No abstract

Among 58,000 amniocenteses completed, our laboratories found one case of true cytogenetic trisomy 2 mosaicism in a fetus with multiple abnormalities. In contrast, 11 fetuses phenotypically normal at birth were found to have true trisomy 2 mosaicism in their chorionic villus cells among the 10,500 fetuses tested by chorionic villus sampling (CVS). In our single abnormal case, amniocentesis performed at 19 weeks after finding an elevated maternal serum AFP found two independent cultures with trisomy 2 karyotypes in 8 of 25 and 7 of 31 amniocytes, respectively. Although oligohydramnios was noted by ultrasound, the mother elected to continue the pregnancy. At 26 weeks the fetus had intrauterine growth retardation (IUGR), hydronephrosis, and cardiac abnormalities. When delivered by Cesarean section at 30 weeks, the infant had multiple anomalies and developed necrotizing enterocolitis and severe cholestasis. At 5 months coronal magnetic resonance imaging (MRI) displayed delayed myelination and abnormal brain morphology. The patient also exhibited significant growth failure and developmental delay. Although chromosomes were normal in blood, skin fibroblasts, and ascites fluid cells, 4 of 100 hepatic biopsy fibroblasts were 47,XY,+2. Molecular analysis excluded uniparental disomy (UPD) of chromosome 2 in the 46,XY cell line. This and other reports of rare phenotypically abnormal trisomy 2 mosaic fetuses identified by karyotyping amniocytes emphasizes the substantially higher fetal risk of abnormal development than when trisomy 2 is found only in chorionic villus cells.

The recessive hemochromatosis gene is both linked to the HLA region on chromosome 6 and nonrandomly associated with certain HLA alleles. The use of linked HLA markers to trace known hemochromatosis genes within a family is well known, but using the population associations to detect unsuspected disease genes has not been fully appreciated. Thus, while HLA typing has been utilized to detect asymptomatic affected siblings, it has not been applied to other relatives. We propose a method in which Bayes' rule is used to calculate the probability that designated HLA marker haplotypes, brought into the family by spouses, have attendant hemochromatosis genes. The A3, B14 and A3, B7 haplotypes are such high risk markers. When these haplotypes are inherited from the unaffected parent, the offspring of an individual with hemochromatosis is at marked increased risk for the disease. When A3 and B14 are absent from the HLA marker haplotype, however, the risk of having a hemochromatosis gene is less than that for the general population. This approach should be helpful in identifying family members at a higher risk for developing the disease and who may then undergo appropriate periodic screening.

Based on a two‐locus, double recessive model, we derive formulas for the risks that relatives of individuals with gluten‐sensitive enteropathy (GSE) will also develop the disease. The calculations take advantage of: (i) the linkage between the HLA locus and one of the two proposed GSE loci, and (ii) the preferential association of the HLA‐DR3 and DR7 alleles with the GSE disease allele that occupies the HLA‐linked locus. We use Bayes' rule to quantitate the strength of the association between the GSE disease allele and the HLA marker allele. This method predicts that siblings of the proband have an overall 10% risk for GSE, which is consistent with observed family data. This predicted risk rises to 30% when siblings are HLA‐identical to the proband (also consistent with observed data) or when the sibling has the DR3 allele in the HLA haplotypes not shared with the proband. In those populations where DR7 also is associated with GSE, siblings of probands have a 10% predicted risk for GSE when only one HLA haplotype is shared with the proband and DR7 is included in the unshared haplotype. Other DR alleles are associated with much lower disease risks. By separating individuals into high and low risk groups, HLA typing identifies those individuals who would benefit from further diagnostic procedures. This general strategy should be applicable to other multilocus, marker‐associated diseases.