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1.
Hum Mol Genet ; 33(12): 1090-1104, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38538566

RESUMO

RATIONALE: Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis. OBJECTIVES: Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants. METHODS: A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts. RESULTS: Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0-47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0-54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines. CONCLUSION: Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.


Assuntos
Fibroblastos , Estudos de Associação Genética , Síndrome de Loeys-Dietz , Músculo Liso Vascular , Proteína Smad3 , Humanos , Proteína Smad3/genética , Proteína Smad3/metabolismo , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/patologia , Masculino , Feminino , Fibroblastos/metabolismo , Adulto , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Diferenciação Celular/genética , Linhagem Celular , Miócitos de Músculo Liso/metabolismo , Estudos Retrospectivos , Fenótipo , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Mutação
2.
Am J Med Genet A ; 194(1): 17-30, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37743782

RESUMO

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos dos Movimentos , Transtornos do Neurodesenvolvimento , Criança , Humanos , Deficiências do Desenvolvimento/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , Deficiência Intelectual/genética , Convulsões/genética , Fenótipo , Marcha
3.
Prenat Diagn ; 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39349395

RESUMO

BACKGROUND: The aim of this study was to evaluate the diagnostic yield of routine exome sequencing (ES) in fetuses with ultrasound anomalies. METHODS: We performed a retrospective analysis of the ES results of 629 fetuses with isolated or multiple anomalies referred in 2019-2022. Variants in a gene panel consisting of approximately 3400 genes associated with multiple congenital anomalies and/or intellectual disability were analyzed. We used trio analysis and filtering for de novo variants, compound heterozygous variants, homozygous variants, X-linked variants, variants in imprinted genes, and known pathogenic variants. RESULTS: Pathogenic and likely pathogenic variants (class five and four, respectively) were identified in 14.0% (88/629, 95% CI 11.5%-16.9%) of cases. In the current cohort, the probability of detecting a monogenetic disorder was ∼1:7 (88/629, 95% CI 1:8.7-1:5.9), ranging from 1:9 (49/424) in cases with one major anomaly to 1:5 (32/147) in cases with multiple system anomalies. CONCLUSIONS: Our results indicate that a notable number of fetuses (1:7) with ultrasound anomalies and a normal chromosomal microarray have a (likely) pathogenic variant that can be detected through prenatal ES. These results warrant implementation of exome sequencing in selected cases, including those with an isolated anomaly on prenatal ultrasound.

4.
Lab Invest ; 103(11): 100233, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37567389

RESUMO

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal congenital lung disorder that presents shortly after birth with respiratory failure and therapy-resistant pulmonary hypertension. It is associated with heterozygous point mutations and genomic deletions that involve the FOXF1 gene or its upstream regulatory region. Patients are unresponsive to the intensive treatment regimens and suffer unnecessarily because ACDMPV is not always timely recognized and histologic diagnosis is invasive and time consuming. Here, we demonstrate the usefulness of a noninvasive, fast genetic test for FOXF1 variants that we previously developed to rapidly diagnose ACDMPV and reduce the time of hospitalization.


Assuntos
Síndrome da Persistência do Padrão de Circulação Fetal , Alvéolos Pulmonares/anormalidades , Recém-Nascido , Humanos , Síndrome da Persistência do Padrão de Circulação Fetal/diagnóstico , Síndrome da Persistência do Padrão de Circulação Fetal/genética , Síndrome da Persistência do Padrão de Circulação Fetal/patologia , Relevância Clínica , Alvéolos Pulmonares/patologia , Fatores de Transcrição Forkhead/genética
5.
Clin Endocrinol (Oxf) ; 99(1): 58-63, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36905105

RESUMO

OBJECTIVE: Individuals with 45,X/46,XY or 46,XY gonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone (AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. DESIGN, PATIENTS AND MEASUREMENTS: Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999-2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. RESULTS: Thirteen males and 16 females were included, 20 with 46,XY and 9 with 45,X/46,XY DSD. Three females had dysgerminoma alongside gonadoblastoma; two gonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. CONCLUSIONS: Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XY or 46,XY gonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.


Assuntos
Disgerminoma , Disgenesia Gonadal 46 XY , Disgenesia Gonadal , Gonadoblastoma , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Masculino , Feminino , Humanos , Gonadoblastoma/genética , Gonadoblastoma/cirurgia , Hormônio Antimülleriano , Disgerminoma/cirurgia , Estudos Retrospectivos
6.
Prenat Diagn ; 43(2): 162-182, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35808910

RESUMO

OBJECTIVE: To report uptake of genetic counseling (GC) and prenatal genetic testing after the finding of atypical genitalia on prenatal ultrasound (US) and the clinical and genetic findings of these pregnancies. METHODS: A retrospective cohort study (2017-2019) of atypical fetal genitalia in a large expert center for disorders/differences of sex development. We describe counseling aspects, invasive prenatal testing, genetic and clinical outcome of fetuses apparently without [group 1, n = 22 (38%)] or with [group 2, n = 36 (62%)] additional anomalies on US. RESULTS: In group 1, 86% of parents opted for GC versus 72% in group 2, and respectively 58% and 15% of these parents refrained from invasive testing. Atypical genitalia were postnatally confirmed in 91% (group 1) and 64% (group 2), indicating a high rate of false positive US diagnosis of ambiguous genitalia. Four genetic diagnoses were established in group 1 (18%) and 10 in group 2 (28%). The total genetic diagnostic yield was 24%. No terminations of pregnancy occurred in group 1. CONCLUSIONS: For optimal care, referral for an expert fetal US scan, GC and invasive diagnostics including broad testing should be offered after prenatal detection of isolated atypical genitalia.


Assuntos
Aconselhamento Genético , Testes Genéticos , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Ultrassonografia Pré-Natal , Aconselhamento , Genitália/diagnóstico por imagem , Diagnóstico Pré-Natal
7.
Genet Med ; 24(10): 2112-2122, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36053285

RESUMO

PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies. METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire. RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively. CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Actinas/genética , Adulto , Dissecção Aórtica/genética , Aorta , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/genética , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
8.
Genet Med ; 23(7): 1246-1254, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33824500

RESUMO

PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Linhagem , Sequenciamento do Exoma
9.
Clin Genet ; 100(6): 647-658, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34155632

RESUMO

Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Genômica , Diagnóstico Pré-Natal , Tomada de Decisão Clínica , Gerenciamento Clínico , Feminino , Estudos de Associação Genética/métodos , Genômica/legislação & jurisprudência , Genômica/métodos , Política de Saúde , Humanos , Guias de Prática Clínica como Assunto , Gravidez , Diagnóstico Pré-Natal/métodos , Incerteza
10.
Am J Med Genet A ; 185(1): 168-181, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33108066

RESUMO

Descriptions of the clinical features of Angelman syndrome (AS) have mainly been focused on children. Here, we describe the evolution of the clinical phenotypes of AS in adulthood, using clinical data from 95 individuals (mean age 31.6 years, median 29.0 years, range 18-83 years), with genetically confirmed AS. Data was collected through physical examination and inspection of medical records, combined with questionnaires and interviews. Adults with AS experience substantial debilitating health problems. Constipation, reflux, visual problems, scoliosis, behavioral and sleeping problems occurred frequently and require appropriate attention. Epilepsy was reported in 57% of adults, negatively affecting the level of functioning. Non-convulsive status epilepticus was not observed in the adults, however some individuals developed prolonged episodes of rhythmic shaking while awake. A decline in mobility was noted in the majority of adults. A minority of adults with AS showed microcephaly. Taken together, this first phenotypic study of adults with AS to include in person interviews with care-givers and physical examination of patients, including the eldest adult reported to date, provides important insight in the development of the syndrome into adulthood. This knowledge is required to improve care for adult individuals with AS and to evaluate future therapies for this group.


Assuntos
Síndrome de Angelman/diagnóstico , Síndrome de Angelman/epidemiologia , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Angelman/complicações , Síndrome de Angelman/fisiopatologia , Epilepsia/complicações , Epilepsia/fisiopatologia , Feminino , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
11.
Acta Obstet Gynecol Scand ; 100(6): 1106-1115, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33249554

RESUMO

INTRODUCTION: The aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results. MATERIAL AND METHODS: In the period 2013-2016, 391 pregnant women with fetal ultrasound anomalies who received normal chromosomal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre- and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (prenatal or postnatal). RESULTS: In 76 of 391 fetuses (19.4%, 95% CI 15.8%-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, 73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis. CONCLUSIONS: Our retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increase the diagnostic yield in fetuses with ultrasound anomalies and would allow early diagnosis of a genetic disorder irrespective of the (incomplete) fetal phenotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Transtornos Cromossômicos/diagnóstico , Sequenciamento do Exoma/métodos , Doenças Fetais/diagnóstico , Testes Genéticos/métodos , Diagnóstico Pré-Natal/métodos , Anormalidades Múltiplas/genética , Adulto , Transtornos Cromossômicos/genética , Feminino , Doenças Fetais/genética , Humanos , Gravidez , Estudos Retrospectivos , Ultrassonografia Pré-Natal/métodos
12.
J Med Genet ; 57(9): 581-589, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32303604

RESUMO

We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles. Recent initiatives striving for uniform high-quality care across Europe, and beyond, such as the completed COST action 1303 and the European Reference Network for rare endocrine conditions (EndoERN), have generated several excellent papers covering nearly all aspects of DSD. The Dutch-Flemish guideline follows these international consensus papers and covers a number of other topics relevant to daily practice. For instance, although next-generation sequencing (NGS)-based molecular diagnostics are becoming the gold standard for genetic evaluation, it can be difficult to prove variant causality or relate the genotype to the clinical presentation. Network formation and centralisation are essential to promote functional studies that assess the effects of genetic variants and to the correct histological assessment of gonadal material from DSD patients, as well as allowing for maximisation of expertise and possible cost reductions. The Dutch-Flemish guidelines uniquely address three aspects of DSD. First, we propose an algorithm for counselling and diagnostic evaluation when a DSD is suspected prenatally, a clinical situation that is becoming more common. Referral to ultrasound sonographers and obstetricians who are part of a DSD team is increasingly important here. Second, we pay special attention to healthcare professionals not working within a DSD centre as they are often the first to diagnose or suspect a DSD, but are not regularly exposed to DSDs and may have limited experience. Their thoughtful communication to patients, carers and colleagues, and the accessibility of protocols for first-line management and efficient referral are essential. Careful communication in the prenatal to neonatal period and the adolescent to adult transition are equally important and relatively under-reported in the literature. Third, we discuss the timing of (NGS-based) molecular diagnostics in the initial workup of new patients and in people with a diagnosis made solely on clinical grounds or those who had earlier genetic testing that is not compatible with current state-of-the-art diagnostics.


Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Patologia Molecular , Doenças Raras/diagnóstico , Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/epidemiologia , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/patologia , Europa (Continente) , Feminino , Testes Genéticos/tendências , Guias como Assunto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Gravidez , Doenças Raras/epidemiologia , Doenças Raras/genética , Doenças Raras/patologia
13.
Int J Mol Sci ; 23(1)2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-35008861

RESUMO

Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-ß gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options.


Assuntos
Doenças da Aorta/genética , Genômica , Síndrome de Marfan/genética , Adulto , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/patologia , Respiração Celular , Feminino , Fibrilina-1/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Síndrome de Marfan/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
16.
Am J Med Genet A ; 173(9): 2451-2455, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28631899

RESUMO

We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.


Assuntos
Hiperventilação/genética , Deficiência Intelectual/genética , Patologia Molecular , Síndrome de Prader-Willi/genética , Fator de Transcrição 4/genética , Adolescente , Sequência de Bases/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Hibridização Genômica Comparativa , Exoma/genética , Fácies , Feminino , Humanos , Hiperventilação/diagnóstico , Hiperventilação/fisiopatologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Obesidade/diagnóstico , Obesidade/genética , Obesidade/fisiopatologia , Fenótipo , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/fisiopatologia , Gêmeos Monozigóticos
17.
Clin Endocrinol (Oxf) ; 85(2): 247-57, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26935236

RESUMO

OBJECTIVE: The objective of this study was to determine the aetiological spectrum of disorders of sex development (DSD) in a large cohort of underprivileged and undiagnosed patients from Indonesia. METHODS: A total of 286 patients with atypical external and/or internal genitalia were evaluated using clinical, hormonal, molecular genetic and histological parameters. RESULTS: The age (years) at presentation was 0-0·5 in 41 (14·3%), >0·5-12 in 181 (63·3%) and >12 in 64 cases (22·4%). 46,XY DSD was most common (68·2%, n = 195), 46,XX DSD was found in 23·4% (n = 67) and sex chromosomal DSD in 8·4% (n = 24). In 61·2% of 46,XX DSD patients, 17·9% of 46,XY DSD patients and all sex chromosome DSD patients (29·4% in total), a final diagnosis was reached based on genetic or histological gonadal tissue evaluation. 17-hydroxyprogesterone and androstenedione levels were the most distinctive parameters in 46,XX DSD patients. In 46,XY DSD, diagnostic groups were identified based on the external masculinization score: androgen action disorder (AAD), unknown male undermasculinization (UMU), and gonadal dysgenesis (GD). LH, FSH and testosterone levels were most informative especially in the older age group. HCG tests were of no additional value as no patients with androgen synthesis disorders were found. Hormonal profiles of patients with sex chromosome DSD and a Y-chromosome sequence containing karyotype showed high levels of LH and FSH, and low levels of AMH, inhibin B and testosterone compared with the normal male range. Gene mutations were found in all patients with CAH, but in only 24·5% and 1·8% of patients with AAD and UMU. In 32% of 46,XY GD patients, copy number variants of different genes were found. CONCLUSION: A stepwise diagnostic approach led to a molecularly or histologically proven final diagnosis in 29·4% of the patients. The most informative parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients, and serum LH, FSH and testosterone levels in 46,XY DSD patients.


Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Hormônios/sangue , 17-alfa-Hidroxiprogesterona/sangue , Adolescente , Fatores Etários , Androstenodiona/sangue , Criança , Pré-Escolar , Transtornos do Desenvolvimento Sexual/sangue , Transtornos do Desenvolvimento Sexual/genética , Feminino , Hormônio Foliculoestimulante/sangue , Genótipo , Disgenesia Gonadal 46 XY , Humanos , Indonésia , Lactente , Recém-Nascido , Hormônio Luteinizante/sangue , Masculino , Fenótipo , Cromossomos Sexuais/genética , Testosterona/sangue
18.
Hum Genet ; 134(8): 881-93, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26017485

RESUMO

Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA.


Assuntos
Aneurisma da Aorta Abdominal/genética , Colágeno Tipo III/genética , Doenças Genéticas Inatas/genética , Cadeias Pesadas de Miosina/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adulto , Idoso , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptor do Fator de Crescimento Transformador beta Tipo II
19.
Epigenetics ; 19(1): 2392048, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39151125

RESUMO

In patients with proximal hypospadias, often no genetic cause is identified despite extensive genetic testing. Many genes involved in sex development encode transcription factors with strict timing and dosing of the gene products. We hypothesised that there might be recurrent differences in DNA methylation in boys with hypospadias and that these might differ between patients born small versus appropriate for gestational age. Genome-wide Methylated DNA sequencing (MeD-seq) was performed on 32bp LpnPI restriction enzyme fragments after RE-digestion in leucocytes from 16 XY boys with unexplained proximal hypospadias, one with an unexplained XX testicular disorder/difference of sex development (DSD) and twelve, healthy, sex- and age-matched controls. Five of seven differentially methylated regions (DMRs) between patients and XY controls were in the Long Intergenic Non-Protein Coding RNA 665 (LINC00665; CpG24525). Three patients showed hypermethylation of MAP3K1. Finally, no DMRs in XX testicular DSD associated genes were identified in the XX boy versus XX controls. In conclusion, we observed no recognizable epigenetic signature in 16 boys with XY proximal hypospadias and no difference between children born small versus appropriate for gestational age. Comparison to previous methylation studies in individuals with hypospadias did not show consistent findings, possibly due to the use of different inclusion criteria, tissues and methods.


Assuntos
Metilação de DNA , Hipospadia , Humanos , Masculino , Hipospadia/genética , Projetos Piloto , Epigênese Genética , Ilhas de CpG , RNA Longo não Codificante/genética , Criança , Pré-Escolar , Lactente , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles
20.
Cardiovasc Res ; 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38636100

RESUMO

AIM: Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor ß (TGF-ß)-signaling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-ß maturation. METHODS AND RESULTS: Rare FURIN variants were detected by whole-exome sequencing of 781 unrelated aortic aneurysm patients and affected relatives. Thirteen rare heterozygous FURIN variants occurred in 3.7% (29) unrelated index AA patients, of which 72% had multiple aneurysms or a dissection.FURIN maturation and activity of these variants were decreased in vitro. Patient-derived fibroblasts showed decreased pro-TGF-ß processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-ß-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibers were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-ß signaling variably, indicating effect modification by individual genetic backgrounds. CONCLUSION: FURIN is a novel, frequent genetic predisposition for abdominal-, thoracic-, and multiple aortic or middle sized artery aneurysms in older patients, by affecting intracellular TGF-ß signaling, depending on individual genetic backgrounds.

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