Gaucher disease: Variability in phenotype among siblings

Although many mutations of the GBA gene have been described as causing Gaucher disease, there is generally poor correlation between genotype and phenotype, with a few exceptions. However, most previous reports of genotype–phenotype correlation have involved unrelated individuals, who, even if they share the same mutations, are not as genetically close as siblings. We havestudied 24 groups (mostly pairs) of Canadian siblings with type I (non‐neuronopathic) Gaucher disease. Since most Canadian provinces have adopted similar criteria for instituting enzyme replacement therapy (ERT), the age at which ERT is begun can serve as a rough surrogate for disease severity, and concordance (or lack of concordance) can be examined between siblings. In 14 of the 24 sibling families, there was sibling concordance: either both siblings were not on ERT, or both were on ERT and had begun at roughly the same age. In these families, there was also much similarity in the clinical features of the disease between siblings. In the other 10 families there was lack of sibling concordance, with only one sibling receiving ERT (or, in one family with three affected siblings, two of three on ERT). In these families, there was also much discrepancy between siblings in the clinical features (as might be expected in a setting where the guidelines for starting ERT are relatively uniform). Possible reasons for thediscordances between siblings include macro‐environmental and micro‐environmental differences. The latter may include micro‐environments at the level of the cell (e.g. lysosomal pH, alternative substrates) or at the level of the chromosome (contiguous genes, modifier genes, neutral polymorphisms in GBA).