ClinVar Genomic variation as it relates to human health

Obesity (present) , Dysphagia (present) , Movement disorder (present) , Poor head control (present) , Developmental regression (present) , Short stature (present) , Hypotonia (present) , Multifocal seizures (present) , Severe global developmental delay (present) (less)

Developmental regression (present) , Cherry red spot of the macula (present) , Muscular hypotonia (present) , Seizures (present) , Hyperacusis (present) , Hepatomegaly (present) , EEG abnormality (present) , Abnormal thalamic MRI signal intensity (present) (less)

Myerowitz and Costigan (1988) demonstrated that the most frequent DNA lesion in Tay-Sachs disease (272800) of Ashkenazi Jews is a homozygous 4-bp insertion in exon 11. This mutation introduces a premature termination signal in exon 11, resulting in a deficiency of mRNA. Using a dot-blot assay to screen patients and heterozygous carriers for the insertion mutation, Myerowitz and Costigan (1988) found the lesion in about 70% of carriers tested, thus identifying it as the most frequent defect underlying Tay-Sachs disease in the Ashkenazi Jewish population. Triggs-Raine and Gravel (1990) showed that this insertion mutation of only 4 bp can be detected by the formation of heteroduplexes. This mutation causes a frameshift and a termination codon 9 nucleotides downstream. By site-directed mutagenesis, Nishimoto et al. (1991) examined the basis of the paradox that the mutant gene with the 4-base insertion in exon 11 is transcribed normally but the mRNA is essentially undetectable. They found no evidence of interference with normal splicing of the transcript and the mutation did not destabilize properly spliced mRNA. Thus, the studies left open the question of the mechanism of the mutation. The possibility was mentioned that another still unidentified abnormality in the same allele may be responsible for the nearly complete absence of mRNA. There appears to be an increased frequency of TSD in the Cajun population of southwest Louisiana which numbers less than one million persons. McDowell et al. (1992) reported that in the previous 3 decades, at least 8 infants from 6 apparently unrelated Cajun families had been identified. They found that the mutation in 11 of 12 of the TSD alleles in these 6 families was the exon 11 insertion present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The remaining allele was a single-base transition in the donor splice site of intron 9 (606869.0033). To trace the origins of these 2 mutations in the Cajun population, the TSD carrier status was determined enzymatically in 90 members of 4 of the 6 families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggested that this mutation has been in the Cajun population since its founding and that it may be widely distributed within the population. In contrast, the intron 9 mutation was apparently introduced later and is probably limited to a few Louisiana families. Zlotogora (1993) argued that 2 mutations would not be unexpected in the Cajun population. Thurmon (1993) gave a historical account of the 'Jews of Acadiana.' He indicated that the Jews were assimilated into the Acadian culture and suggested that this was the source of the Tay-Sachs genes. He also pointed out that about the same time Jewish merchants began to arrive in Acadiana, the French Revolution produced an influx of non-Acadian French immigrants. Many were of aristocratic lineage and held themselves aloof from the Acadians. This mutation is alternatively designated 1277TATC or 1278insTATC. See 606869.0054. To investigate the genetic history of the 1278insTATC mutation, the most frequent cause of Tay-Sachs disease in Ashkenazi Jews, Frisch et al. (2004) identified a conserved haplotype in 1278insTATC chromosomes for 55 unrelated Ashkenazi Jewish individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When 2 methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for study of the decay of LD over time, the estimated age of the insertion was found to be 40 +/- 12 generations (95% confidence interval, 30 to 50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th or 9th century. This corresponds with the demographic expansion of Ashkenazi Jews in central Europe, following the founding of the Ashkenazi settlement in the early Middle Ages. The results were also consistent with the geographic distribution of the mutation and with the coalescent times of mutations causing 2 other lysosomal storage diseases frequent in Ashkenazi Jews: Gaucher disease (230800) and mucolipidosis IV (252650). Evidence for the absence of a heterozygote advantage of the mutation was provided by comparison between the estimated age of 1278insTATC and the probability of the current Ashkenazi Jewish frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust and parsimonious hypothesis explaining the spread of 1278insTATC-related TSD in Ashkenazi Jewish individuals. (less)