How I communicate with patients and families about germ line genetic information

We read with great interest the recent “How I communicate with patients and families about germline genetic information” 1, that covers the most important issues raised by these questions. Authors had to select clinical situations and telomere related genes (TRG) may deserves a specific focus due to specific concerns.

DKC1 was the first TRG explaining hematological diseases: myelodysplasia or bone marrow failure. Hematological disease is rarely isolated and TRG variants cause a variable penetrance of hematological, hepatic, cutaneous or pulmonary diseases. Thus the presence in an individual or the association of evocative hematological and pneumological abnormalities is strongly associated with the presence of a TRG pathogenic variant 2. More than 20 TRG have been associated with these telomeropathies with a genotype-phenotype correlation and very few de novo mutations3. Most gene are of autosomal dominant transmission but some are autosomal recessive and DKC1 is X-linked 3.

Finally, TRG variants are associated with telomerase activity and loss of function variants are expected to induce reduced telomere length. However, the impact on telomere length varies depending on the variants and telomere length is transmitted to children independently of the germline variants. This transmission of short telomeres is one of the main mechanisms of the classic anticipation phenomenon that should be mentioned during genetic counseling of TRG variants4,5. These short telomeres are also thought to be the cause of the phenomenon of phenocopies, the observation of the phenotype of telomeropathy in relatives not carrying the pathogenic variant of TRG found in the family.

Germline TRG variants raise issues of multidisciplinary management, complex genetic analyses and - telomere length and genetic somatic rescue when communicating with patients and families about TRG germline genetic information, requiring specific expertise.



Raphael Borie1, Flore Sicre de Fontbrune2, Aurélie Plessier3, Cécile Guérin1, Caroline Kannengiesser4
1. Service de Pneumologie A Hôpital Bichat, APHP, Paris, France, Université Paris Cité, Inserm, PHERE, Université Paris Cité, 75018 Paris, France
2. Service d'Hématologie Greffe de Moelle & Centre de référence national des aplasies médullaires acquises et constitutionnelles, Hôpital Saint-Louis, APHP, Paris, France
3. Service d’Hépatologie, Hôpital Beaujon, APHP, Paris, France.
4. Departement de Génétique, Hôpital Bichat, APHP, Paris, Paris Cité Université Paris Cité, 75018 Paris, France


Bibliography

1. Hamilton KV, Fox LC, Nichols KE. How I communicate with patients and families about germ line genetic information. Blood. 2023;141(26):3143–3152.
2. Parry EM, Alder JK, Qi X, Chen JJ, Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood. 2011;117(21):5607–11.
3. Niewisch MR, Giri N, McReynolds LJ, et al. Disease progression and clinical outcomes in telomere biology disorders. Blood. 2022;139(12):1807–1819.
4. Schratz KE, Gaysinskaya V, Cosner ZL, et al. Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders. J. Clin. Invest. 2021;131(18):e147598.
5. Vulliamy T, Marrone A, Szydlo R, et al. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet. 2004;36(5):447–9.

We read with great interest the recently published “How I treat” article by Hamilton et al., which aims in facilitating the communication of germline genetic information in families with suspicion of germline conditions related to hematologic malignancies1. Germline investigation is currently part of the standard clinical praxis for patients with hematologic malignancies, especially myeloid neoplasms2-5. The authors provide detailed and clear guidelines related to this very important issue that will certainly be of great help for clinical hematologists. That said, we feel that the role of clinical geneticists is rather understated. The involvement of genetic counselors in the whole process is suggested but not considered mandatory. Meanwhile, many of the actions that are recommended to be taken by the clinical hematologists are actually part of the daily duties of certified and trained clinical geneticists. Clinical genetics is an officially recognized specialty with well determined professional duties including genetic counseling and communicating of germline genetic findings. We believe that the involvement of a certified genetic counselor is imperative in every germline condition including syndromes predisposing for hematological malignancies. Such an approach can only improve the overall management of the patients and the counseling of the respective families, facilitating the identification of relatives at risk and providing information about options for prenatal testing. We do however, need to acknowledge the rather low number of certified clinical geneticists as well as the potential delay that may be caused by referring the patient to another department, especially in the context of allogeneic stem cell transplantation where the timing is extremely crucial. Therefore, we favor a very close collaboration between the departments of hematology and clinical genetics and the establishment of specific clinical routines to optimize the management of patients with germline predisposition for hematological malignancies including the surveillance of healthy carriers5.



References
1. Hamilton KV, Fox LC, Nichols KE. How I communicate with patients and families about germ line genetic information. Blood. 2023;141(26):3143-3152.
2. Dohner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377.
3. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228.
4. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719.
5. Baliakas P, Tesi B, wartiovaara-Kautto U, et al. Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up. Hemasphere. 2019;00(00).