Doyne's Phenotype in the Absence of the Arg345trp Mutation of the Efemp1 Gene

Abstract

Abstract: : Background: The Arg345Trp mutation in the EFEMP1 gene was identified as the cause of the autosomal dominant macular diseases Doyne Honeycomb Retinal Dystrophy (DHRD) and Malattia Leventinese (ML). Both diseases exhibit pathognomonic phenotypes and present with drusen between the 2nd and 4th decade. The Arg345Trp mutation is reported to be present in all individuals with DHRD and ML phenotypes. We report a case of classic DHRD phenotype without this mutation. Purpose: Analysis of the EFEMP1 gene in a family with early onset drusen. Methods: Members of a large sibship of Spanish origin were noted to have early onset asymptomatic drusen, one of whom had classic DHRD phenotype.We examined 10 siblings, their mother and some of their children. Dilated fundus photographs and blood samples were taken. Dideoxysequencing was performed on the DNA from all samples looking for the presence of the Arg345Trp mutation in the EFEMP1 gene. Results: 3 siblings and a niece had early onset drusen: a 45 year old female had bilateral asymptomatic drusen typical of Doyne Honeycomb Retinal Dystrophy (juxtapapillary drusen and confluent drusen in the macula region); a 35 year old male had bilateral soft macular drusen; a 37 year old male had significant amounts of large soft drusen bilaterally and a 17 year old niece (daughter of an unaffected female sibling) had occassional hard drusen. Dideoxysequencing of all the family did not reveal the base pair change responsible for the Arg345Trp mutation, including the female sibling who presented with classic DHRD appearance. Conclusions: Previous investigations of the EFEMP1 gene in DHRD/ML have found that the Arg345Trp mutation is present in all individuals exhibiting these phenotypes from around the world including the UK, Europe, Canada, USA, and Australia. It has also been suggested that a common founder allele is responsible for this mutation since all individuals share a common Swiss haplotype. The absence of the Arg345Trp mutation in the 45 year old female sibling of Spanish origin suggests for the first time that another mutation may be responsible for a DHRD phenotype. In addition, this unusual sibship contains 3 siblings and a niece each of whom present with a different form of early onset drusen. Such a finding has not been described before in families with DHRD. The classic DHRD phenotype without the Arg345Trp mutation within this family of variable macular phenotypes indicates the possible involvement of least one other gene/mutation in dominant drusen. Dideoxysequencing of the 10 coding exons and and 2 non-coding exons of the EFEMP1 gene in the index case is currently being performed.

Keywords: retinal degenerations: hereditary • genetics • mutations