.1739C>T (p.Thr580Ile) variation, on the other hand, has been reported to cause autosomal recessive nonsyndromic mental retardation, but there are conflicting interpretations about its pathogenicity. Overall, to our knowledge, this is the first patient representing a severe ciliopathy phenotype caused by a homozygous synonymous AHI1 variation. Further investigations should be performed to determine any involvement of the CC2D1A gene in ciliopathy phenotypes such as Joubert syndrome.
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Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Cerebelo/anormalidades , Ciliopatias/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Fenótipo , Retina/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Cerebelo/patologia , Ciliopatias/patologia , Anormalidades do Olho/patologia , Homozigoto , Humanos , Doenças Renais Císticas/patologia , Masculino , Mutação de Sentido Incorreto , Retina/patologiaRESUMO
Background During 19th century, the Circassians were secluded from their lands and forced to migrate to Ottoman Empire properties. Approximately 2,346 Circassians were exiled from Istanbul to Cyprus Island. During the deportation journey, many of Circassian passed away in consequence of malaria and unknown reasons. Overall, 1,351 survivor Circassians managed to reach the island, however, many of them had faced with endemic malaria again in Cyprus. An autosomal recessive hematological disorder thalassemia was the second endemic health condition after malaria, whereas thalassemia carriers show resistance to malaria infections. Materials and Methods A large Cypriot family with 57 members whose grandparents were supposed to be in that ship journey has been investigated in this study. Polymerase chain reaction (PCR)-amplification refractory mutation system (ARMS) analysis technique was used for genotyping the HHB gene. Results The human ß-globin ( HBB ) gene c.316-106C > G (IVS-II-745) (II-745) heterozygous variation have been detected. Conclusion Overall, this study is a very good example for a typical natural selection. In this case, one single gene point mutation did not limit survival in the society; natively, it increased their survival changes to form new colonization and the inheritance of the mutation to the next generations.
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Next-generation sequencing technology and advanced sequence analysis techniques are markedly speeding up the identification of gene variants causing rare genetic diseases. Pseudoachondroplasia (PSACH, MIM 177170) is a rare disease inherited in an autosomal dominant manner. It is known that variations in the cartilage oligomeric matrix protein (COMP) gene are associated with the disease. Here, we report a 39-month-old boy with short stature. He gave visible growth and development delayed phenotype after 12 months. Further genetic resequencing analysis was carried out to identified the disease-causing variant. Furthermore, computational approaches were used to characterize the effect of the variant. In this study, we identify and report a novel variation in the COMP gene, c.1420_1422del (p.Asn47del), causing a spontaneous form of PSACH in our patient. Our in silico model indicated that any mutational changes in this region are very susceptible to PASCH phenotype. Overall, this study is the first PSACH case in the Turkish Cypriot population. Moreover, this finding contributes to the concept that the genotype-phenotype correlation in COMP is still unknown and also improves our understanding of this complex disorder.
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Acondroplasia/genética , Sequência de Aminoácidos , Proteína de Matriz Oligomérica de Cartilagem/genética , Deleção de Sequência , Pré-Escolar , Humanos , MasculinoRESUMO
We aimed to investigate the relationship between single nucleotide polymorphism (SNP) in the promoter region of the 5-HT-R2C gene and stress-related disease psoriasis in the Turkish population. The putative association between the 5-HTR2C variant (rs6318 Cys23Ser allele) and patients with psoriasis was investigated. 100 patients with psoriasis and 100 age-sex matched, unrelated healthy subjects representing the control group were included in the study. The PCR-RFLP method was used for genotyping the 5-HTR2C variation. There was no statistically difference in terms of genotype distributions and allele frequencies between the control subjects and patients with psoriasis (P=0.360 and P=0.439, respectively). The comparison between the presence and absence of the 5-HTR2C gene rs6318 G allele within the determined clinical subsets resulted in a significant difference with regard to treatment methodology only when conventional therapy and one or more medical therapy was compared (P=0.021). This study is the first clinical study to investigate the association between 5-HTR2C polymorphism and psoriasis. The role of the 5-HTR2C gene should be examined with more parameters in a larger case series.
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Polimorfismo de Nucleotídeo Único , Psoríase , Receptor 5-HT2C de Serotonina , Alelos , Estudos de Casos e Controles , Demografia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Psoríase/genéticaRESUMO
Male infertility affects â¼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.
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Pontos de Checagem do Ciclo Celular/genética , Infertilidade Masculina/genética , Meiose/genética , Mutação/genética , Proteínas/genética , Espermatogênese/genética , Adulto , Alelos , Animais , Azoospermia/genética , Homozigoto , Humanos , Masculino , Camundongos , Fenótipo , Espermatozoides/anormalidades , Testículo/anormalidades , Turquia , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits. OBJECTIVE: A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population. METHODS: A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP. RESULTS: The allelic frequency and genotype distribution results of this study showed a strong association (P<0.0001) between smokers and non-smokers. No statistical significance was found between non-smokers and ex-smokers. CONCLUSION: This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.
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Predisposição Genética para Doença , Nicotina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Tabagismo/genética , Adulto , Estudos Transversais , Ex-Fumantes/estatística & dados numéricos , Feminino , Frequência do Gene , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , não Fumantes/estatística & dados numéricos , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Fumantes/estatística & dados numéricos , Tabagismo/epidemiologia , Turquia/epidemiologiaRESUMO
Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.
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Autopsia , Morte Súbita Cardíaca/patologia , Testes Genéticos/normas , Cardiopatias/genética , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , União Europeia/organização & administração , Cardiopatias/mortalidade , Cardiopatias/patologia , Humanos , Miocárdio/patologiaRESUMO
Marfan syndrome (MFS) is a multi-systemic autosomal dominant condition caused by mutations in the gene (FBN1) coding for fibrillin-1. Mutations have been associated with a wide range of overlapping phenotypes. Here, we report on an extended family presenting with skeletal, ocular and cardiovascular clinical features. The 37-year-old male propositus, who had chest pain, dyspnea and shortness of breath, was first diagnosed based on the revised Ghent criteria and then subjected to molecular genetic analyses. FBN1 sequencing of the proband as well as available affected family members revealed the presence of a novel variant, c.7828G>C (p.Glu2610Gln), which was not present in any of the unaffected family members. In silico analyses demonstrated that the Glu2610 residue is part of the conserved DINE motif found at the beginning of each cbEGF domain of FBN1. The substitution of Glu2610 with Gln decreased fibrillin-1 production accordingly. Despite the fact that this variation appears to be primarily responsible for the etiology of MFS in the present family, our findings suggest that variable clinical expressions of the disease phenotype should be considered critically by the physicians.
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Fibrilina-1/genética , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Mutação/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Simulação por Computador , Família , Feminino , Fibrilina-1/química , Heterozigoto , Humanos , Masculino , Linhagem , FenótipoRESUMO
We present three siblings afflicted with a disease characterized by cerebellar ataxia, cerebellar atrophy, pyramidal tract damage with increased lower limb tendon reflexes, and onset of 31 to 57 years, which is not typical for a known disease. In a region of shared homozygosity in patients, exome sequencing revealed novel homozygous c.*240T > C variant in the 3'UTR of STUB1, the gene responsible for autosomal recessive spinocerebellar ataxia 16 (SCAR16). In other genes, such an alteration of the evolutionarily highly conserved polyadenylation signal from AATAAA to AACAAA is known to highly impair polyadenylation. In contrast, RNA sequencing and quantification revealed that neither polyadenylation nor stability of STUB1 mRNA is affected. In silico analysis predicted that the secondary structure of the mRNA is altered. We propose that this change underlies the extremely low amounts of the encoded protein in patient leukocytes.
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Variação Genética , Poli A , Poliadenilação , Ubiquitina-Proteína Ligases/genética , Regiões 3' não Traduzidas , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Análise Mutacional de DNA , Humanos , Imageamento por Ressonância Magnética , LinhagemRESUMO
BACKGROUND: Jervell and Lange-Nielsen syndrome (JLNS) isa recessive model of long QT syndrome which might also be related to possible hearing loss. Although the syndrome has been demonstrated to be originated from homozygous or compound heterozygous mutations in either the KCNQ1 or KCNE1 genes, additional mutations in other genetic loci should be considered, particularly in malignant course patients. CASE PRESENTATIONS: Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively; moreover all three patients had congenital sensorineural hearing-loss. Their electrocardiograms showed markedly prolonged QT interval. Implantable defibrillator was implanted and left cardiac sympathetic denervation was performed due to the progressive disease in case 1. She had countless ventricular fibrillation and appropriate shock while using an implantable defibrillator. The DNA sequencing analysis of the KCNQ1 gene disclosed a homozygous c.728G > A (p.Arg243His) missense mutation in case1. Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene and a heterozygous c.809G > A (p.Cys270Tyr) variant in NKX2-5 gene in the same patient. Additional gene alterations in RYR2 and NKX2-5 genes were thought to be responsible for progressive and malignant course of the disease. As a result of DNA sequencing analysis of KCNQ1 and KCNE1 genes, a compound heterozygosity for two mutations had been detected in KCNQ1 gene in case 2: a maternally derived c.477 + 1G > A splice site mutation and a paternally derived c.520C > T (p.Arg174Cys) missense mutation. Sanger sequencing of KCNQ1 and KCNE1 genes displayed a homozygous c.1097G > A (p.Arg366Gln) mutation in KCNQ1 gene in case 3. ß-blocker therapy was initiated to all the index subjects. CONCLUSIONS: Three families of JLNS who presented with long QT and deafness and who carry homozygous, or compound heterozygous mutation in KCNQ1 gene were presented in this report. It was emphasized that broad targeted cardiac panels may be useful to predict the outcome especially in patients with unexplained phenotype-genotype correlation. Clinical presentations and molecular findings will be discussed further to clarify the phenotype genotype associations.
Assuntos
Perda Auditiva Neurossensorial/congênito , Síndrome de Jervell-Lange Nielsen/genética , Canal de Potássio KCNQ1/genética , Polimorfismo de Nucleotídeo Único , Antagonistas Adrenérgicos beta/uso terapêutico , Pré-Escolar , Eletrocardiografia , Feminino , Perda Auditiva Neurossensorial/etiologia , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteína Homeobox Nkx-2.5/genética , Homozigoto , Humanos , Lactente , Síndrome de Jervell-Lange Nielsen/diagnóstico , Síndrome de Jervell-Lange Nielsen/tratamento farmacológico , Masculino , Linhagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Análise de Sequência de DNA/métodos , TurquiaRESUMO
INTRODUCTION: Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare disease characterized by low adrenocorticotropic hormone (ACTH) and cortisol levels. To date, recurrent pulmonary infections in infancy have not been reported as an accompanying symptom of CIAD. CASE PRESENTATION: A 7-year-old boy was hospitalized nine times for recurrent lower respiratory tract infections. The results of all tests for the possible causes of wheezing were within the normal limits. His ACTH and cortisol levels were persistently low. All other pituitary hormone levels, and adrenal ultrasound and pituitary magnetic resonance imaging results, were normal. Molecular analyses confirmed the diagnosis of CIAD by identifying compound heterozygosity for two mutations in the TBX19 gene. The first was a novel frameshift c.665delG variant in exon 4 of the TBX19 gene, leading to premature termination that was predicted to result in a non-functional truncated protein. The second was a nonsense C-to-T transition in exon 6 of the TBX19 gene, resulting in an arg286-to-ter mutation (dbSNP: rs74315376). Both parents were heterozygous for one of the mutations. CONCLUSION: Here, we presented a new mutation in the TBX19 gene in a patient with CIAD who presented with recurrent respiratory tract infections. This expands the mutation spectrum in this disorder. To conclude, adrenal insufficiency should be considered in patients with unexplained recurrent infections to prevent a delay in diagnosis.