Phenotypes of Patients with “Simple” Mendelian Disorders Are Complex Traits: Thresholds, Modifiers, and Systems Dynamics

Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus–Merzbacher-like disease

“…Different genotypes -homozygous P128frameshift, M283T, G233S, or L278frameshift mutations, compound heterozygotes for P87S/P327frameshift or Y269D/ R237stop mutations -cause the same phenotype, including alleles that would be predicted to disrupt the protein (P128frameshift, R237stop, and L278frameshift, P327frameshift), as well as ones that may not (P87S, G233S, Y269D, and M283T). Although the similar phenotypes caused by different mutations implies all these mutations cause loss-of-function, the rarity of PMLD, the finding that dominant mutations of other connexin genes cause disease in a cell autonomous manner (White and Paul 1999), and examples of monogenic recessive disorders whose phenotype is altered by other genes (Scriver and Waters 1999;Dipple and McCabe 2000), leave this issue unsettled.…”

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

“…Previous reviews have proposed several reasons for the existence of complexities in singlegene disorders such as GKD [3,[14][15][16], one of which is the role of systems dynamics, including flux through other metabolic pathways, in imparting a phenotype that is not easily deduced from the genotype. Further, the significance of direct measurement of metabolic flux in understanding IEM has been pointed out recently [17].…”

Molecular analysis of PCCB gene in Korean patients with propionic acidemia

“…In general, the phenotypes of ''simple'' Mendelian disorders are complex traits. Dipple et al [22] described that for most genetic disorders, they were unable to accurately predict phenotype from genotype for any individual. They proposed that the absence of absolute genotype-phenotype correlations is due to protein activity threshold, modifier genes, and systems dynamics.…”