Chromosomal 17p13.3 microdeletion unmasking recessive Canavan disease mutation

Unmasking a recessive allele on one chromosome by a deletion on the other is a disease causing mechanism often invoked but rarely proven. We report on an Italian female patient with Canavan disease (OMIM# 271900) due to a missense mutation of the aspartoacylase (ASPA) gene and a 17p13.3 chromosomal microdeletion. In the case described herein, Canavan disease was suspected for relative macrocephaly and developmental delay. HPLC analysis of body fluids [1] revealed an increased N-acetylaspartic acid (NAA) in both plasma (16.3 μmol/l; not detected in normal controls) and urine (680 μmol/mmol creatinine; 1.65 ± 1.50 μmol/mmol creatinine in normal controls), thereby confirming the diagnosis of Canavan disease. ASPA sequencing identified an apparently homozygous mutation (c.G859A) resulting in the substitution of alanine with threonine at the amino acid position 287 (p.A287T) which was previously reported in Canavan disease patients [2]. However, parental studies showed that only the mother was a carrier of the p.A287T. Therefore, a microdeletion affecting ASPA gene was suspected and a loss of copy number on 17p13.3 in both the proband and her father was detected by an Affymetrix Genome Wide Human SNP array 6.0 (Fig. 1A). The deletion was confirmed by real time quantitative PCR (qPCR) using primers within and flanking the deleted region (primer sequences are available upon request; Fig. 1B). The 74 Kb copy number loss encompasses nucleotide 3,324,311-to-3,398,497 and includes ASPA and TRPV3 genes (Fig. 1A). TRPV3 has not been so far associated to human diseases. A previous patient with large homozygous deletion involving ASPA and TRPV3 genes did not show additional clinical features to those commonly observed in Canavan patients [3].In summary, the patient described in this report illustrates that large deletions encompassing the ASPA gene should be considered in Canavan disease patients when mutations cannot be identified by direct gene sequencing. This information is important for accurate carrier testing and prenatal diagnosis. Therefore, high resolution SNP array and qPCR are valuable diagnostic tools for detection of chromosomal deletion unmasking recessive Canavan disease alleles.