Paternal Age Effect In Progeria

Figure 2 Paternal age effect noted in progeria. Ages of fathers and mothers of 24 cases of progeria are compared with control fathers' ages. Approximately 20% of the fathers were about 20 years older than the mothers.

pected to be 25%. In progeria, it is clearly much less than 25%. Almost all cases are sporadic, and there is no evidence of increased miscarriage rates to suggest selection against the homozygote in utero. A case of identical twins with progeria with 14 normal siblings has been reported (27). Here, three or four affected siblings would be expected if it was a recessive disease. It is recognized that for new dominant mutations, occasionally the mutation can occur in a germ line leading to somatic mutations. Several cases could then occur within one family. Probable cases of familial progeria have been reported in only a few instances among more than 100 families (28-33). We believe that these reports of progeria cases most likely represent misidentified cases of other progeroid syndromes, such as mandibuloacral dysplasia. Among the 50 cases we examined, no family had more than one affected child except for one set of identified twins. There were 80 unaffected siblings. One would expect there to be 20 of the 80 siblings affected (25%) if a recessive mode of inheritance were to apply to these progeria families.

In general, the lack of consanguinity, the paternal age effect, and the lack of affected siblings, argues that progeria is not a rare recessive disorder but most probably is a sporadic dominant mutation. Because of a lack of consanguinity, a lack of affected siblings, and a paternal age effect, we suggested progeria should be classified as a sporadic autosomal dominant mutation (34). The possibility of genetic heterogeneity in progeria, in which some cases have a similar clinical presentation but with a recessive mode of inheritance, seems possible but unlikely owing to the rarity of the condition. The majority of cases appear to represent isolated sporadic dominant mutations, although a few may be the result of a germ line mutation. For genetic counseling of families with a child with progeria, the recurrence risk can be stated to be very low, but may be on the order of 1 in 500 with each pregnancy to allow for the possibility of somatic mosaicism such as has been occasionally seen in other new dominant mutations.

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