Cartilage-hair hypoplasia gene assigned to chromosome 9 by linkage analysis.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive skeletal dysplasia of unknown pathogenesis leading to short-limbed stature. Associated features include hypoplasia of hair, abnormal cellular immunity, deficient erythrogenesis, increased risk of malignancies, Hirschsprung disease, and Diamond-Blackfan type hypoplastic anaemia. We mapped the CHH gene by linkage analysis with 5 markers to chromosome 9. Multipoint linkage analysis gives a lod score of 9.94 for a location between D9S43 and D9S50. Based on strong linkage disequilibrium the closest marker, D9S50, is likely to be less than 1 cM from the gene. No heterogeneity was observed in 14 Finnish families, nor was there evidence of reduced penetrance. These results provide a starting point for the eventual cloning and characterization of the CHH gene.

Uniparental disomy in cartilage-hair hypoplasia.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder that presents with pleiotropic manifestations including impaired skeletal growth and cellular immunity. It is most prevalent among two founder populations, the Old Order Amish in the USA and the Finns. The gene has been localized to 9p13 by linkage analysis and linkage disequilibrium mapping. A statistically significant deficiency of affected members resulting in a lower than expected segregation ratio has been reported in the Amish, but was not found in a previous study in Finnish CHH families. Reduced penetrance was the mechanism suggested in the Amish, but could not be verified by haplotype analyses performed after the assignment of the CHH gene. Here we have carried out segregation analysis of 101 Finnish CHH families, but again, evidence of a significant deficiency of affected members was not found. Nevertheless, among 54 uniplex families, 2 patients with CHH and uniparental disomy (UPD) for chromosome 9 were discovered. UPD might contribute to low segregation ratios by increasing the number of families with only 1 affected individual. These observations show that UPD may occur in an unexpectedly high number of the patients and should be taken into account in the genetic counselling and prenatal diagnostics of CHH families.

Early prenatal diagnosis of cartilage-hair hypoplasia (CHH) with polymorphic DNA markers.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder resulting in short stature and hypoplasia of hair. Associated features include impaired T-cell-mediated immunity, deficient erythropoiesis, gastrointestinal dysfunction, and an increased risk of malignancies. As the condition may, in some cases, be severe or even fatal during childhood, families with a previous history of CHH may wish to have prenatal diagnosis. We have previously assigned the gene for CHH to the proximal 9p by linkage analysis using several polymorphic DNA markers. Here we report the prenatal testing for CHH in three Finnish and one Australian family using three DNA markers closely linked to the CHH gene. In three cases a fetus unaffected with CHH was predicted at the probability level of more than 94 per cent. In one case, an affected fetus was predicted. The results were in concordance with ultrasonography performed for all fetuses. The three children born to date were unaffected as predicted. The DNA marker-based analysis thus provides a useful method for early prenatal testing for CHH.

High-resolution linkage-disequilibrium mapping of the cartilage-hair hypoplasia gene.

We recently assigned the gene for an autosomal recessive skeletal dysplasia, cartilage-hair hypoplasia (CHH), to 9p21-p13 in Finnish and Amish families. An association was observed between CHH and alleles at D9S163 in both family series, suggesting that these loci are in linkage disequilibrium and close to each other. Here we extended these studies by exploiting the linkage-disequilibrium information that can be obtained from families with a single affected child, and we studied 66 Finnish CHH families with seven microsatellite markers. The analysis based on the Luria and Delbrück (1943) method and adapted to the study of human founder populations suggests that the distance between CHH and D9S163 is approximately 0.3 cM. An eight-point linkage analysis modified to take advantage of all possible information in 15 Finnish and 17 Amish families was capable of narrowing the likely location of CHH to within an interval of 1.7 cM on a male map. The peak lod score of 54.92 was attained 0.03 and 0.1 cM proximal to D9S163 on the male and female maps, respectively. These results confirm the power of genetic resolution, that lies in the study of linkage disequilibrium in well-defined founder populations with one major ancestral disease mutation.

High-resolution genetic mapping of the cartilage-hair hypoplasia (CHH) gene in Amish and Finnish families.

We recently assigned the gene for cartilage-hair hypoplasia (CHH) to chromosome 9 in Finnish families. Here we have extended and refined our previous linkage analyses by studying 22 Amish and 15 Finnish CHH families and by testing additional markers. The CHH gene maps to 9p in both series and shows no evidence of heterogeneity either within or between the populations. CHH is very closely linked to marker locus D9S163, with no recombinations observed and a combined maximum multipoint lod score of 26.30 for a location at D9S163. Although the odds against a location of the CHH gene between two more distal marker loci, D9S52 and D9S165, are only 48:1, the evidence provided by an observed recombination between the CHH locus and D9S165 and haplotype data at D9S165 and D9S163 in the Amish families allow this interval to be excluded as the location of CHH. We observed strong allelic association between CHH and D9S163 in both Amish and Finnish families, confirming the likely location of the CHH gene very close to this marker. Haplotype analysis of D9S163 and D9S165 in the Amish families suggests that only one mutation accounts for most CHH cases among them, as was expected and as is the case in Finland. Our data do not support the previously suggested hypothesis of a reduced penetrance as an explanation for the deficiency of affected children in the Amish families. We conclude that CHH is a single disease entity in the Amish and Finnish families and that the CHH gene is very close to D9S163 in 9p21-p13.

Genetic homogeneity of cartilage-hair hypoplasia.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by short stature and hypoplasia of the hair. Associated pleiotropic features include deficient erythrogenesis, impaired T-cell mediated immunity, Hirschsprung's disease, and an increased risk of malignancies. CHH is most prevalent among the Old Order Amish in the United States and among the Finns, but sporadic families have been described among many other populations. We have previously mapped the gene for CHH to the short arm of chromosome 9 in Finnish and Amish families. The CHH locus resides close to D9S163 within an interval of 1.5 cM flanked by D9S165 and D9S50. In order to investigate the genetic homogeneity of CHH in various populations, we studied nine families with no genealogical connections to either Amish or Finns. No recombinants were detected between the CHH gene and any of the three closest marker loci studied, suggesting that CHH in these families results from mutation(s) at the same locus as in the Amish and Finnish families.