Tay-Sachs Carrier Screening by Enzyme and Molecular Analyses in the New York City Minority Population

Abstract

Background and Aims: Carrier screening for Tay-Sachs disease is performed by sequence analysis of the HEXA gene and/or hexosaminidase A enzymatic activity testing. Enzymatic analysis (EA) has been suggested as the optimal carrier screening method, especially in non-Ashkenazi Jewish (non-AJ) individuals, but its utilization and efficacy have not been fully evaluated in the general population. This study assesses the reliability of EA in comparison with HEXA sequence analysis in non-AJ populations. Methods: Five hundred eight Hispanic and African American patients (516 samples) had EA of their leukocytes performed and 12 of these patients who tested positive by EA (“carriers”) had subsequent HEXA gene sequencing performed. Results: Of the 508 patients, 25 (4.9%) were EA positive and 40 (7.9%) were inconclusive. Of the 12 patients who were sequenced, 11 did not carry a pathogenic variant and one carried a likely deleterious mutation (NM_000520.4(HEXA):c.1510C>T). Conclusions: High inconclusive rates and poor correlation between positive/inconclusive enzyme results and identification of pathogenic mutations suggest that ethnic-specific recalibration of reference ranges for EA may be necessary. Alternatively, HEXA gene sequencing could be performed.

Measurement of lysosomal enzyme activities: A technical standard of the American College of Medical Genetics and Genomics (ACMG)

“…[63][64][65][66][67] Furthermore, the use of ethnic-specific reference ranges has been shown to reduce false-positive results in certain populations (eg, individuals of African and Central or South American descent). 68 DNA testing can be used to confirm the presence of pathogenic variants, identify pseudodeficiency alleles, clarify indeterminate enzyme results, and provide molecular information for prenatal diagnosis and carrier screening for other family members.…”

Tay-Sachs disease

“…TSD is an autosomal recessive, neurodegenerative disorder that is part of a group of three lysosomal storage diseases known as gangliosidosis GM2. (4,7,11) These diseases are caused by a defect in GM2catabolism, which is in turn caused by the deficiency of the lysosomal β-hexosaminidase A (HexA) enzyme, whose function is to transform ganglioside GM2 into ganglioside GM3 (4,11,22), thus triggering the abnormal accumulation of gangliosides GM2, mainly in neurons; this leads to cell death and to the development of the disease. (4,(23)(24)(25)(26) In April 1881, Warren Tay, a British ophthalmologist, general surgeon and dermatologist, presented the case of a 12-month-old boy to the Ophthalmological Society of the United Kingdom.…”

“…(12,29,(32)(33)(34) It is also high among Pennsylvania Dutch, Canadians from eastern Quebec, Cajuns, Irish and Italians. (7,29) Three common mutations account for more than 99% of all mutations in the Ashkenazi Jewish community. (9) Because the TSD rate is higher among Jews, it is important to clarify that this community is not only found in Israel, where 44% of the population is of this ethnicity, since the remaining 56% is distributed in different countries such as the United States (39.3%), France (3.1%), Canada (2.7%) and United Kingdom (2.0%).…”

Thirty two novel nsSNPs May effect onHEXAprotein Leading to Tay-Sachs disease (TSD) Using a Computational Approach

“…Tay-Sachs disease (TSD -[OMIM* 272800] also called GM2 gangliosidosis type 1 is an autosomal recessive lysosomal storage disorder which mainly affects Ashkenazi Jewish (AJ) population with low occurrences in non-AJ populations [1][2][3][4][5]. It's incidence is one in 100,000 live births (carrier frequency of about one in 250) [6].…”

“…Patients with HexA deficiency suffer from GM2 ganglioside accumulates inside neural's lysosomes. Therefore, HexA deficiency primarily affects the nervous system [1,2,4,[6][7][8][9][10][11][12][13][14].According to the disease onset age, TSD is differentiated into three types which are: acute infantile, juvenile, and late-onset. Acute infantile TSD is the most common type.…”