Karyotype-phenotype correlations in autosomal chromosomal aberrations.

Karyotype phenotype correlation studies on the basis of clinical findings released the following consistent results. 1. Monosomy for an autosomal segment causes more and more severe alterations to the phenotype and restricts survival more than does trisomy for the same segment. The clinical pictures of monosomy versus trisomy for the same segment do not go into an opposite direction (the type-contratype approach). 2. For trisomy versus tetrasomy of a given autosomal segment, clinical pictures are principally similar, but tetrasomy leads to more severe alterations of the phenotype and to more restricted survival. Therefore, tetrasomy seems to allow for survival in only few segments, and often only in mosaic state. 3. Mapping of specific traits to the aneuploid segment of a specific chromosome region is partially successful. 3.1. For certain patterns of minor anomalies, the aneuploid segment can be narrowed down to a very short region. Both in trisomy and monosomy, these regions tend to be closer to the telomere. 3.2. Deletion mapping has allowed the mapping of a number of autosomal dominant gene mutations to small segments of a chromosome and hereby often gave the first hint towards the fine localization and cloning of these genes. Both deletion and duplication mapping have also shown associations of some congenital anomalies, mostly rarer malformations, to the aneuploid state of a small chromosome segment. The approach, however, has not been successful for most of the malformations frequent in many autosomal chromosome aberrations. 4. Comparison of congenital anomalies in monozygotic twins with autosomal chromosome aberrations revealed the following. 4.1. Monozygotic twins are highly concordant for patterns or minor anomalies. 4.2. Monozygotic twins tend to be concordant for rare congenital defects and malformations, but they are predominantly discordant for more common major malformations; the more undergrown twin is usually more severely affected. The latter finding might be explained by differences in placental blood supply between the twins during early embryogenesis, either due to different placental nutrition in general or to differences in secondary mutations in the placentas allowing for a better embryonic blood supply during organogenesis. 5. The data are in accordance with a multifactorial model for frequent congenital malformations in which placental function is the modifying environmental influence besides the action of more than one gene in aneuploid state.