Identifying causal genetic variants using next-generation sequencing technologies at the individual level improves healthcare, and at the population level increases our understanding of disease mechanisms. The crucial step is the ability to accurately identify those genetic variants which are causing a given disease or phenotype. In this issue, Houge and colleagues propose an “ABC” classification system to complement existing protocols [1]. A is a functional classification: is the variant predicted to alter protein function? B is a clinical classification: e.g. does the phenotype fit the gene? C is then selection of a comment to classify the variant. More efficient identification of copy number variants from genome sequencing data will also increase the accuracy of variant detection. A study in this month’s EJHG suggests that combining variant callers improves copy number variant detection and may offer better breakpoint resolution than comparative genomic hybridisation [2].
In this issue, accurate variant interpretation and exome sequencing enables the reporting of novel disease phenotypes. A child with bi-allelic SOX4 variants and neurodevelopmental delay is described [3]. This is yet another example of a gene that has both heterozygous and bi-allelic variant phenotypes. Premature ovarian insufficiency (menopause before age 40) occurs in 1:100 women. The aetiology is not fully understood. Here, Tucker and colleagues use exome sequencing to identify variants in HROB and REC8 [4]. This implicates alterations to meiosis as a pathological mechanism. TP63 variants are a recognised cause of ectodermal abnormalities. Schmidt et al. describe a unique family with the striking phenotype of a split tongue and a dominantly inherited variant in the translation initiation codon [5]. Studying genetic variants in underrepresented populations is crucial, to reduce healthcare inequalities and also aid variant interpretation. A study of genetic variants causing Alkaptonuria in Russia helps expand our knowledge of pathogenic variants in this disease [6].
Of course exome sequencing can identify variants not only in genes relevant to the patient’s presentation, but also in genes that might cause medical conditions such as cancer many years in the future (secondary findings). Van der Shoot and colleagues’ work demonstrates that such secondary (or unsolicited) findings are rare on exome sequencing (0.58% of patients) [7]. Many of these were, however, medically actionable and disclosed to participants. Interestingly, not all of these genes were in the “ACMG-59” list of actionable secondary findings. This suggests that the list of genes for which secondary findings should be reported might need to expand. Sharing information on genetic variants within families has long been recognised as problematic. Having a genetic counsellor directly discuss genetic risk with at risk relatives was investigated in a randomised controlled trial for inherited heart disease [8]. It had no effect on increasing uptake of genetic testing. Deciding whether or not to have a genetic test is challenging for lay people. King et al describe the development of a decision aid to assist with choices around testing for carriage of recessive disease variants [9]. Similarly, Yeates et al. explore the decision making process in couples have preimplantation genetic diagnosis for inherited heart conditions [10].
Traditionally genetic testing took many months to complete. Advances in sequencing platforms and variant interpretation pipelines have now led to exome sequencing being used to diagnose acutely unwell children. Stark and Ellard review the state of the art and argue that rapid genome/exome sequencing should be the standard of care for acutely unwell children [11]. We assume that acutely unwell children will have a “serious” genetic disease, here Felicity Boardman and Corinna Clarke explore differing definitions of “serious” [12].
References
Houge G, Laner A, Cirak S, de Leeuw N, Scheffer H, den Dunnen JT. Stepwise ABC system for classification of any type of genetic variant. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00903-z.
Coutelier M, Holtgrewe M, Jäger M, Flöttman R, Mensah MA, Spielmann M, et al. Combining callers improves the detection of copy number variants from whole-genome sequencing. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00983-x.
Ghaffar A, Rasheed F, Rashid M, van Bokhoven H, Ahmed ZM, Riazuddin S, et al. Biallelic in-frame deletion of SOX4 is associated with developmental delay, hypotonia and intellectual disability. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00968-w.
Tucker EJ, Bell KM, Robevska G, van den Bergen J, Ayers KL, Listyasari N, et al. Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00977-9.
Schmidt J, Schreiber G, Altmüller J, Thiele H, Nürnberg P, Li Y, et al. Familial cleft tongue caused by a unique translation initiation codon variant in TP63. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00967-x.
Soltysova A, Kuzin A, Samarkina E, Zatkova A Alkaptonuria in Russia. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00955-1.
van der Schoot V, Haer-Wigman L, Feenstra I, Tammer F, Oerlemans AJM, van Koolwijk MPA, et al. Lessons learned from unsolicited findings in clinical exome sequencing of 16,482 individuals. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00964-0.
van den Heuvel LM, Hoedemaekers YM, Baas AF, Baars MJH, van Tintelen JP, Smets EMA, et al. A tailored approach to informing relatives at risk of inherited cardiac conditions: results of a randomised controlled trial. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00993-9.
King E, Halliday J, Archibald AD, Delatycki M, Barlow-Stewart K, Newson AJ, et al. Development and use of the Australian reproductive genetic carrier screening decision aid. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00991-x.
Yeates L, McDonald K, Burns C, Semsarian C, Carter S, Ingles J Decision-making and experiences of preimplantation genetic diagnosis in inherited heart diseases: a qualitative study. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00963-1.
Stark Z, Ellard S Rapid genomic testing for critically ill children: time to become standard of care? Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00990-y.
Boardman FK, Clark CC What is a ‘serious’ genetic condition? The perceptions of people living with genetic conditions. Eur J Hum Genet. 2021. https://doi.org/10.1038/s41431-021-00962-2.
Author information
Authors and Affiliations
Contributions
AM conceived and wrote this editorial.
Corresponding author
Ethics declarations
Competing interests
The author declares no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
McNeill, A. A new system for variant classification?. Eur J Hum Genet 30, 137–138 (2022). https://doi.org/10.1038/s41431-021-01032-3
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41431-021-01032-3