Mutation and Haplotype Studies of Familial Mediterranean Fever Reveal New Ancestral Relationships and Evidence for a High Carrier Frequency with Reduced.

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Mutation and Haplotype Studies of Familial Mediterranean Fever Reveal New Ancestral Relationships and Evidence for a High Carrier Frequency with Reduced Penetrance in the Ashkenazi Jewish Population Ivona Aksentijevich, Yelizaveta Torosyan, Jonathan Samuels, Michael Centola, Elon Pras, Jae Jin Chae, Carole Oddoux, Geryl Wood, Maria Pia Azzaro, Giuseppe Palumbo, Rosario Giustolisi, Mordechai Pras, Harry Ostrer, Daniel L. Kastner The American Journal of Human Genetics Volume 64, Issue 4, Pages 949-962 (April 1999) DOI: 10.1086/302327 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 DNA sequence electropherograms and rapid-screening assays for seven missense mutations identified in the present survey. The P369S and M680I mutations are novel. The upper three panels depict individuals who were normal, heterozygous, and, where available, homozygous for each of these sites. The downward arrow indicates the point of the single-base mutation. The lower panels depict rapid-screening assays that were developed for each of the mutations. ARMS assays were developed for E167D, K695R, A744S, and R761H. For these assays, the upper photograph in the lower panel represents the product of the mutant-specific primer pair, and the lower photograph represents the product of the wild-type primer pair. Restriction endonuclease analyses of PCR products were used for E148Q, P369S, and M680I. “W” denotes wild-type, “C” denotes the carrier for the mutation, “H” denotes homozygous for the mutation, and “D” denotes the distilled-water control. The American Journal of Human Genetics 1999 64, 949-962DOI: (10.1086/302327) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigree of an Ashkenazi Jewish family previously thought to exhibit dominant inheritance of FMF. The diagram is adapted from the report by Yuval et al. (1995). Microsatellite typings are listed from telomere (top) to centromere (bottom), with MEFV residing between D16S2617 and D16S3275. Affected individuals in the first two generations were not available for genotyping. In the report by Yuval et al. (1995), individual 43-03 was explained as a nonpenetrant carrier of a dominant mutation. The American Journal of Human Genetics 1999 64, 949-962DOI: (10.1086/302327) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 Haplotype analysis of a Sicilian family with FMF. Microsatellite marker order is the same as in figure 2. Three different MEFV mutations, with associated haplotypes, segregated in this family. The haplotype with the M694V mutation has been observed in several Mediterranean populations; the haplotypes associated with E148Q and M680I have been observed in Arab and Armenian families, respectively. Individual III-2 is age 13 years and has experienced no symptoms of FMF to date. The American Journal of Human Genetics 1999 64, 949-962DOI: (10.1086/302327) Copyright © 1999 The American Society of Human Genetics Terms and Conditions