[Causal mutation or rare polymorphism? Frequency of mutation not found in 3 chromosome is less than 3 divided by n].

Unité INSERM U129, Paris, France.
Annales de Génétique 02/1996; 39(3):133-8.
Source: PubMed

ABSTRACT The problem of distinguishing rare polymorphism from deleterious mutations is an important question in molecular medicine. In order to estimate the frequency of a sequence variation, unrelated normal individuals are usually screened for the mutation concerned. A sequence variation that is not found in non-affected individuals becomes more likely to be the cause of the disease. The aim of this paper is to provide a practical estimation of the fortuitous occurrence of a private polymorphism in one or several patients. The frequency of a sequence variation is not difficult to estimate in a population. The 95% upper frequency limit of a gene variant not observed in n chromosomes is 1-n+1 square root of 0.05. This can conveniently be approximated as 3/n. While the likelihood for finding a sequence variation only in patients is easily calculated, it is practically impossible to compute the exact probability that this variation is indeed the cause of the disease.

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    ABSTRACT: Mental retardation affects 30 to 50% more males than females, and X-linked mental retardation (XLMR) is thought to account for the major part of this sex bias. Nonsyndromic XLMR is very heterogeneous, with more than 15 genes identified to date, each of them accounting for a very small proportion of nonsyndromic families. The Aristaless X (ARX) gene is an exception since it was found mutated in 11 of 136 such families, with a highly recurrent mutation (dup24) leading to an expansion of a polyalanine tract in the protein. The rather high frequency of dup24 reported in families with clear X-linked MR (6.6%) contrasts with the very low prevalence of this mutation observed in sporadic male MR (0.13%). We conclude that monogenic XLMR has much lower prevalence in male MR (< 10%) than the 23% that would be required to account for a 30% male excess of mental retardation.
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