A classical clinical genetics rule is that multiple neoplasms are suggestive of a genetic cancer predisposition syndrome. This is true of renal carcinoma. Zhang and colleagues provide a timely review of multiple primary renal neoplasms [1]. In over 60% of cases multiple primary renal neoplasms are synchronous. Von Hippel Lindau disease and Birt-Hogg-Dube syndrome were the most common genetic cancer predisposition syndromes. Of course, not all lesions which occur in people with cancer predisposition syndromes are malignant. For example, around 30% of people with BAP1 tumour predisposition syndrome have benign splenic lesions on imaging [2]. POT1 cancer predisposition syndrome is associated with alterations to telomere length and genomic instability. POT1 is an autosomal dominant condition, with unknown penetrance. In this issue of European Journal of Human Genetics, a broader range of neoplasms associated with POT1 germline variants is reported [3]. A possible association with early onset prostate cancer was noted.

Exome and genome sequencing technologies are complex and require highly skilled staff to manage both the wet lab work and dry lab variant interpretation. Maver and colleagues present the ERN-rare neurological diseases quality assurance framework for next generation sequencing diagnosis of neurological disorders [4]. It is well known that, once identified by sequencing, classifying a variant as pathogenic, or not, can be challenging. Andhika et al. report an approach to improve PAX6 variant classification [5]. PAX6 missense variants are frequently classified as variants of uncertain significance. Ten commonly used pathogenicity prediction tools were evaluated, and thresholds for pathogenicity prediction optimised. Suggestions as to the best performing tools for PAX6 missense variant classification are made. Structural variants, such as deletions and duplications, are a common genomic cause of rare conditions. Most next generation sequencing pipelines are not capable of reliably detecting structural variants. If exome/genome sequencing could detect both structural variants and single nucleotide variants it would improve resource utilisation. Demidov et al. present a diagnostic uplift of 0.4% in unsolved SOLVE-RD participants when adding structural variant calling to exome sequencing [6]. Identifying and classifying splice variants is another challenge in clinical genomics. Zhang et al. use a series of beta-globin gene constructs to identify intron 1 deletions which are likely to cause clinically significant mis-splicing [7]. Such data is valuable for clinical interpretation of splice variants.

In this issue, we publish a range of papers describing the genotypes and phenotypes of rare conditions. Bi-allelic variants in FUZ are reported in additional patients with a syndrome of orofacialdigital syndrome, helping confirm the association [8]. Sajan et al. provide a case series of individuals with neurodevelopmental condition, with or without seizures, in association with GABRA4 variants [9]. Sadly, few genetic neurodevelopmental conditions are treatable. Bi-allelic variants in SLC5A6 are associated with a neurological condition, with potential vitamin treatments [10]. COQ7 pathogenic variants cause a variable disorder, with associated cardiac and neurological involvement, treatable with COQ10 supplements [11]. A prenatal onset of COQ7 disorder was ameliorated by early treatment with COQ10. Layo-Carris and colleagues provide an expansion on the phenotype associated with H3.3 (histone) variants, presenting evidence of possible genotype-phenotype correlations [12]. Noonan syndrome has multiple different genetic associations. In this issue, RAF1 Noonan syndrome is reported to have a severe phenotype - with prominent hypertrophic cardiomyopathy [13]. Dentici et al. report variants in ERF as a novel cause of Noonan syndrome, associated with craniosynostosis [14]. A further patient with a GTDC1 microdeletion is presented; providing further evidence this may be a novel neurodevelopmental condition [15].

Genomics technologies can also be applied in healthcare for common diseases. One application is pharmacogenetics - using genomic variants to predict responses to medications. Massmann et al. provide evidence that genotyping of CYP2C19 can help selection of appropriate anti-platelet therapy [16]. Manson et al. report the Dutch Pharmacogenetics Working Group guideline on pharmacogenetics for anti-epileptic drugs [17]. Pharmacogenomics is a fast developing field, with potential to benefit both people with rare and common medical conditions.