32 research outputs found
Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families
Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias. Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes. Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling. Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families
Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK âAlert Level 4â phase of the B-MaP-C study
From Springer Nature via Jisc Publications RouterHistory: received 2020-08-11, rev-recd 2020-12-04, accepted 2020-12-10, registration 2020-12-11, pub-electronic 2021-03-25, online 2021-03-25, pub-print 2021-05-25Publication status: PublishedAbstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated âstandardâ or âCOVID-alteredâ, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had âCOVID-alteredâ management. âBridgingâ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2â9%) using âNHS Predictâ. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of âCOVID-alteredâ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown
Breast cancer management pathways during the COVID-19 pandemic: Outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study
Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated âstandardâ or âCOVID-alteredâ, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had âCOVID-alteredâ management. âBridgingâ endocrine therapy was used (nâ=â951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (nâ=â299). Where adjuvant chemotherapy was omitted (nâ=â81), the median benefit was only 3% (IQR 2â9%) using âNHS Predictâ. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (nâ=â781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of âCOVID-alteredâ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown
Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK âAlert Level 4â phase of the B-MaP-C study
Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated âstandardâ or âCOVID-alteredâ, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had âCOVID-alteredâ management. âBridgingâ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2â9%) using âNHS Predictâ. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of âCOVID-alteredâ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown
Correction: Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK âAlert Level 4â phase of the B-MaP-C study
From Springer Nature via Jisc Publications RouterHistory: registration 2021-03-26, online 2021-04-12, pub-electronic 2021-04-12, pub-print 2021-08-31Publication status: PublishedA Correction to this paper has been published: https://doi.org/10.1038/s41416-021-01378-
Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK âAlert Level 4â phase of the B-MaP-C study
Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated âstandardâ or âCOVID-alteredâ, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had âCOVID-alteredâ management. âBridgingâ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2â9%) using âNHS Predictâ. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of âCOVID-alteredâ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown
Generation of induced pluripotent stem cells (iPSCs) from a hereditary spastic paraplegia patient carrying a homozygous Y275X mutation in CYP7B1 (SPG5)
Skin fibroblasts were obtained from a 47-year-old hereditary spastic paraplegia patient carrying a homozygous mutation Y275X in CYP7B1 (Cytochrome P450, Family 7, Subfamily B, Polypeptide 1), responsible for causing hereditary spastic paraplegia type 5 (SPG5). Induced pluripotent stem cells (iPSCs) were generated by transfection with episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC and hLIN28. The generated line iPS-SPG5-Y275X was transgene-free, retained the specific mutation with no additional genomic aberrations, expressed pluripotency markers and was able to differentiate into cells of all germ layers in vitro. The generated iPS-SPG5-Y275X line may be a useful resource for disease modelling of SPG5
Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias
Background
The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrierâparent. Detection of UPDâcaused homozygous diseaseâcausing variants is detrimental to accurate genetic counseling. Wholeâexome sequencing can allow for the detection of such events.
Methods
We systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX.
Results
One hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous diseaseâcausing mutation in the SPG35 disease gene was then identified within this region.
Conclusion
This study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX.
Uniparental disomy, the inheritance of two copies of a chromosomal region from one parent, may generate homozygosity for a deleterious recessive variant when the chromosomal region is from the same parental allele (isodisomy). In this study, we identified chromosomal uniparental isodisomy from one proband's wholeâexome sequencing (WES) while screening 96 simplex, nonâconsanguineous families of patients affected by hereditary ataxia and a spectrum of motoneuron diseases including ALS, ALSâFTD and Hereditary Spastic Paraplegia (HSP)
Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias
Este estudo Ă© baseado na anĂĄlise da anatomia macroscĂłpica e da estrutura histolĂłgica de 452 ovĂĄrios de fĂȘmeas de Cathorops spixii coletadas nas Ilhas Pai Matos (regiĂŁo estuarino-lagunar de CananĂ©ia-Iguape - 24°59'42"S 47°54'27"W), SĂŁo Paulo, Brasil. Foram consideradas seis fases de desenvolvimento ovocitĂĄrio, com base nas caracterĂsticas citolĂłgicas das cĂ©lulas germinativas durante o processo de maturação, e sete estĂĄdios de maturação ovarianos, determinados pela estrutura histolĂłgica dos ovĂĄrios e pela ocorrĂȘncia e freqĂŒĂȘncia relativa das seis fases ovocitĂĄrias: "A"(imaturo), "Bi" (em maturação inicial), "Bf'(em maturação final), "Ci"(parcialmente maduro), "CfâŹïżœ'(maduro), "D"(esvaziado) e "R"(em recuperação). A presença de apenas um lote ovocitĂĄrio, unido durante a desova por uma substncia adesiva acelular, sugere desova total, e o desenvolvimento ovocitĂĄrio Ă© classificado como sincrĂŽnico em grupos. A anatomia ovariana macroscĂłpica e a estrutura histolĂłgica verificadas sĂŁo caracterĂsticas do tipo cistovariano.This study is based on the analysis of macroscopic anatomy and histological structure of 452 ovaries from females of Cathorops spixii caught in the "Pai Matos" islands (CananĂ©ia-Iguape lagoonal-estuarine region - 24°59'42"S 47°54'27"W), SĂŁo Paulo, Brazil. Six phases of oocyte development are considered, based on cytological characteristics of the germinative cells during the maturation process, and seven ovarian maturity stages, determined by histological structure of ovaries and by the occurrence and relative frequency of the six oocyte phases: "A"(immature), "Bi"(initial maturation), "Bf'(advanced maturation), "Ci"(partially mature), "Cf'(mature), "D"(spent) and "R"(recuperation). The presence of a single patch of oocytes clustered during the spawn by an acellular adhesive substance, suggests total spawning, and the oocyte development is classified as synchronic in groups. The examined ovarian macroscopic anatomy and histological structure are characteristic of the cistovarian type