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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2597-2602
PERSPECTIVE
Discrepancies between genotype and phenotype in hematology:
an important frontier
Ernest Beutler
From the Department of Molecular and Experimental
Medicine, The Scripps Research Institute, La Jolla, CA.
An African American male infant with sickle cell disease has a
devastating stroke; an African American soldier is surprised when he is
informed that he has sickle cell disease. They are both homozygous for
the same mutation. An Ashkenazi Jewish woman with Gaucher disease has a
huge spleen and severe thrombocytopenia; her older brother, homozygous
for the same 1226G glucocerebrosidase mutation, is found on routine
examination to have a barely palpable spleen tip. The fact that
clinical manifestations of genetic diseases can vary widely among
patients has been recognized for many decades. In the past, however, it
could often be attributed to the pleomorphic nature of mutations of the
same gene: the patient with severe disease, it was averred, must have a
different mutation than the one with mild disease. Even before a
precise definition of mutations could be achieved at the DNA level,
such an explanation did not serve to clarify the differences that
existed between siblings with the same autosomal recessive disease.
Such siblings must surely be carrying the same 2 disease-producing
alleles. With the advent of sequence analysis of genes, the great
extent of phenotype variation in patients with the same genotype has
come to be more fully appreciated, but understanding of why it occurs continues to be meager. It is the purpose of this review to explore some of the variations in phenotype seen by hematologists in patients with identical mutations, to indicate where some progress has been
made, and to suggest how understanding in this important area may be expanded.
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