Patient and family support groups have long been a feature of medical care. This month, Bertonazzi and colleagues report a systematic review of the effectiveness and impact of patient support groups for BRCA1 and BRCA2 variant carriers [1]. The qualitative synthesis identified that these support groups may help with decisions around risk-reducing treatments. These groups also helped provide emotional support and helped reduce feelings of isolation. What is the need for such support groups in terms of numbers of potential participants? Woodward and colleagues report a 30-year experience of cancer gene predisposition testing [2]. On average, for a range of cancer genes, they found that for each positive index case, 3.05 further cascade tests in unaffected relatives were generated. Cancer Genetics services have a clear potential to produce a large pool of people with variants in cancer predisposition genes who may need ongoing support. Some malignancies do not have a single gene in which a large proportion of causal variants are found. For example, in multiple myeloma at least 23 risk loci, with low individual penetrance, have been identified. Even when combined into a polygenic risk score, these loci only explain a fraction of the disease risk [3]. For most loci identified in Genome-Wide Association Studies, the mechanisms of disease susceptibility are unclear. A study of the 2p23.2 ER-negative breast cancer susceptibility locus identifies potential candidate genes [4]. Genotype-phenotype correlations can also help in clinical practice, Moualed and colleagues describe the effect of NF2 pathogenic variants on tumour progression [5].

In both rare diseases and cancer, correct interpretation of genetic variants is vital to safe practice. Mur and colleagues provide evidence against pathogenicity of the POLD1 p.V295M variant [6]. POLD1 variants in the exonuclease domain are the most frequent POLD1 variants associated with cancer. In this study, a missense variant near the exonuclease domain was conclusively shown not to affect exonuclease activity. This has implications for variant interpretation. In vitro assays have long been used to provide evidence for genetic variant pathogenicity in research practice. Some of these are now being translated in clinical care. Assays of DNA methylation being one such example. Wang and colleagues report a blood DNA methylation signature for ZNF711, which is associated with non-syndromal X-linked intellectual disability [7]. Given the lack of a distinctive clinical phenotype, a distinct DNA methylation pattern helps support the classification of ZNF711 as a distinct clinical entity.

Deciding whether or not to have a genetic test can be complicated. Ahmed reports on the use of a decision support aid for beta-thalassaemia testing [8]. It was felt by participants to be appropriate and to help with certain aspects of decision-making. It was noted that it could not help with broader issues such as feelings of stigma. Decision-making in prenatal genetic testing is an especially complicated scenario. In the month’s EJHG a retrospective study of 90 pregnancies suggests that singleton exome sequencing can be diagnostically useful in such scenarios [9].

Exome sequencing remains a useful tool for variant identification, expanding our knowledge of pathogenic variants and phenotype associations. Bi-allelic variants in SLC5A6 were previously associated with a multi-system disorder; in this issue a role for these variants in motor neuropathies is defined [10]. Previously, the role of LMOD2 in dilated cardiomyopathy was unclear, with evidence from a single patient. Via exome sequencing, Yuen et al identify a further sibship with homozygous LMOD2 variants providing further evidence for its role in cardiomyopathy [11]. Wade and colleagues identify deletion of the last 2 exons of FGF10 as a novel molecular genetic cause of lacrimo-auriculo-dental-digital syndrome [12]. Such reports help in clinical classification of variants and counselling families.