Most cases of cri du chat syndrome are sporadic; only 10% to 15% of the patients are the offspring of translocation carriers. The breakpoints and extent of the deleted segment of chromosome 5p is highly variable among different patients, but the critical region missing in all patients with the phenotype has been identified as band 5p15. Many of the clinical findings have been attributed to haploinsufficiency for a gene or genes within specific regions; the degree of intellectual impairment usually correlates with the size of the deletion, although genomic studies suggest that haploinsufficiency for particular regions within 5p14-p15 may contribute disproportionately to severe intellectual disability (see Fig. 6-6).
Although many large deletions can be appreciated by routine karyotyping, detection of other idiopathic deletions requires more detailed analysis by microarrays; this is particularly true for abnormalities involving subtelomeric bands of many chromosomes, which can be difficult to visualize well by routine chromosome banding. For example, one of the most common idiopathic abnormalities, the chromosome 1p36 deletion syndrome, has a population incidence of 1 in 5000 and involves a wide range of different breakpoints, all within the terminal 10 Mb of chromosome 1p. Approximately 95% of cases are de novo, and many (e.g., the case illustrated in Fig. 6-6) are not detectable by routine chromosome analysis.
Detailed genomic analysis of various autosomal deletion syndromes underscores the idiopathic nature of these abnormalities. Typically, and in contrast to the genomic disorders presented in Table 6-3, the breakpoints are highly variable and reflect a range of different mechanisms, including terminal deletion of the chromosome arm with telomere healing, interstitial deletion of a subtelomeric segment, or recombination between copies of repetitive elements, such as Alu or L1 elements (see Chapter 2).