Clinical And Molecular Genetics Of

About two-thirds of TSC cases are sporadic, representing new mutations. Tuberous sclerosis occurs in up to 1 in 6000 live births without apparent ethnic clustering. Large families with the condition are rare due to reduced reproduction among those affected.[1-3]

The TSC1 gene consists of 23 exons with an 8.6-kb mRNA encoding the 130-kDa hamartin, and occupies 53 kb on 9q34 (Fig. 1).[3] The TSC2 gene consists of 42 exons with a 5.4-kb mRNA encoding the 200-kDa tuberin and resides in 40 kb on 16p13 (Fig. 1).[3]

More than 600 mutations in TSC1 and TSC2 have been identified.[3] Comprehensive mutational analyses indicate that about 85% of TSC patients will have a mutation found in either TSC1 or TSC2.[4,5] TSC2 mutations are about 4.2 times as common as TSC1 mutations, reflecting a higher germline mutation rate.

In TSC1, about half of the mutations are single base substitutions, of which most are nonsense mutations (Fig. 1). Just over half of the nonsense mutations are recurrent C to T transitions at six of the seven CGA codons within the TSC1 coding region. Missense mutations are rare in TSC1, but have been confirmed as disease causing in a few cases. In TSC2 as well, about half of the mutations are single-base substitutions (Fig. 1).[3] Nonsense mutations comprise about a third of these and commonly occur at five of the seven CpG sites which can transition to nonsense codons in TSC2. In contrast to TSC1, missense mutations are relatively common in TSC2 (Fig. 1). TSC2 has two CpG sites that are mutational hotspots which lead to missense mutations—1831-2 (611R>W and 611R>Q) and 5024-5 (1675P>L). These two CpG sites account for nearly half of the missense mutations in TSC2. Another relatively common mutation in TSC2 is an 18-bp in-frame deletion mutation near the C-terminus (Fig. 1). However, no mutation in either gene is seen in more than 2% of all TSC patients.

About a third of TSC1 mutations are small deletions (<29 bp), while half that number are small insertions (<34 bp). Nearly all small insertions and most deletions arise as duplications/deletions of a tandem repeat of single or multiple bases. Similar observations apply to small deletions and insertions found in TSC2. Large deletions and rearrangements are relatively common in TSC2, accounting for 16% of all mutations, whereas they are rare in TSC1, accounting for only 2%. In TSC2, deletions show no consistency in either size or junction fragments involved, ranging in size from 1 kb to over 100 kb.[3]

Patients with TSC1 mutations have symptoms and clinical features that are milder on average than patients with TSC2 mutations, although there is considerable overlap in severity.[4] Linkage studies provide evidence against a third TSC gene. Patients in whom mutations cannot be found are likely partially explained by mosaicism, which is well documented in TSC, and hinders efforts at mutation detection.[3]

Tuberous sclerosis molecular genetic testing is available commercially in the United States through Athena Diagnostics, and through several academic laboratories in Europe. In most laboratories the overall mutation detection rate is less than 80%, and findings of sequence variation of uncertain significance are often made, including possible missense and splice site mutations. Mutation identification has benefit for genetic counseling and prenatal diagnosis, particularly for individuals who have TSC. For parents of sporadic cases of TSC, the benefit is less clear, as such parents have a very low recurrence risk (~ 2%) if they are thoroughly screened clinically (exam by an experienced clinician and imaging studies of brain and kidney) and have no evidence of TSC.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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