DETECTION OF SUBTLE CHROMOSOMAL ABERRATIONS IN CHILDREN WITH UNDIAGNOSED ANOMALY SYNDROMES BY STRP ANALYSIS. • 471

Abstract

Duplication or deletion of segments of chromosomes is a well-known cause of multiple anomaly syndrome. Currently, these chromosomal aberrations are detected by microscopic visualization of Giemsa-banded chromosome spreads. This technique is widely and effectively used in clinical diagnosis. This technique has a theoretical limit of resolution of 2-5 Mb under ideal conditions and a higher practical limit that varies among and within laboratories. In addition, the technique requires significant analysis time by highly trained technicians and is relatively expensive. We have explored the practical and theoretical considerations for the strategy of detecting these aberrations by short tandem repeat polymorphisms. For the theoretical studies we have developed a computer software program called DECIDE (DEtecting Chromosomal Insertions and DEletions). We have used this program to model the sensitivity of a whole genome STRP scan for segmental aneusomy. By specifying parameters of marker number and distribution the sensitivity for detecting segmental aneusomy of varying sizes can be determined. We used this program to demonstrate that an STRP-based approach yields a sensitivity comparable to that of microscopic cytogenetics. In addition to this theoretical approach, we have initiated two pilot studies to test the implementation of this approach and determine the frequency of submicroscopic segmental aneusomy. The study entrance criteria include major or minor anomalies, negative family history, normal G-banded karyotype and absence of known syndromic diagnosis. Thirty-six children have been partially or completely analyzed by two approaches. The first is a subtelomeric scan (all 36 subjects) with high marker density and the second (a subset of the 36 subjects)is a genome-wide scan with lower density. Using the first approach we have found two definite abnormalities(22q duplication and 18q deletion) and three possible abnormalities. Using the second (whole genome) approach we have detected one definite abnormality (4q interstitial deletion). We conclude that an STRP-based strategy for the detection of segmental aneusomy is practical on a theoretical basis. In addition, our pilot studies demonstrate that the STRP-based technique can detect aberrations that are inapparent with microscopic techniques.