Disorders Caused by Genetic Mosaicism

Abstract

Background: Genetic mosaics arise through new mutations occurring after fertiliza- tion (i.e., postzygotic mutations). Mosaics have been described in recent years as the cause of many different disorders; many of these are neurocutaneous diseases and syndromal developmental disorders, each with a characteristic phenotype. In some of these disorders, there is a genetic predisposition to the development of tumors. This article is intended as an overview of selected mosaic diseases.

Methods: This review is based on publications retrieved by a selective search in PubMed, with particular attention to recent articles in high-ranking journals dealing with asymmetric growth disturbances, focal brain malformations, mosaic diseases due to dysregulation of the RAS/RAF signaling pathway (mosaic RASopathies), and vascular malformations.

Results: The identification of postzygotic mutations has led to the reclassification of traditional disease entities and to a better understanding of their pathogenesis. Diagnosis is aided by modern next-generation sequencing (NGS) techniques that allow the detection even of low-grade mosaics. Many mosaic mutations are not detectable in blood, but only in the affected tissue, e.g., the skin. Genetic mosaic diseases often manifest themselves in the skin and brain, and by facial dysmorphism, asymmetrical growth disturbances, and vascular malformations.

Conclusion: The possibility of a mosaic disease should be kept in mind in the diag- nostic evaluation of patients with asymmetrical growth disturbances, focal neuronal migration disturbances, vascular malformations, and linear skin abnormalities. The demonstration of a postzygotic mutation often affords relief to the parents of an affected child, since this means that there is no increased risk for recurrence of the same disorder in future children. Correct classification is important, as molecular available for certain mosaic diseases, e.g., PIK3CA-related overgrowth spectrum (PROS) disorder.

Figure 1

Schematic representation of types of mosaicism. Each square represents an individual. The ellipses represent individual cells. White denotes normal alleles. Light blue denotes heterozygosity for a mutated allele; dark blue represents the occurrence of a second mutation event in an individual with a heterozygous mutation and an autosomal-dominant disorder (modified from [7]).

Figure 2:

Mosaic RASopathy due to a mosaic KRAS mutation in a 21-year-old woman with linear hyperpigmentation and sebaceous nevi primarily on the left side of the body. The patient also exhibited a smaller left leg, scoliosis, a hairless fatty tissue nevus involving the scalp (nevus psiloliparus), and fibrous dysplasia of the left femur (not shown). The mutation was detectable in DNA from affected scalp tissue, but not in blood DNA.

Figure 3

PI3K/AKT and RAS/RAF signaling pathways with main genes involved. Following binding of a growth factor to the corresponding receptor, for example,receptor tyrosine kinase (RTK), insulin growth factor 1 receptor (IGF-1R), both signal pathways are activated. There is also interaction (crosstalk) between several subsequently activated genes. The PI3K/AKT signaling pathway (left) results in increased cell division and angiogenesis. The PIK3CA gene encodes for a catalytic subunit (p110α) of phosphatidylinositol-3-kinase (PI3K). PIK3CA mutations (usually present in mosaic form) cause PIK3CA-related overgrowth spectrum (PROS). This includes megalencephaly capillary malformation (MCAP), hemimegalencephaly, fibroadipose overgrowth (FAO), and congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies (CLOVES). The proteinkinase AKT activates mammalian target of rapamycin (mTOR), leading to increased cell division and tissue growth. Mosaic mutations in the AKT1 gene are the cause of Proteus syndrome, while MTOR mutations are responsible for Smith–Kingsmore syndrome, as well as hemimegalencephaly and focal cortical dysplasia. Mutations in the above-mentioned genes are gain-of-function mutations. Antagonists of growth activation via the PI3K/AKT signaling cascade include PTEN (Cowden syndrome, macrocephaly/autism syndrome, Bannayan–Riley–Ruvalcaba syndrome), and tuberous sclerosis (TSC1/2); the loss of which also results in overgrowth due to loss-of-function mutations. These mutations are usually not present in mosaic form, but are instead constitutional mutations. The RAS/RAF signaling pathway (right) regulates the cell cycle, cell differentiation, and apoptosis. Mutations in the involved genes result in what are referred to as RASopathies (Noonan syndrome: PTPN11, SOS1, RAF1, KRAS, NRAS, SHOC2, CBL genes; Costello syndrome: HRAS gene; cardiofaciocutaneous (CFC) syndrome: BRAF, MAP2K1/2). Gain-of-function mutations are found in the above-mentioned genes. Neurofibromatosis type 1 (NF1) is a negative regulator of the RAS/RAF signaling pathway. As in syndromes associated with the PI3K/AKT signaling pathway, the phenotypic overlap is great (7, 15).

Figure 4

MCAP syndrome due to mosaic PIK3CA mutation in a 5-month-old boy. Facial phenotype with marked asymmetry and overgrowth of the left cheek as well as cMRI showing pronounced left hemimegalencephaly. MCAP, megalencephaly-capillary malformation-polymicrogyria; MRI, magnetic resonance imaging