The genetics of congenital isolated ptosis

Abstract

The first part of this study focused on a large, previously unreported pedigree with dominantly inherited bilateral congenital isolated ptosis.  The pedigree was assessed clinically and tested for linkage to the only previously known isolated ptosis locus, on chromosome 1p32-1p34.1 (Engle et al., 1997a).  Strong evidence was obtained that the phenotype was not linked to the markers tested on chromosome 1p.  The inheritance pattern observed in the pedigree suggested that the condition was X linked dominant.  Firm evidence for linkage to markers on the X chromosome was demonstrated providing a cumulative LOD score of 5.89, and the critical region was defined as Xq24-Xq27.1 by meiotic recombinations.  Interestingly, males and females were equally affected in this pedigree so it is an example of X linked truly dominant inheritance, which is extremely rare.  These observations define a previously unreported condition, namely X linked dominant congenital isolated ptosis.

The second part of the study focused on a patient with bilateral congenital isolated ptosis and a de novo balanced translocation, 46,XY,t(1;8)(p34.3-q21.12).  This translocation was of particular interest because one of the translocation breakpoints was in the same cytogenetic region of chromosome 1p as the only previously reported locus associated with congenital isolated ptosis.  By cloning the breakpoints of the translocation I hoped to isolate the gene responsible for the ptosis.  Both breakpoints of the translocation were identified using molecular cytogenetic techniques.  The chromosomes involved in the translocation were flow sorted to allow sequencing of the junction fragments.  The breakpoint in chromosome 1 was not found to interrupt a gene and furthermore was shown to be a considerable distance away from the previously described locus, making it unlikely that this breakpoint was relevant to the patient’s ptosis.  However, the breakpoint in 8q21.12 was found to interrupt a gene, which is almost identical to a mouse gene encoding a zinc finger homeodomain transcription factor.  This is expressed in brain and muscle and is therefore a candidate gene for congenital isolated ptosis.

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