Digenic or oligogenic mutations in presumed monogenic disorders: A review

Ben‐Mahmoud, Afif; Gupta, Vijay; Kim, Cheol‐Hee; Layman, Lawrence C; Kim, Hyung‐Goo

doi:10.5734/jgm.2023.20.1.15

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…It could also drive the development of treatment by highlighting multiple potential targets. Therefore, identifying an oligogenic component of risk in a disease considered to be predominantly monogenic has direct implication for genetic counseling and risk assessment 1 . Although not well studied, oligogenicity has been described in a selected number of diseases such as Bardet-Biedl syndrome, Charcot-Marie-Tooth (CMT), and long QT syndrome [2][3][4][5][6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

Iacoangeli,

Dilliott,

Al Khleifat

et al. 2024

Preprint

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Recently, large-scale case-control analyses have been prioritized in the study of ALS. Yet the same effort has not been put forward to investigate additive moderate phenotypic effects of genetic variants in genes driving ALS risk, despite case-level evidence suggesting a potential oligogenic risk model. Considering its direct clinical and therapeutic implications, a large-scale robust investigation of oligogenicity in ALS is greatly needed. Here, we leveraged the Project MinE ALS Sequencing Consortium genome sequencing datasets of individuals with ALS (n = 6711) and controls (n = 2391) to identify signals of association between oligogenicity in known ALS genes (n=26) and disease risk, as well as clinical outcomes. Applying regression models to a discovery and replication cohort, we observed that the risk imparted from carrying rare variants in multiple known ALS genes was significant and was greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes, such as C9orf72. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, might not follow the same pattern as we did not observe any associations. Our findings represent the first large-scale, case-control assessment of oligogenic associations in ALS to date and confirm that oligogenic events involving known ALS risk genes are indeed relevant for the risk of disease in approximately 6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring the use of comprehensive gene panels even when a potential pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need of a complete genetic profile for the correct choice of therapy in all ALS patients.

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