Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
CAG trinucleotide repeat expansion in Huntington disease and potential impact in disease presentation
October 2024—Huntington disease is a neurodegenerative disease caused by abnormal CAG trinucleotide repeats in exon one of the HTT gene, in which the number of CAG repeats affects disease presentation. Alleles with 40 or more CAG (cytosine, adenine, guanine) repeats are fully penetrant and age at disease onset is inversely correlated with number of repeats, while 36 to 39 CAG repeats are associated with reduced penetrance and fewer than 36 are not considered to cause Huntington disease. It is thought that inherited CAG repeats may undergo somatic expansion until a harmful threshold is reached before the degenerative process begins. Alleles with 27 to 35 repeats, or intermediate alleles, have received much attention in the past decade because of their link with Huntington disease-compatible phenotypes. The latter are associated with movement disorders and cognitive and behavioral changes. A group of researchers at Hospital Universitario de Navarra, in Spain, conducted a study in which they hypothesized that intermediate alleles in the HTT gene are somatically unstable and undergo somatic expansion, leading to phenotypic presentation in some intermediate allele carriers. The authors identified 490 people with Huntington disease and their family members, as well as 191 intermediate allele carriers from 11 Spanish Huntington disease diagnostic laboratories. Through their study, 355 blood samples from cases with at least 27 CAG repeats were sequenced. Capillary electrophoresis was used to confirm CAG repeat length. For each allele genotyped for its inherited number of CAG repeats, the authors quantified the number of variants up to 10 CAGs longer than the inherited alleles using a measure that has been termed the ratio of CAG expansions. The authors observed that the ratio of CAG expansions was associated with CAG length—the larger the allele, the stronger the association. They showed that the ratio of expansions was age dependent in CAG repeats of 29 or more. Furthermore, they observed a notable positive interaction between CAG and age—that is, the higher the age, the higher the effect of CAG length on the proportion of CAG expansions. Alleles with more than 35 repeats demonstrated a higher increase in CAG expansion per extra CAG unit and year. In addition, intermediate allele carriers who had Huntington disease-compatible phenotypic presentations did not show CAG length-dependent onset of symptoms or increased somatic expansion when compared with intermediate allele carriers who did not have phenotypic presentations. Interestingly, the average age at symptom onset for symptomatic intermediate allele carriers was 58.7 ± 18.6 years, which is significantly lower than what was observed in reduced penetrance allele carriers and markedly higher than what was observed in those with full penetrance alleles. The authors concluded that intermediate allele carriers may undergo somatic expansion and the ratio of expansion is higher in older people with larger inherited CAG alleles. However, disease presentation in intermediate allele carriers is independent of age or inherited allele size.
Ruiz de Sabando A, Ciosi M, Galbete A, et al. Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype. Eur J Hum Gen. 2024;32:770–778.
Correspondence: Dr. Maria A. Ramos-Arroyo at ma.ramos.arroyo@navarra.es
Psychological impact of genetic testing on patients and families in a pediatric cancer setting
Somatic or germline genomic sequencing is necessary for diagnosis, prognosis, and treatment decisions in pediatric oncology. However, targeted or whole genome sequencing may introduce information that can cause psychological and ethical issues for the child, family, and caregivers. More specifically, it may identify clinically consequential incidental or secondary findings that are unrelated to the patient’s current disease, and the implications of reported variants of unknown significance can be difficult to understand. Guidelines for genetic testing in adults can be applied to children and adolescents and young adults (AYA), but studies of the psychological and ethical issues related to genetic testing in these groups of patients are limited. The authors conducted a study on the views of children and AYA with cancer and their parents pertaining to their experience with genetic testing. They investigated 21 families in France (19 children and AYA between 10 and 25 years old and 18 parents) whose child had cancer or had a past history of cancer and had undergone somatic or germline testing in a clinical or research setting. The authors performed two interviews with patients and parents. The first interview, which occurred after the test was proposed, focused on discussing family and disease context, parental and patient knowledge about the test and possible results, expectations and fears, and consent. The second interview occurred after patients received their test results and focused on associated emotions, whether results met expectations, parental and patient knowledge about the test outcome, consequences and implications of the results, and need for psychological consultation. Five families withdrew from the study because they were overwhelmed or felt uninformed about the genetic approach. The authors found that consent for genetic testing was influenced by many factors, including whether the testing was proposed by a genetic counselor versus an oncologist and whether sufficient information and psychological support were provided. Some families wanted to defer testing due to the overwhelming nature of the cancer diagnosis and treatment planning. Other families initially showed lack of interest and needed further discussion to understand the benefits. During the first interview, all children and AYA reported relative or complete lack of understanding about genetic testing, while parents’ reported understanding was more variable. During the second interview, only one patient reported general understanding of some basic concepts of genetic test results, and most parents reported that the situation was overwhelming, affecting their ability to understand. One parent reported that the initial consultation and a family pedigree analysis helped them better understand the result. Most patients and families described a high mental and emotional burden that affected their ability to comprehend all aspects of genetic testing. Interestingly, patients and parents who had one or more onco-genetic consultations before genetic testing had better understanding of the indication, result implications, and secondary findings compared with those who received information during an oncology consultation. Patients primarily had two reactions to the test results: relief because it matched their expectations or distance from the results because it did not seem to affect their daily life. However, parents had a spectrum of reactions—most commonly relief followed by disappointment, distance, and surprise. The authors concluded that this study highlights the emotional and psychological aspects of genetic testing and emphasizes the importance of informed consent for genetic testing and adequately explaining results to maximize the patient’s and family’s understanding.
Droin-Mollard M, de Montgolfier S, Gimenez-Roqueplo AP, et al. Psychological and ethical issues raised by genomic in paediatric care pathway, a qualitative analysis with parents and childhood cancer patients. Eur J Hum Genet. 2024. doi.org/10.1038/s41431-024-01653-4
Correspondence: Dr. Sandrine de Montgolfier at sandrine.demontgolfier@u-pec.fr