Molecular investigations on chromosome 21 in relation to Down syndrome and familial congenital hypothyroidism

Sammanfattning: Chromosomal abnormalities as well as mutations in single genes are genetic changes that can cause syndromes or inherited diseases. Down syndrome (DS), usually a consequence of trisomy 21, is a gene dosage disorder caused by an extra copy of genes on chromosome 21, but the mechanisms whereby specific genes contribute to the clinical features of DS are not known. This thesis presents molecular investigations undertaken to contribute to the identification of the chromosomal segments and genes involved in the pathogenesis of DS. In addition, candidate genes for familial autosomal recessive congenital hypothyroidism (CH) have been investigated.A woman with a phenotype of DS, but apparently normal chromosomes, was found to have no part of chromosome 2 1 in three copies. Autosomal recessive inheritance of the DS phenotype is suggested, based on the family history. If this is so, this is the first time that au autosomal recessive disorder is known to have resulted in a phenotype indistinguishable from DS.Partial trisomy of most of chromosome 21 and partial trisomy 7p was found in a boy without a DS phenotype but with mild facial dysmorphism and severe psychomotor retardation. The DS critical region on 21q22.2 was, however, not found in three copies, thereby confirming the importance of this region for the development of DS features.A deletion of chromosome 21 was found in a girl with mild mental retardation and CH. Although large, the deletion did not extend into the DS critical region on 21q22.2. These findings show that large proximal deletions of 21q when not involving the DS critical region can result in only mild mental impairment. The presence of CH in this girl indicates that genes located on proximal 21q could possibly be involved in the pathogenesis of CH.CH is a heterogeneous disorder affecting 1/3000-4000. Of these, some 10-20% are familial cases. By genetic linkage analysis in 22 families with a presumably autosomal recessive CH, chromosome 21 was excluded from containing any major disease-causing gene. Furthermore, linkage to the thyrotropin receptor was excluded by using markers identified by radiation hybrid mapping. Linkage to the thyroglobulin (TG) locus was found in 40% of the families, however, thereby confirming genetic heterogeneity and suggesting that defects in the TG gene is a major cause of familial CH.