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- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
- Gunn, Harriet M., et al.
(författare)
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Metabolic Health in Childhood Cancer Survivors: A Longitudinal Study in a Long-Term Follow-Up Clinic
- 2016
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Ingår i: Journal of Adolescent and Young Adult Oncology. - : MARY ANN LIEBERT, INC. - 2156-5333 .- 2156-535X. ; 5:1, s. 24-30
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Childhood cancer survivors (CCS) are at increased risk of metabolic dysfunction as a late effect of cancer treatment. However, pediatric metabolic syndrome (MetS) lacks a unified definition, limiting the diagnosis of MetS in CCS. This study evaluated individual metabolic health risk factors and potential areas for intervention in this at-risk population. Methods: This single center, retrospective observational longitudinal study evaluated the metabolic health of all CCS attending an oncology long-term follow-up clinic at a university hospital in Sydney, Australia (January 2012-August 2014). Participants were 276 CCS (52.2% male; mean age 18.0 years; range 6.8-37.9 years), at least 5 years disease free with a broad spectrum of oncological diagnoses. Primary metabolic health risk factors included raised body mass index, hypertension, and hypertransaminasemia. Participants treated with cranial radiotherapy (n=47; 17.0% of cohort) had additional biochemical variables analyzed: fasting glucose/insulin, HDL/LDL cholesterol, and triglycerides. Results: Hypertension was common (19.0%), with male sex (pamp;lt;0.01) and being aged 18 years or above (pamp;lt;0.01) identified as risk factors. Cranial irradiation was a risk factor for overweight/obesity (47.8% in cranial radiotherapy-treated participants vs. 30.4%; p=0.02). Hypertransaminasemia was more prevalent among participants treated with radiotherapy (15.6% vs. 7.3%; p=0.03), and overweight/obese participants (17.6% vs. 8.2%; p=0.04). Conclusion: Metabolic health risk factors comprising MetS are common in CCS, placing this population at risk of premature adverse cardiovascular consequences. Proactive surveillance and targeted interventions are required to minimize these metabolic complications, and a unified definition for pediatric MetS would improve identification and monitoring.
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| 3. |
- Gunn, Harriet M., et al.
(författare)
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Primary Gonadal Insufficiency in Male and Female Childhood Cancer Survivors in a Long-Term Follow-Up Clinic
- 2016
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Ingår i: Journal of Adolescent and Young Adult Oncology. - : MARY ANN LIEBERT, INC. - 2156-5333 .- 2156-535X. ; 5:4, s. 344-350
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Childhood cancer survivors (CCS) are at increased risk of primary gonadal insufficiency (PGI). This study evaluated the prevalence and clinical characteristics of PGI in CCS. Methods: In this single-center, retrospective, observational, longitudinal study, we characterized CCS with PGI attending the oncology Long-Term Follow-Up (LTFU) Clinic at an Australian university hospital (January 2012-August 2014). From a cohort of 276 CCS, 54 (32 males) met criteria for PGI: elevated gonadotropins plus low estradiol/amenorrhoea (females) or low testosterone/small testicles for age (males). Results: Median age at primary diagnosis was 4.8 years (inter-quartile range [IQR] 3.0-9.7 years) and at LTFU, it was 22.3 years (IQR 18.2-25.7 years). Fifty-three participants (98.1%) were treated with known highly gonadotoxic therapies: alkylating chemotherapy (96.3%), radiotherapy (70.3%), total body irradiation (29.6%), bone marrow transplantation (51.9%), or multimodal protocols (68.5%). At primary diagnosis, 86.7% participants were Tanner stage I and at LTFU, 89.1% participants were Tanner stage V. More females (95.5%; n=21) than males (40.6%; n=13) were treated with hormone development therapy (HDT) (pamp;lt;0.01). Of these, more than half (n=18; 7 males) required pubertal induction. There was no significant difference in serum luteinizing hormone/follicle stimulating hormone (LH/FSH), testosterone/estradiol between those untreated and those treated with HDT. Among those on HDT, 60.7% had persistently elevated FSHLH and 33.3% had low testosterone or estradiol. Six males had semen analysis (five azoospermic, one oligospermic). Psychological assessment was documented in 61.1% of participants, and two-thirds reported fertility concerns. Conclusion: PGI is an evolving phenotype that is common in CCS. Suboptimal treatment and non-adherence occur frequently. Ongoing assessment is essential to ensure prompt diagnosis, adequate intervention and to promote HDT adherence.
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| 4. |
- Zamora, Juan Carlos, et al.
(författare)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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