Pedigree studies

Hereditary deficiency of phosphoglycerate kinase (PGK) is associated with hereditary hemolytic anemia and often with central nervous system dysfunction and/or myopathy. The first case, reported by Kraus et al. (K24), is a heterozygous female, and the results are not so clear. The second family, reported by Valentine et al. (V3), is a large Chinese family, whose pedigree study indicates that PGK deficiency is compatible with X-linked inheritance. To date, 22 families have been reported (04, T25, Y3). Nine of these have manifested both symptoms five have shown only hemolysis seven have shown the central nervous system dysfunction and/or myopathy but without hemolysis and one case, PGK Munchen, is without clinical symptoms (F5). PGK II is an electrophoretic variant found in New Guinea populations (Y2). Red blood cell enzyme activity, specific activity, and the kinetic properties of this polymorphic variant are normal. 

Bolos, A. M., M. Dean, S. Lucas-Derse, M. Ramsburg, G. L. Brown, and D. Goldman. 1990. "Population and Pedigree Studies Reveal a Lack of Association Between the Dopamine D2 Receptor Gene and Alcoholism." founuit of the American Medical Association 264 3156-60. 

Human pedigree studies of families with Lesch-Nyhan syndrome (Seegmiller et al., 1976) showed that the HPRT gene was X-linked, and this was confirmed by analysis of human-mouse cell hybrids which had lost most of their human chromosomes (Ricciuiti and Ruddle, 1973). 

For the purpose of pedigree studies to identify sporadic cases of dominant diseases, the routine records in their linked form would provide information on family composition for whole populations and would serve as an aid in finding the cases. While the extent of the labor saved would be considerable, it is probable that substantial further work of conventional kinds would be needed where the coded diagnoses lacked the required specificity. This would be true also where it was decided to extend the family histories to include events of ill health not represented in the routine records for the region, e.g., because of the movements of people into and out of the area under study. 

Genetic transmission in nemaline myopathy is the subject of some uncertainty. A Japanese study of 50 pedigrees came to the conclusion that autosomal dominant with reduced penetrance was the most probable mode. However a Finnish study presented evidence for autosomal recessive transmission. There is no evidence that severe and mild forms are genetically distinct and several pedigrees contain members showing widely differing clinical severity. A candidate gene for autosomal dominant nemaline myopathy has been localized to chromosome Iq 21—23. 

Extensive linkage studies Large families with defined pedigrees are desirable. Dominant genes are easier to recognize than recessives. 

The observed CEPH population mean IC50 for both docetaxel and 5-fluorouracil was similar to IC50 values observed across the NCI60 panel of human tumor cell lines (http //dtp.nci.nih.gov) (17). In addition, docetaxel- and 5-fluorouracil-induced cell death is mediated by caspase-3 cleavage, similar to that observed in tumor cells (17). These data are encouraging for the use of CEPH pedigrees as a discovery tool. However, the ultimate proof of the value of the cell-based models will be the human validation of markers derived from this process. These studies he ahead and will help position cell-based models in their correct place in the drug development process. 

Figure 1. Pedigree pattern of the B family. Relationship of the proband (T.B.) with the clinical phenotype of homozygous familial hypercholesterolemia to her other relatives whom we studied is shown. Lipoprotein patterns were determined after ultracentrifugation using NIH outpoints (51). F indicates that fibroblast cell lines were established from skin biopsies. Males, H Females, O.

Association mapping is appropriate for monogenic and complex diseases, and may always be preferable to linkage analyses for late onset diseases where it is difficult to obtain nuclear families, rare diseases for which multiplex pedigrees may not be available, e.g., type-1 diabetes and multiple sclerosis in China, and infectious diseases. Study design can incorporate disease heterogeneity and interaction effects between loci (Sec. 7.2). 

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