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Many clinicians will encounter a given rare condition only a few times in their career. This makes management guidelines even more important—since personal clinical experience cannot guide

clinical care. In this issue, ERN Genturis provides 2 guidelines for rare cancer syndromes [1, 2]. The guideline for Birt-Hogg-Dube defines clinical scenarios in which FLCN gene testing

should be considered—including renal carcinomas, skin manifestations and pneumothorax [1]. Guidelines for renal cancer surveillance are also provided. ERN Genturis also provides guidelines

on constitutional mismatch repair deficiency [2]. The guideline identifies scenarios in which genetic testing for this rare cancer predisposition syndrome should be considered and cancer

surveillance recommendations. Genomic testing is central to the diagnosis of many cancer predisposition syndromes. Fortuno et al. report that many variants of uncertain significance in

breast cancer predisposition genes could be reclassified as clinically actionable if variant reclassification is practiced [3]. Ancestry plays a key role in the spectrum of causal genetic

variants encountered in given clinical scenarios—Kerr et al. report 2 highly prevalent BRCA variants in Orkney and Shetland islanders [4]. In this issue, novel genetic causes of rare

conditions are also characterised. Mol et al. identify further people with connective tissue phenotypes and EFEMP1 gene variants [5]. The clinical presentation was notable for marfanoid body

habitus and multiple herniae. Braddock et al. report autosomal dominant missense variants in SPARCL1 as a novel cause of corneal dystrophy [6]. SPARCL1 is known to regulate Decorin, which

is a validated genetic cause of corneal dystrophy. Karimi et al. define the clinical spectrum of DEGCAGS (Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and

Skeletal Abnormalities syndrome), which will aid clinical recognition and publish a diagnostic episignature [7]. A brief report in this issue also confirms the association of SOX11 variants

with hypogonadotropic hypogonadism [8]. Autism is generally a multifactorial condition, but there are monogenic causes. Using exome and microarray analysis, Miyake et al. identified a

monogenic cause in 16% of people with autism [9]. Some rare genetic conditions are treatable. Charpié et al. provide evidence that bisphosphonate therapy can reduce fracture risk in rare

forms of osteogenesis imperfecta [10]. Discussing the benefits and limitations of genomic testing is crucial before people undergo diagnostic tests. Traditionally genetic counselling and

testing occurred in specialist genetics clinics. Modern healthcare systems are removing this boundary and “mainstreaming” genomics testing in non-specialist clinics. Do et al. report a study

of genetic counsellors views on mainstreaming genomic testing [11]. Genetic counsellors play a crucial role in supporting families with rare conditions. Wilsnack et al. report a mixed

methods study of the support needs of families affected by telomere biology disorders, which highlights areas of focus for clinical care [12]. REFERENCES * Geilswijk M, Genuardi M, Woodward

ER, Nightingale K, Huber J, Madsen MG, et al. ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome. Eur J Hum

Genet. 2024. https://doi.org/10.1038/s41431-024-01671-2. * Colas C, Guerrini-Rousseau L, Suerink M, Gallon R, Kratz CP, Ayuso É, et al. ERN GENTURIS guidelines on constitutional mismatch

repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01708-6. * Fortuno C, Cops

EJ, Davidson AL, Hadler J, Innella G, Mckenzie ME, et al. Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer

centres. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01705-9. * Kerr SM, Klaric L, Muckian MD, Cowan E, Snadden L, Tzoneva G, et al. Two founder variants account for over 90%

of pathogenic BRCA alleles in the Orkney and Shetland Isles in Scotland. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01704-w. * Mol MO, Van Ham TJ, Bannink N, Bruggenwirth HT,

Escher JC, Kros JM, et al. Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder. Eur J Hum Genet. 2024.

https://doi.org/10.1038/s41431-024-01692-x. * Braddock FL, Gardner JC, Bhattacharyya N, Sanchez-Pintado B, Costa M, Zarouchlioti C, et al. Autosomal dominant stromal corneal dystrophy

associated with a SPARCL1 missense variant. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01687-8. * Karimi K, Weis D, Aukrust I, Hsieh T-C, Horackova M, Paulsen J, et al.

Epigenomic and phenotypic characterization of DEGCAGS syndrome. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01702-y. * Schincariol-Manhe B, Campagnolo É, Spineli-Silva S, De

Leeuw N, Correia-Costa GR, Pessoa A, et al. Novel variants in the SOX11 gene: clinical description of seven new patients. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01695-8. *

Miyake N, Tsurusaki Y, Fukai R, Kushima I, Okamoto N, Ohashi K, et al. Molecular diagnosis of 405 individuals with autism spectrum disorder. Eur J Hum Genet. 2023.

https://doi.org/10.1038/s41431-023-01335-7. * Charpié M, Brunelle P, Baujat G, Michot C, Van Gils J, Leheup B, et al. Clinical spectrum of rare bone fragility disorders and response to

bisphosphonate treatment: a retrospective study. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01645-4. * Do TT, Martyn M, Mcclaren B, Mcewen A, Gaff C. Becoming agents for

genomic change: genetic counsellors’ views of patient care and implementation influences when genomics is mainstreamed. Eur J Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01686-9. *

Wilsnack C, Rising CJ, Pearce EE, Forbes Shepherd R, Thompson AS, Majid A, et al. Defining the complex needs of families with rare diseases—the example of telomere biology disorders. Eur J

Hum Genet. 2024. https://doi.org/10.1038/s41431-024-01697-6. Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Neuroscience and Neuroscience Institute, The

University of Sheffield, Sheffield, UK Alisdair McNeill * Sheffield Clinical Genetics Service, Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, UK Alisdair McNeill Authors *

Alisdair McNeill View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS AM conceived and wrote this paper. CORRESPONDING AUTHOR Correspondence to

Alisdair McNeill. ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to

jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE McNeill, A. New guidelines for

rare cancer syndromes. _Eur J Hum Genet_ 32, 1517 (2024). https://doi.org/10.1038/s41431-024-01735-3 Download citation * Published: 29 November 2024 * Issue Date: December 2024 * DOI:

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