The Clinical Spectrum of Mosaic Genetic Disease

Abstract

Genetic mosaicism is defined as the presence of two or more cell lineages with different genotypes arising from a single zygote. Mosaicism has been implicated in hundreds of genetic diseases with diverse genetic etiologies affecting every organ system. Mosaic genetic disease (MDG) is a spectrum that, on the extreme ends, enables survival from genetic severe disorders that would be lethal in a non-mosaic form. On the milder end of the spectrum, mosaicism can result in little if any phenotypic effects but increases the risk of transmitting a pathogenic genotype. In the middle of the spectrum, mosaicism has been implicated in reducing the phenotypic severity of genetic disease. In this review will describe the spectrum of mosaic genetic disease whilst discussing the status of the detection and prevalence of mosaic genetic disease.

Keywords: X-linked lethal disease; chimera; heteroplasmy; mosaic; mosaicism.

Figure 1

Stages of early embryogenesis: from fertilization to blastocyst formation. Early embryogenesis begins with fertilization, where a sperm and oocyte merge to form a zygote. The zygote undergoes rapid divisions (cleavage), forming smaller cells called blastomeres. As it reaches the 16–32 cell stage, the embryo becomes a compact morula. Around day 5, the morula develops into a blastocyst, consisting of an outer trophoblast (which will form the placenta) and an inner cell mass (which will become the embryo), along with a fluid-filled cavity.

Figure 2

Schematic representation of mosaicism occurring when early zygotic mutations lead to distinct cell populations within the individual. Mosaicism arises when a mutation occurs during the mitotic division of a zygote, formed by the conjugation of sperm and egg. As the zygote undergoes further mitotic division, the mutated cells (in blue) continue to proliferate alongside normal cells (in purple), leading to the coexistence of genetically distinct cell populations within the individual.

Figure 3

Types of genetic mutations and their roles in somatic and gonadal mosaicism. (A) Normal healthy individual without any genetics mutations or mosaicism. (B) De novo mutation: A genetic mutation arises in a single gonadal cell or in the zygote within the first few divisions in a germline mutation. The offspring may be heterozygous in every cell. (C) Somatic mosaicism: A mosaic mutation occurs in soma (non-gonadal) cells after fertilization. The offspring may have two genetically different cell lines, with some cells carrying the mutation and others not. (D) Gonadal mosaicism: A mosaic mutation arises exclusively in the gonadal cells (ess or sperm) of an unaffected parent. Offspring may be heterozygous in every cell.

Figure 4

Spectrum of mosaic genetic diseases and their impact on phenotype and reproductive fitness. The spectrum of mosaic genetic diseases (MGD) ranges from severe conditions compatible with life due to mosaicism (left) to disorders with minimal phenotypic impact where mosaicism primarily affects reproductive cells (right). In severe cases, mosaicism is associated with high severity and low reproductive fitness. In intermediate cases, mosaicism reduces the severity of the phenotype. At the mild end, gonadal mosaicism has little effect on phenotype but may be transmitted to offspring as non de novo mutations in future generations, associated with high reproductive fitness.

Figure 5

Replicative segregation of heteroplasmic mitochondrial DNA mutations. As mitochondrial DNA replicates, the mitochondria undergo fission and fusion, leading to the random distribution of mutant and wild-type DNA into daughter cells, which may result in varying proportions of each. A parent cell with low-level mutant mitochondrial DNA heteroplasmy can produce progeny with varying heteroplasmy levels, potentially exceeding the threshold for expressing a mutant phenotype after replication. Mitochondrial DNA mutations, often heteroplasmic, can coexist with wild-type mitochondrial DNA in the same cell. A pathogenic mutation generally requires a heteroplasmy level above 80% to surpass the biochemical threshold.