Multiple different types of genomic variants can cause human disease. Expansions of short tandem repeats (STRs) are a classic example. In this issue of the European Journal of Human Genetics, we have an up to date review on the topic of STRs [1]. STRs compose around 3% of the human genome. Due to their repetitive nature, STRs are prone to slippage, with expansion or contraction. STRs are among the most mutable elements of the human genome. The review summarises the role of STRs in population genetics, human disease and methods for detecting and sizing STRs. Fascioscapulohumeral dystrophy (FSHD1) is associated with contractions in the D4Z4 repeat array. Vishnu et report the contraction range in Indian FSHD patients [2]. Long read sequencing can be used to size STRs and detect other challenging variant classes. For example, detecting HYDIN variants in primary ciliary dyskinesia is challenging due to the presence of the HYDIN2 pseudogene [3]. Long read sequencing can be used to detect cryptic HYDIN variants, as described in this issue.

Chromosome deletions are a well studied class of pathogenic variants. 9p deletion syndrome is clinically heterogeneous, associated with varying deletion size. In this issue, the method of “unique non-overlapping regions” is used to draw genotype-phenotype correlations in a group of 9p deletion patients with breakpoints mapped by genome sequencing [4]. This analysis supported a role for FREM1 deletion and trigonocephaly.

Novel genomic technologies have transformed our ability to diagnose rare genetic conditions. Faye et al. report a survey of people living with rare disease (plwRD) in Europe [5]. The length of time it takes to achieve a diagnosis is one of the biggest challenges facing plwRD. The average time delay to diagnosis is 4.7 years in Europe. PlwRD who had onset of symptoms early in life tended to have longer diagnostic delays. Sixty-five percent of plwRD reported having to consult between 2 and 7 clinicians before obtaining a diagnosis. This paper also highlighted some of the benefits of receiving a diagnosis for a plwRD. Exome and genomic technologies can clearly reduce diagnostic delays. Bhatia et al. report the role of next generation sequencing in facilitating rapid diagnoses in neonates [6]. Most rare genetic conditions are primarily diagnosed in paediatric populations, and the clinical descriptions derive from these. In this issue, the adult presentation of Myhre syndrome is reported. Overweight and obesity are reported as common associations of Myhre syndrome [7]. Joint conditions were frequent as was diabetes and hypertension. Over 2/3 had intellectual disability. Exome and genome sequencing have identified a broader phenotypic spectrum of mendelian disorders. Sentell et al report an adult with isolated renal disease and biallelic variants in CC2D2A [8]. Variants in this gene are more typically associated with a ciliopathy spectrum. Paulet et al. provide a report expanding the clinical phenotypic spectrum of EEF1A2 variants [9]. Initial reports of the clinical presentations of this condition emphasised severe neurodevelopmental delay and epilepsy. The expanded cohort published in this issue of EJHG demonstrated a much milder phenotype; many were walking and had developed speech, compared to a much lower frequency of attaining these milestones reported in the literature. They also suggest genotype-phenotype correlations for mild versus severe phenotypes.

Using genomic technologies to identify gene variants that might cause disease in future is entirely different to the diagnostic setting for unwell individuals. Current proposals are to use whole genome sequencing to perform newborn screening. Parfett assesses the views of children and young people on genomic screening [10]. They held mixed views on the value of newborn genome screening. Positive aspects were around the potential to identify treatable conditions, but there were concerns about concealment of diagnoses and mental health impacts of later disclosure. This work also highlighted the need for more research to understand how to incorporate children and young people into decision making around genomic screening. Secondary findings from exome sequencing done in a diagnostic setting can also be viewed as a form of genomic screening. There is debate around whether secondary findings from paediatric exome tests should be returned; since many will not benefit the child directly. A French study provides strong parental support for return of secondary findings [11]. This is especially true if they are actionable. The authors note that issues around return of findings for late onset, incurable disease remain a topic for further consideration.

One end goal from the identification of genomic basis of disease is treatment with gene therapies. Ormondroyd et al report the views of cardiology patient communities on gene therapy for cardiomyopathy [12]. A survey of over 600 people found that over 90% felt gene therapy should be developed. Most would consider taking part in a clinical trial. Respondents were more willing to take part in clinical trials aimed at people with symptomatic cardiomyopathy with greater severity or of progressive nature.

Genomics also contributes to understanding of common diseases. For example, Teder-Laving et al report a genome wide association study of acne vulgaris [13]. They studied 3 independent European cohorts and confirmed 19 previous loci and identified 4 novel loci. Around 10% of the phenotypic variance of acne is explained by GWAS risk loci. The identified loci also enable them to identify mechanistic pathways involved in acne. Obesity predisposes to many common diseases. Abdominal obesity being of greater risk than peripheral adiposity. A study based on the EPIC-Potsdam cohort identified candidate genes that can potentially influence both body fat mass and distribution [14].