In this issue, we have a selection of papers describing the genotypes and phenotypes of a range of rare (and ultra rare) diseases. Terradas et al. provide important confirmation that heterozygous variants in MBD4 are not associated with colorectal cancer . Smith et al. provide a second report of PRORP variants being associated with a mitochondrial phenotype, confirming the clinical entity . ALDH1A3 variants account for around 10% of severe inherited ocular conditions. Kesim and colleagues expand the phenotype by reporting neurodevelopmental phenotypes in affected individuals . Hadar et al. provide insights into a novel genetic cause of haemolytic uraemic syndrome . Ganapathi et al. update us on the clinical spectrum associated with NR2F2 variants .
Genome sequencing to identify genetic variants predisposing to cancer is well established in adult practice. Schroeder et al. report the role of trio genome sequencing in paediatric cancers . A high proportion of paediatric cancer patients were found to have a genetic variant in a cancer predisposition gene. When these were inherited from an apparently unaffected parent it could have implications for their health and potential cancer screening.
To support genomic testing for rare diseases an adequate genetic counsellor workforce is required. Zakaria et al. review trends in research in genetic counselling . They note an increasing amount of research being published in this area; with access to genetic services and workforce issues recurrent themes in the research area. Yanes et al. report a novel initiative to embed a genetic counsellor in an inherited metabolic disease clinic . This was found to improve access to genomic testing.
Detailed discussion of the pros and cons of genome sequencing is required to enable a person or a child’s parents to consent to such testing. But what is the critical information required to be given in this process? A North American study of clinical genetics clinicians suggests that a core set of information can be defined for various scenarios and that totally comprehensive or exhaustive discussions may not be required .
Despite technological advances, many patients remain undiagnosed after exome or genome sequencing. Periodic reanalysis has been suggested as a strategy to uplift diagnostic rates. In this issue, an increased diagnostic rate with a 5-yearly reanalysis is reported . The emergence of novel gene-disease associations was seen as crucial to increasing the proportion of solved cases.
Studying large cohorts of patients helps to improve genomic diagnostic strategies. Kim et al. report the diagnostic utility of a nationwide genomics diagnosis program in the Republic of Korea . A large clinical series of over 600 people with Niemann-Pick Type C identified novel genotype-phenotype correlations .
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Smith TB, Rea A, Thomas HB, Thompson K, Oláhová M, Maroofian R, et al. Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01437-2.
Kesim Y, Ceroni F, Damián A, Blanco-Kelly F, Ayuso C, Williamson K, et al. Clinical and genetic analysis further delineates the phenotypic spectrum of ALDH1A3-related anophthalmia and microphthalmia. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01342-8.
Hadar N, Schreiber R, Eskin-Schwartz M, Kristal E, Shubinsky G, Ling G, et al. X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-022-01278-5.
Ganapathi M, Matsuoka LS, March M, Li D, Brokamp E, Benito-Sanz S, et al. Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01434-5.
Schroeder C, Faust U, Krauße L, Liebmann A, Abele M, Demidov G, et al. Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01423-8.
Zakaria WNA, Yoon S-Y, Wijaya A, Ahmad AH, Zakaria R, Othman Z. Global trends and themes in genetic counseling research. Eur J Hum Genet. 2023;1–4. https://doi.org/10.1038/s41431-023-01371-3.
Yanes T, Sullivan A, Barbaro P, Brion K, Hollway G, Peake J, et al. Evaluation and pilot testing of a multidisciplinary model of care to mainstream genomic testing for paediatric inborn errors of immunity. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01321-z.
Hallquist MLG, Borensztein MJ, Coughlin CR, Buchanan AH, Andrew Faucett W, Peay HL, et al. Defining critical educational components of informed consent for genetic testing: views of US-based genetic counselors and medical geneticists. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01401-0.
Bartolomaeus T, Hentschel J, Jamra RA, Popp B. Re-evaluation and re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 18. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01425-6.
Kim MJ, Kim B, Lee H, Lee J-S, Chae SW, Shin HS, et al. The Korean Genetic Diagnosis Program for Rare Disease Phase II: outcomes of a 6-year national project. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01415-8.
Guatibonza Moreno P, Pardo LM, Pereira C, Schroeder S, Vagiri D, Almeida LS, et al. At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01408-7.
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McNeill, A. Expanding what we know about rare genetic diseases. Eur J Hum Genet 31, 1091–1092 (2023). https://doi.org/10.1038/s41431-023-01453-2