A benign polymorphism in the aspartoacylase gene may cause misinterpretation of Canavan gene testing

Propheta, Oshrat; Magal, Nurit; Shohat, Mordechai; Eyal, Nurit; Navot, N.; Horowitz, Miri

doi:10.1038/sj.ejhg.5200225

Cited by 6 publications

(5 citation statements)

References 1 publication

(1 reference statement)

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“…This indicates that there is a conserved haplotype containing the 854C mutation and the 693T allele in this population, indicating an ancestral AJ founder for this mutation, as seen in many of the common AJ diseases which have only one or two major disease‐causing mutations. The disequilibrium of the A854C mutation and the 693T allele has also been noted by Propheta et al [1998], who reported allele frequencies for the 693C and T alleles as 0.75 and 0.25, respectively, based on analysis of 101 randomly selected Israeli non‐carrier individuals. In our 1,073 non‐carrier samples tested we found the frequencies for the 693C and T alleles to be 0.69 and 0.31, respectively.…”

Section: Discussionsupporting

confidence: 60%

“…Reports have appeared of a potential source of misinterpretation of ‘home‐brew’ molecular assays for CD [Alford et al, 1998; Propheta et al, 1998] caused by the 693C/T polymorphism at the site of the C693A (Y231X) mutation. Our assay was designed to detect the reported 693C/T polymorphism seen at the site of C693A (Y231X) mutation.…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

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Canavan disease: Carrier‐frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay

Feigenbaum

Moore

Clarke

et al. 2003

American J of Med Genetics Pt A

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Canavan disease (CD) is an autosomal recessive progressive neurodegenerative disorder prevalent in the Ashkenazi Jewish (AJ) population. The carrier rate for the most common mutations that cause CD in the AJ population is often quoted as 1:37-1:40. This is not supported by our finding of only two diagnosed cases of CD in the last 20 years in the Toronto AJ population of 160,000 and an estimated birth rate of 1,500-2,000 per year. Therefore, we embarked on a prevalence cross-sectional screening study to determine the carrier rate of CD in this population. In order to perform low-cost, high-throughput population testing for CD using molecular techniques, we first developed a novel molecular assay using multiplex fluorescent allele specific polymerase chain reaction (PCR) to test for the three most common mutations causing CD in the AJ population (A854C, C693A, C914A) and a neutral polymorphism at the site of the C693A mutation. During testing it was noted that individuals who were carriers of the A854C mutation also had a T polymorphism at the site of the C693A mutation (Y231X). We confirmed that in all A854C carriers the 854C mutation was in disequilibrium with the 693T polymorphism, indicating a founder chromosome for the A854C mutation in the AJ population. Twenty-five carriers were found from 1,423 samples yielding a carrier rate of 1:57, differing from the widely quoted frequency of 1:40 and supporting our observed frequency of disease.

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Section: Discussionsupporting

confidence: 60%

Section: Subjects Materials and Methodsmentioning

confidence: 99%

Canavan disease: Carrier‐frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay

Feigenbaum

Moore

Clarke

et al. 2003

American J of Med Genetics Pt A

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“…There are several reports of TAC to TAT in the aspartoacylase gene; however, both code for tyrosine and so do not change the amino acid substitution. 20,21 In our patient, we observed a tyrosine-to-cysteine change at amino acid position 288 (Y288C) of aspartoacylase resulting from an A to G transition. This amino acid change did not decrease the enzyme activity, indicating polymorphism.…”

Section: Discussionmentioning

confidence: 68%

Mild Elevation of N-Acetylaspartic Acid and Macrocephaly: Diagnostic Problem

et al. 2003

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Patients with slightly increased excretion of N-acetylaspartic acid in urine, together with macrocephaly, present a dignostic dilemma for Canavan's disease. We describe a 13-year-old male patient with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia bilaterally, partial cortical blindness, and retinitis pigmentosa. Although the clinical course and magnetic resonance imaging findings did not resemble typical Canavan's disease, N-acetylaspartic acid excretion in the patient's urine was slightly elevated, 99.90 +/- 4.00 microg/mg creatinine, whereas the normal control range was < 83 microg/mg creatinine. Cultured skin fibroblasts from the patient showed no aspartoacylase activity. Cloning of genomic DNA isolated from the patient's fibroblasts showed an intronic mutation, specifically deletion of -2A and -3C at the acceptor site of exon 3 and disrupting the normal splicing of the gene. A second mutation was found in exon 6, 863 A-->G in aspartoacylase complementary DNA, causing a tyrosine-to-cysteine (Y288C) amino acid substitution. Expression of the mutation on exon 6 showed normal aspartoacylase activity. These data suggest that expression of the mutation may help to understand the enzyme defect in a patient with slightly increased N-acetylaspartic acid excretion.

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“…66,67 Quality assurance Laboratories should follow molecular pathology guidelines established by the College of American Pathology (CAP), be in compliance with the NIH-DOE Task Force on Genetic Testing, 68 and follow the ACMG Standards and Guidelines for Clinical Genetics Laboratories. With the exception of GD, an incorrect assignment of homozygous mutant is suggested when the indication is carrier screening.…”

Section: Incorrect Assignment Of Homozygositymentioning

confidence: 99%

Technical standards and guidelines for reproductive screening in the Ashkenazi Jewish population

Monaghan

Feldman

Palomaki

et al. 2008

Genetics in Medicine

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These Technical Standards and Guidelines were developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular standard or guidelines was adopted, and to consider other relevant medical and scientific information that becomes available after that date.

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A benign polymorphism in the aspartoacylase gene may cause misinterpretation of Canavan gene testing

Cited by 6 publications

References 1 publication

Canavan disease: Carrier‐frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay

Canavan disease: Carrier‐frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay

Mild Elevation of N-Acetylaspartic Acid and Macrocephaly: Diagnostic Problem

Technical standards and guidelines for reproductive screening in the Ashkenazi Jewish population

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