Why have we failed to fully explain incomplete penetrance in lhon?
Authors: Carelli Valerio 
Published: January 2025

Leber hereditary optic neuropathy (LHON) remains puzzling in many aspects, one of these is the incomplete penetrance. Three mitochondrial DNA (mtDNA) point mutations affecting genes that encode for complex I subunits are associated with LHON in over 90% of cases.

As mtDNA variants may co‐exist with wild type genomes, a condition known as “heteroplasmy”, the disease expression may need a high threshold of mutant load. However, heteroplasmy occurs occasionally in LHON families, as in most cases the mtDNA primary LHON mutation is found to be homoplasmic, i.e. 100% mutant mtDNA, but yet the affected individuals remain only a limited subset of the mutation carriers.

Variation of the mitochondrial genome has been also studied as possible source of incomplete penetrance. In fact, constitutive variants defining mtDNA haplogroup J have been found to increase penetrance in families with the m.11778G>A and, more consistently, with the m.14484T>C mutations. Yet this observation does not completely explain incomplete penetrance. Remarkably, incomplete penetrance is also found to occur with the new entity of recessive LHON, in families with DNAJC30 mutations.

Environmental factors, such as tobacco smoking and alcohol consumption, are also invoked as disease triggers able to impact on penetrance.

Last, nuclear DNA (nDNA) variants have been intensively investigated, but with rare exceptions, to date no common polymorphic or hypomorphic variants have been found to segregate with affected or unaffected mutation carriers, thus modulating penetrance. Furthermore, no clearcut digenic model with variants in chromosome X, as initially hypothesized to explain also male prevalence, have been convincingly documented.

It seems obvious that all models hypothesized until now did not work and a paradigm shift seems necessary. Multi‐omic approaches are ongoing to further investigated the unsolved issue of incomplete penetrance in LHON, under the assumption that variants burden in multiple genes belonging to specific pathways related to LHON pathogenic mechanisms may be key to modulate penetrance. One of these pathways is hypothesized to be the machinery regulating mitochondrial biogenesis and mtDNA copy number, as there is evidence that successfully upregulated mito‐biogenesis is a compensatory mechanism characterizing unaffected mutation carriers as compared to affected and controls. Other candidate pathways may include the whole machinery necessary for complex I biogenesis and maintenance, as recently shown for the digenic cases of Leigh syndrome occurring with the m.11778G>A or DNAJC30 mutations. Furthermore, the genetics underlying some anatomical traits that may be relevant to favoring disease conversion, such as optic nerve head dimension, may be other good candidates to screen. Epigenetics remains unexplored, as well as the confounder of environmentally driven affected cases may reduce statistical power in identifying relevant genetic modifying variants.

Overall, it is necessary to join new strategies and hypothesis with a common international multicentric effort to build a large LHON cohort to convincingly solve the controversial issue of incomplete penetrance in LHON.