Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Hum Genet ; 142(1): 21-32, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35997807

RESUMO

Lambdoid craniosynostosis (CS) is a congenital anomaly resulting from premature fusion of the cranial suture between the parietal and occipital bones. Predominantly sporadic, it is the rarest form of CS and its genetic etiology is largely unexplored. Exome sequencing of 25 kindreds, including 18 parent-offspring trios with sporadic lambdoid CS, revealed a marked excess of damaging (predominantly missense) de novo mutations that account for ~ 40% of sporadic cases. These mutations clustered in the BMP signaling cascade (P = 1.6 × 10-7), including mutations in genes encoding BMP receptors (ACVRL1 and ACVR2A), transcription factors (SOX11, FOXO1) and a transcriptional co-repressor (IFRD1), none of which have been implicated in other forms of CS. These missense mutations are at residues critical for substrate or target sequence recognition and many are inferred to cause genetic gain-of-function. Additionally, mutations in transcription factor NFIX were implicated in syndromic craniosynostosis affecting diverse sutures. Single cell RNA sequencing analysis of the mouse lambdoid suture identified enrichment of mutations in osteoblast precursors (P = 1.6 × 10-6), implicating perturbations in the balance between proliferation and differentiation of osteoprogenitor cells in lambdoid CS. The results contribute to the growing knowledge of the genetics of CS, have implications for genetic counseling, and further elucidate the molecular etiology of premature suture fusion.


Assuntos
Craniossinostoses , Camundongos , Animais , Craniossinostoses/genética , Craniossinostoses/metabolismo , Mutação , Transdução de Sinais/genética , Fatores de Transcrição/genética , Diferenciação Celular , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo
2.
Am J Med Genet A ; 188(5): 1464-1475, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35080095

RESUMO

Craniosynostosis (CS) is a common congenital anomaly defined by premature fusion of one or more cranial sutures. Syndromic CS involves additional organ anomalies or neurocognitive deficits and accounts for 25%-30% of the cases. In a recent population-based study by our group, 84% of the syndromic CS cases had a genetically verified diagnosis after targeted analyses. A number of different genetic causes were detected, confirming that syndromic CS is highly heterogeneous. In this study, we performed whole-exome sequencing of 10 children and parents from the same cohort where previous genetic results were negative. We detected pathogenic, or likely pathogenic, variants in four additional genes (NFIA, EXTL3, POLR2A, and FOXP2) associated with rare conditions. In two of these (POLR2A and FOXP2), CS has not previously been reported. We further detected a rare predicted damaging variant in SH3BP4, which has not previously been related to human disease. All findings were clustered in genes involved in the pathways of osteogenesis and suture patency. We conclude that whole-exome sequencing expands the list of genes associated with syndromic CS, and provides new candidate genes in osteogenic signaling pathways.


Assuntos
Craniossinostoses , Osteogênese , Proteínas Adaptadoras de Transdução de Sinal/genética , Criança , Suturas Cranianas , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Humanos , Transdução de Sinais/genética , Sequenciamento do Exoma/métodos
3.
World J Surg Oncol ; 14: 63, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26940557

RESUMO

BACKGROUND: Abdominoperineal excision is performed in patients with locally advanced, low rectal carcinoma. Reconstruction of the dorsal vagina and perineum using the vertical rectus abdominis myocutaneous flap following extensive surgery results in favorable surgical outcome and quality of life. However, the rectus abdominis muscle, as part of the anterior abdominal wall, may develop fibrous lesions also as a transplant. CASE PRESENTATION: A 39-year-old female patient with low rectal cancer and extensive colorectal polyposis was treated with neoadjuvant chemoradiotherapy followed by colectomy and abdominoperineal excision with resection of the dorsal vaginal wall and subsequent reconstruction of the perineum using the vertical rectus abdominis myocutaneous flap. At the 6-month follow-up, a suspected 2 × 2 cm tumor recurrence was detected in the transposed tissue and was subsequently surgically removed. Histologic examination concluded with fibromatosis. Genetic testing revealed a known disease-causing mutation in the adenomatous polyposis coli gene, confirming the diagnosis of familial adenomatous polyposis. CONCLUSIONS: Fibromatosis may affect the anterior abdominal wall, that is the rectus abdominis muscle, at the primary site or may develop in the muscle after its transposition into the perineum at pelvic reconstruction. Fibromatosis in the muscle flap after pelvic reconstruction may present a difficult diagnostic challenge for the multidisciplinary team.


Assuntos
Fibroma/diagnóstico , Retalho Miocutâneo/patologia , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Retais/cirurgia , Reto do Abdome/patologia , Adulto , Diagnóstico Diferencial , Feminino , Fibroma/etiologia , Humanos , Recidiva Local de Neoplasia/etiologia , Prognóstico , Neoplasias Retais/complicações
4.
Eur J Hum Genet ; 29(6): 920-929, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33288889

RESUMO

An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.


Assuntos
Craniossinostoses/genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Fenótipo , Adulto , Criança , Craniossinostoses/diagnóstico , Feminino , Loci Gênicos , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Masculino , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas , Síndrome
5.
J Neurosurg Pediatr ; 26(1): 68-75, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32244202

RESUMO

OBJECTIVE: The authors present population-based epidemiological data for craniosynostosis regarding incidence, age at diagnosis, sex differences, and frequency of syndromic and familial cases. METHODS: The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve data on all individuals with craniosynostosis treated between 2003 and 2017. The cohort was divided into three 5-year groups based on year of birth: 2003-2007, 2008-2012, and 2013-2017. RESULTS: The authors identified 386 individuals with craniosynostosis. Of these, 328 (85%) consented to be registered with further information. The incidence increased significantly during the study period and was 5.5 per 10,000 live births (1/1800) in the last 5-year period. The increase was seen almost exclusively in the nonsyndromic group. Syndromic craniosynostosis accounted for 27% of the cases, and the incidence remained stable throughout the three 5-year periods. Both syndromic and nonsyndromic craniosynostosis were highly suture specific. There was a male preponderance (male/female ratio 2:1), and males accounted for 75% of the individuals with midline synostosis. Overall, 9.5% were index individuals in families with more than one affected member; of these, 73% were nonsyndromic cases. CONCLUSIONS: The incidence of craniosynostosis increased during the study period, and the observed incidence is among the highest reported. The authors attribute this to increasing awareness among healthcare professionals. The number of syndromic cases was high, likely due to a broader definition compared to the majority of earlier reports. The study revealed a high number of familial cases in both syndromic and nonsyndromic craniosynostosis, thus highlighting the importance of genetics as an underlying cause of craniosynostosis.

6.
Eur J Hum Genet ; 23(12): 1652-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25735484

RESUMO

We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A>G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.


Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação de Sentido Incorreto , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Pessoa de Meia-Idade , Dados de Sequência Molecular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA