L. Leigh Field

CLOSE GENETIC LINKAGE BETWEEN DIABETES MELLITUS AND KIDD BLOOD GROUP

27 polymorphic genetic markers were analysed for possible linkage with insulin-dependent diabetes mellitus (IDDM). The data set contained 71 families with at least one affected member each. Under three different genetic models for IDDM, evidence was found for linkage between the disease and two distinct sets of marker loci: three markers on chromosome 6 (HLA, properdin factor B, and glyoxalase-1), and the Kidd blood group locus. The families apparently do not fall into two groups, one exhibiting linkage to the HLA complex and the other to the Kidd locus. Thus, two distinct disease-susceptibility loci may be involved in the inheritance of IDDM.

Linkage analysis of five pedigrees affected with typical autosomal dominant retinitis pigmentosa.

Five pedigrees (including an expanded version of a previously reported pedigree) exhibited typical autosomal dominant retinitis pigmentosa were analysed for linkage of RP to 29 genetic markers. No significant lod scores resulted. The largest lod score is +1.51 and suggests linkage between RP and Rh blood group at an estimated recombination fraction of 20% in males and 40% in females. Further studies are needed to confirm or refute this suggested linkage.

Transforming growth factor alpha: a modifying locus for nonsyndromic cleft lip with or without cleft palate?

Most (but not all) studies have found weak but significant association between restriction fragment length polymorphisms at the transforming growth factor alpha (TGFA) locus on chromosome 2p13 and nonsyndromic cleft lip with or without cleft palate (CL±P). However, all attempts to demonstrate genetic linkage between TGFA and CL±P in families have produced consistently negative lod scores which provide evidence against linkage. We typed a 3-allele single-strand conformation polymorphism at TGFA in 14 extended families with multiple CL±P members from West Bengal, India. No significant TGFA differences were observed between the entire sample of 34 affected people and a sample of 38 unaffected people unrelated to each other (p = 0.39). However, affected individuals with CL only showed significant differences from unaffected individuals (p = 0.008). More interestingly, the CL only and CL+P groups of individuals differed strongly from each other in their TGFA frequencies (p = 0.0002). Using an autosomal dominant model with reduced penetrance for the inheritance of a major CL±P locus (suggested by our prior segregation analyses), a non-significant maxium lod score of 0.13 at a recombination frequency of 20% was obtained. We suggest that the TGFA locus only modifies expression (severity) of the CL±P trait, which is controlled by a major (necessary) locus elsewhere; this could explain the difficulty in obtaining positive linkage results.

Possible Assignment of a Dominant Retinitis pigmentosa Gene to Chromosome 1

A genetic linkage study, performed on a large family with autosomal dominant retinitis pigmentosa (RP), demonstrated that the RP gene may be linked to the Rh locus, known to be on the short arm of human chromosome 1. Linkage studies on RP along with other studies, can help to more accurately classify these disease entities. Localizing the RP gene locus has the potential for allowing the early diagnosis of individuals at risk.

Hereditary multiple exostoses. Report of a family.

In a family with hereditary multiple exostoses (diaphyseal aclasis), six generations are known to have been affected. Thirty-three of 85 family members have had the disorder. This condition affects the long bones, pelvis, scapulae, and ribs, and the exostoses continue to enlarge until epiphyseal fusion occurs. Associated deformities, including short stature and malformations of the wrist and ankle, were found in 72%. Fifty percent of affected individuals were moderately or severely handicapped; women and men were affected with equal severity. Exostoses were usually noted by two years and always by five years of age. Hereditary multiple exostoses is inherited as an autosomal dominant condition and is inherited as an autosomal dominant condition and in this familial study the gene showed 93% penetrance. Only one individual appeared clinically normal but nevertheless transmitted the gene to offspring. Red cell antigens, enzymes, and serum enzymes were studied, but none were positive for linkage to the gene for this disease. The frequency of sarcomatous change varies between 3% and 25% in reports in the literature, but no cases occurred in six generations of this family.

Chromosome 17: Gene Mapping Studies of Cleft Lip With or Without Cleft Palate in Chinese Families

OBJECTIVEnInvolvement of loci on chromosome 17, including retinoic acid receptor alpha (RARA) in nonsyndromic oral clefts has been reported in Caucasian populations, although never investigated in Asian populations. The purpose of the present study was to investigate several loci on chromosome 17, including RARA, in Chinese families.nnnPARTICIPANTSnThirty-six multiplex families (310 individuals), ascertained through nonsyndromic cleft lip with or without cleft palate surgical probands from hospitals in Shanghai, China, participated in the present study. There were 23 families whose probands had cleft lip and cleft palate (CLP) and 13 with cleft lip alone (CL).nnnRESULTSnSeventeen markers, spanning chromosome 17 and about 10 cM apart were assessed. Logarithm of odds ratio (LOD) scores (two point and multipoint), model-free linkage analyses, and allelic association tests (transmission/disequilibrium, Fishers exact tests, and chi-square) were performed on the total family sample, families with CLP probands (CLP subgroup), and families with CL probands (CL subgroup). LOD scores from the two-point analyses were inconclusive. Multipoint analyses rejected linkage except for a few regions in the CL subgroup. However, positive results were found using the model-free linkage and association methods (p < .05). The markers with positive results varied across the CL and CLP subgroups. However, the RARA region and loci nearby yielded consistently positive results.nnnCONCLUSIONnGenetic variation within the RARA locus or nearby appears to be involved in the pathogenesis of nonsyndromic oral clefts in this population. Furthermore, based on the differing pattern of results in the CL versus CLP subgroups, it appears that the formation of CL and CLP is because of either differing alleles at the same genetic locus or different but related (and/or linked) genes that modify the severity and expression of oral clefting.

Genetic linkage analysis in a high-risk cancer family: HLA and 24 other markers

Family Pi is a high-risk cancer family in which more than 40% of the members of two generations have had cancer, mostly breast, endometrial, and gastrointestinal. An analysis of over 30 polymorphic genetic markers for possible genetic linkage to a gene increasing susceptibility to cancer revealed positive LOD scores to markers within or near the major histocompatibility complex [HLA-A,B (0.639), properdin B (Bf) (0.162), glyoxylase-1 (GLO-1) (0.166)] as well as to acid phosphatas (0.566) and MNSs (0.449). While no LOD score is statistically significant in the linkage analyses of this family alone, the data are compatible with the hypothesis that a cancer-susceptibility gene(s) (CSG) may be located on chromosome 6p, 2p, or 4q. Analyses of additional families with a similar cancer syndrome are warranted to resolve this ambiquity.

Dr. Richard Spielman

Dr. Richard Spielman, the Butterworth Professor of Genetics in the School of Medicine of the University of Pennsylvania, passed away on April 25. He was 63 years old. Dr. Spielman, who joined the Penn faculty in 1974, was a world-renowned expert in the fields of human genetics and genomics. His seminal work with Dr. Warren Ewens of the Biology Department, on family-based genetic associations studies, the Transmission Disequilibrium Test (TDT), has been cited more than 2,400 times to date and has had a major impact on the field. His more recent studies with Dr. Vivian Cheung of the Children’s Hospital of Philadelphia, were the first to investigate the genetics of natural variation of gene expression in humans. Dr. Spielman was committed to teaching both graduate students and medical students. He was the founding chair of the Genomics and Computational Biology Graduate Group, which has become the model for similar programs elsewhere. He also served on multiple academic committees at the School of Medicine over the years. Dr. Spielman received his AB from Harvard College cum laude in 1967, and both master’s and PhD degrees in human genetics from the University of Michigan. After completing his postdoctoral training at Michigan in 1974, he joined what was then the Department of Human Genetics at Penn. He served on the editorial boards of several prominent journals, including the Journal of Clinical Investigation, the American Journal of Human Genetics, and Genome Research. He was a member of multiple NIH study sections, and served on the program committee of the American Society of Human Genetics. Dr. Spielman is survived by his wife, Vivian; and daughter, Anita.

Glutamate pyruvate transaminase null allele (GPT0) in the Navajo

During genetic linkage studies of retinitis pigmentosa in a Navajo Amerindian family, an apparent null allele of erythrocyte GPT (GPT0) was observed in a man and 2 of his daughters. This is the fourth description of a (GPT0) allele, the first outside of Europe and the first in the Navajo.