Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

Abstract

Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy.

Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region.

Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients.

Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

Figure 1

High-resolution oligonucleotide array mapping of 15q13-q13.3 rearrangements (chr 15:25.7–31.4 Mb, Hg 18). Patients 1–16 had a deletion of BP4-BP5, patients 17–18 a deletion of BP3-BP5, patient 19 a deletion of BP3-BP4, patients 20–22 a duplication of BP4-BP5 and patient 23 a duplication of BP3-BP5.

Figure 2

Pedigrees of families in which siblings of the proband were tested. Shaded = mental retardation. Black dot = aberration carrier. A. Pedigree patient 2. The mother carried the same BP4-BP5 15q13.3 deletion as identified in the proband, who attends a regular primary school, with learning problems. The brother also had learning problems at primary school, however normal chromosomes. B. Pedigree patient 3. Both sisters (II-I and II-IV) carried the same BP4-BP5 15q13.3 deletion as identified in the mild mentally retarded proband and her healthy father. The deletion was not found in the healthy mother and brother (II-III). Both sisters had had learning problems for which they attended a period of special schooling, however both had continued regular schooling. C. Pedigree patient 4. Except for female II-III, all sibs carried the same BP4-BP5 15q13.3 deletion as identified in the mentally retarded proband and his healthy mother. Female II-I and male II-V both had had learning problems in childhood but both showed normal adaptive skills in adulthood. The remaining siblings (II-II, II-III and II-VI) never had had learning problems and finished normal primary and secondary school. D. Pedigree patient 12. Both brothers had a mild developmental delay and both carried the BP4-BP5 15q13.3 deletion. The mother was not formally assessed but she appeared to have a borderline level of intelligence. E. Pedigree patient 18. Father and daughter both have a BP3-BP4 deletion. The same deletion was also identified in her oldest brother and paternal uncle who both had had normal development. Her mentally retarded brother was also tested, but did not have the deletion.

Figure 3. Probands with a deletion comprising BP4-BP5

Photographs of probands with a deletion of BP4-BP5 from left to right: A. patient 1 at 26 years. B. patient 2 at 5 years and 6 months. C. patient 3 at 14 years. D. patient 4 at 40 years. E. Patient 8 at 1 year and 6 months. F. Patient 9 at the age of 2 years and 8 months. G. Patient 11 at 4 years and 9 months. H. Patient 13 at 11 years. I. patient 15 at 3.5 years of age. In addition, one patient (J.) with a deletion of BP3-BP5 at 15q13.1q13.3: patient 17 at 17 years. No recognizable facial phenotype could be established based upon the facial and further clinical appearance.