Lowell R. Weitkamp

Discovery of allelic variants of HOXA1 and HOXB1 : Genetic susceptibility to autism spectrum disorders

BACKGROUND Family studies have demonstrated that the autism spectrum disorders (ASDs) have a major genetic etiologic component, but expression and penetrance of the phenotype are variable. Mice with null mutations of Hoxa1 or Hoxb1, two genes critical to hindbrain development, have phenotypic features frequently observed in autism, but no naturally occurring variants of either gene have been identified in mammals. METHODS By sequencing regions of genomic DNA of patients with autism spectrum disorders, we detected a substitution variant at HOXA1 and an insertion variant at HOXB1, both in coding regions of the genes. Fifty-seven individuals ascertained for a diagnosis of an ASD, along with 166 of their relatives, were typed for these variants. Two non-ASD populations were typed, and the frequency of the newly identified alleles was determined in all groups. The genotypes of the ASD families were tested for conformation to Hardy-Weinberg proportions and Mendelian expectations for gene transmission. RESULTS The frequency of the variants was 10-25% in persons of European or African origin. In the ASD families, there was a significant deviation from the HOXA1 genotype ratios expected from Hardy-Weinberg proportions (P = 0.005). Among affected offspring, a significant deviation from Mendelian expectation in gene transmission (P = 0.011) was observed. No statistically significant effects were detected when the same analyses were applied to the HOXB1 locus, but there was evidence of an interaction between HOXA1, HOXB1, and gender in susceptibility to ASDs. CONCLUSIONS The results support a role for HOXA1 in susceptibility to autism, and add to the existing body of evidence implicating early brain stem injury in the etiology of ASDs.

Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin ☆: A clinical and genetic study

Alzheimers disease (AD) occurred in 37 individuals from two kindreds of Jewish ancestry with a mode of transmission suggesting an autosomal dominant genetic trait. Both kindreds originated from Byelorussia and spoke the Lithuanian dialect of Yiddish. In one of the two families one case of pathologically confirmed AD occurred with clinical and neuropathological signs of Parkinsons disease. In the other family one case of amyotrophic lateral sclerosis and one case of Downs syndrome occurred, both without clinical or pathological signs of AD. In the single kindred tested, a study of the chromosome 6 markers HLA, Bf and GLO failed to reveal a correlation between the transmission of AD and the segregation of these markers. The association of increased aneuploidy of peripheral blood chromosomes with AD was not confirmed in either of these families. Genetic differences between the familial and the sporadic form of AD are discussed.

Spinocerebellar ataxia in a large kindred Age at onset, reproduction, and genetic linkage studies

We studied a large kindred with autosomal dominant spinocerebellar ataxia (SCA) to assess reproductive performance, the impact of genetic counseling, and linkage relationships of the SCA locus. Reproduction was not lower in those with SCA than in unaffected sibs or first cousins. Genetic counseling reduced reproduction during the risk period for development of SCA. Given autosomal dominant transmission of a single gene, we found strong evidence that the locus for SCA in this kindred is linked to the HLA loci.

Linkage between the loci for the Lp(a) lipoprotein (LP) and plasminogen (PLG)

SummaryA locus, LP, that determines quantitative variation of Lp(a) lipoprotein phenotypes is linked to the plasminogen (PLG) locus (peak lod score =12.73). This linkage relationship assigns a locus with alleles that have an affect on risk for coronary artery disease to the long arm of chromosome 6.

Lean body mass in twins

A study of 49 pairs of monozygous (MZ) twins and 38 pairs of same-sexed dizygous (DZ) twins showed that lean body mass (LBM), as determined by potassium 40 counting, is under genetic influence. Intrapair variances for LBM are much smaller than those for body fat, which suggests that LBM has a higher degree of heritability. There is a correlation between the magnitude of intrapair LBM differences and intrapair weight differences for both sets of twins, showing that environment is also an important influence. The effect of weight variation on LBM variation is greater for thin people than for those with appreciable burdens of body fat, an observation previously made on individuals who undergo a nutrition-induced weight change.

Transferrin and HLA: Spontaneous Abortion, Neural Tube Defects, and Natural Selection

We report evidence that transferrin C3, a gene present in 9 to 10 per cent of whites, is associated with recurrent spontaneous abortion (P = 0.001) and that maternal transferrin genotype has an effect on the transmission ratio of the common transferrin genes (C1, C2, and C3) from heterozygous fathers to normal offspring (P less than 0.002). The effect of maternal genotype on paternal gene transmission is an unusual example of the operation of selection in the human reproductive process. This effect, together with the separate evidence for association of the transferrin C3 allele with spontaneous abortion, indicates that transferrin is a second marker (in addition to HLA) of genes important in reproduction. On the basis of comparison of the frequencies of transferrin (chromosome 3) and HLA (chromosome 6) mating types in 348 control couples and in 81 couples who had had a child with a neural tube defect, we hypothesize that some combinations of maternal and fetal genes on these two chromosomes may be associated with neural tube defects.

Confirmation of the relationship of HLA (chromosome 6) genes to depression and manic depression II. The Ontario follow-up and analysis of 117 kindreds

HLA typing was conducted on 577 family members of 86 families having at least two first‐degree family members with a lifetime history of major depression or bipolar disorder. The results were combined with a follow‐up study of 10 Newfoundland kindreds and with the data obtained from our previous studies, giving a total cohort of 117 families of diverse ethnic and geographic origin. There was increased sharing of HLA haplotypes, as compared with random expectation, over all possible pairwise comparisons both in the follow‐up studies (P < 0.025) and in the total data (P < 0.01). The increase in HLA haplotype sharing over random expectation was greater if comparisons within heavily loaded sibships (by prior convention, sibships with three or more affected siblings) were omitted from the analysis (P < 0.002). There was also non‐random transmission of HLA haplotypes in 50 families selected for a low‐load, unaffected parent (P < 0.005). Thus, we conclude that genes in the HLA region of chromosome 6 constitute one of the elements in the multifactorial etiology of affective disorder. This conclusion does not depend on any assumption concerning genetic heterogeneity or epistasis or on specific modes of transmission, penetrance values or linkage distances. In addition, the data suggest that chromosome 6 region genes may have a different effect in unipolar and bipolar illness.

High resolution analysis of hemoglobins: polyacrylamide isoelectric focusing.

Abstract For the analysis of hemoglobins, polyacrylamide isoelectric focusing has significant advantages. Unlike standard clinical methods, this method clearly separates hemoglobins F from A, and D from S. Compared to starch gel electrophoresis, this method provides higher resolution, greater reproducibility, readier quantification, higher sensitivity, and greater convenience. Hemoglobin A 2 quantitation is readily provided by gel scanning at two wavelengths.

GENETICS OF THE URINARY PEPSINOGEN ISOZYMES

ABSTRACT . Human urinary pepsinogen isozymes, Pg 2, Pg 3, Pg 4, and Pg 5, have been scored for their absence, presence as a weak band, or presence as an intense band in 652 family members. Pg 3 through Pg 5 were independently classified by the two authors with agreement on a specific category for for 87% of the individuals. Considering all four isozymes, there were, among the 94 black and 65 white unrelated people with distinct patterns, 18 different phenotypes. From the distribution of the intensities of the four bands in a given individual, it is apparent that control of the intensity of one isozyme is not unrelated to that of others. Segregation analysis for each isozyme separately, assuming an intense band is dominant to a weak band and the latter is dominant to absence, demonstrates familial clustering for each type of variant for each isozyme. For some variants there are no exceptions to dominant Mendelian inheritance, but for others the fit is less good. Preliminary data suggest a locus controlling Pg 5 intensity may be linked to the HL-A loci, but control of Pg 2 and 4 is apparently not closely linked to the HL-A region.

Tourette syndrome and HLA

Five kindreds with multiple individuals manifesting Tourette syndrome (TS) or related abnormal movements were evaluated for linkage between TS and HLA-A, B, C and DR antigens. Families were selected to have a constellation of affected individuals which gave the appearance of transmission of a major susceptibility gene. All kindreds had at least two clearly affected first or second degree relatives. Although developmental neurobehavioral disorders are candidates for showing a relationship to specific tissue antigens, we found no evidence for a close linkage between a gene locus determining susceptibility to TS and the HLA loci.