Clinical and genetic characterization of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene
1 Department of Psychology, Catholic University of the Sacred Heart, Milan, Italy
2 Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA
3 DiSCAFF Department, University of Piemonte Orientale, Novara
4 Department of Paediatrics, Athens University, Greece
5 Medical Genetics Center, Korba, Cairo, Egypt
6 Department of Transfusion Medicine and Hematology, Ospedale Alessandro Manzoni, Lecco, Italy
7 Center of Transfusion Medicine, Cellular Therapy and CryoBiology, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
8 Department of Internal Medicine, Ospedale Alessandro Manzoni, Lecco, Italy
9 Department of Internal Medicine, Santa Corona Hospital, Pietra Ligure, Italy
10 Institute of Biochemistry and Clinical Biochemistry, Catholic University, Gemelli Hospital, Rome, Italy
Orphanet Journal of Rare Diseases 2010, 5:33 doi:10.1186/1750-1172-5-33Published: 1 December 2010
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive disorder characterized by nonbullous congenital ichthyosiform erythroderma (NCIE) and an intracellular accumulation of triacylglycerol (TG) droplets in most tissues. The clinical phenotype involves multiple organs and systems, including liver, eyes, ears, skeletal muscle and central nervous system (CNS). Mutations in ABHD5/CGI58 gene are associated with CDS.
Eight CDS patients belonging to six different families from Mediterranean countries were enrolled for genetic study. Molecular analysis of the ABHD5 gene included the sequencing of the 7 coding exons and of the putative 5' regulatory regions, as well as reverse transcript-polymerase chain reaction analysis and sequencing of normal and aberrant ABHD5 cDNAs.
Five different mutations were identified, four of which were novel, including two splice-site mutations (c.47+1G>A and c.960+5G>A) and two large deletions (c.898_*320del and c.662-1330_773+46del). All the reported mutations are predicted to be pathogenic because they lead to an early stop codon or a frameshift producing a premature termination of translation. While nonsense, missense, frameshift and splice-site mutations have been identified in CDS patients, large genomic deletions have not previously been described.
These results emphasize the need for an efficient approach for genomic deletion screening to ensure an accurate molecular diagnosis of CDS. Moreover, in spite of intensive molecular screening, no mutations were identified in one patient with a confirmed clinical diagnosis of CDS, appointing to genetic heterogeneity of the syndrome.