Abstract

Background Deletions of 11q23 are associated with mental retardation, craniofacial dysmorphism, microcephaly and short stature. We present a patient with similar clinical findings plus absence of thumbs, hypoplasia of radii and ulnae, additional vertebrae and ribs, retarded bone age and genital hypoplasia.

Methods Genomic DNA from the patient was screened for chromosomal imbalances by array-based comparative genomic hybridization. DNA sequence analyses and reporter gene assays were performed in order to identify candidate gene mutations.

Results The patient has an ~8 Mbp de novo deletion on the paternal chromosome 11, which includes the promyelocytic leukaemia zinc finger (PLZF) gene. The maternal PLZF allele harbours a recessive missense mutation (c.1849A>G), which leads to the substitution of a highly conserved methionine by valine (p.Met617Val) within a zinc finger motif. Taking into account specific alpha-helical propensities of Val and Met, this mutation is likely to destabilise the alpha-helix of the zinc finger that forms the contact with the DNA-duplex and thus to affect the biological function as shown by reporter gene assays.

Discussion The PLZF gene is one of five partners fused to the retinoic acid receptor alpha in acute promyelocytic leukaemia. We describe the first patient with a germline mutation of PLZF. Our findings as well as observations in Plzf-deficient mice demonstrate that PLZF is a key regulator of skeletal and male germline development. Furthermore, this case highlights the importance to search for a recessive mutation on the non-deleted chromosome in patients with a microdeletion and atypical clinical findings.