Only one of the parents has M694V and E148Q mutations, so what is the risk for child to be carrier or patient?
(Fmf = familial mediterranian fever)
If the two mutations are in cis, an offspring will have 25% possibility of carrying a M694V/E148Q genotype, which is linked to FMF phenotype of either intermediate or severe phenotype.
If the two mutations are in trans, an offspring will have 50% possibility of being either M694V or E148Q heterozygote; while E148Q heterozygosity is benign, M694V heterozygosity is linked to FMF phenotype of intermediate phenotype at about 70% of cases.
The above let aside the severe limitation that a single-gene recessive model of inheritance is inadequate for describing the spectrum of MEFV-associated phenotypes.
This is an interesting question and Dr Vasileios has already answered.
I agree with him, but perhaps I might add some qualification.
1. First of all, I would like to know the clinical picture of the parent with the two mutations: does she or he have FMF? I presume not because, although this person is heterozygous for both, FMF is (nearly always) a recessive disease.
2. If the two mutations are in cis, a child would have (a) 50% probability of inheriting both, and (b) 50% probability of inheriting neither. Under (b) of course the child would not have FMF: under (a) his or her phenotype is likely to be, in first approximation, similar to that of the parent with the two mutations.
3. If the two mutations are in trans, a child must inherit one (and only one) of the two: therefore he or she will be a heterozygote for one of them. The M694V on its own will almost certainly not give FMF; and the E148Q mutation will certainly not give FMF (sometimes even E148Q/E148Q homozygotes do not develop FMF).
4. All of the above is valid under the implicit assumption that the partner has no MEFV mutation. However, if the partner is from a high frequency region this assumption may not be valid: it is clear that for proper risk calculation/genetic counselling both parents should be tested.
Permit to add some piece of information after the very interesting answer of Dr Luzzatto:
- Among Greek FMF patients, two individuals carrying the M694V/E148Q genotype are linked to either intermediate or severe FMF phenotype and 7/11 heterozygotes for M694V mutation presented intermediate FMF phenotype (Giaglis S, Papadopoulos V, Kambas K, Doumas M, Tsironidou V, Rafail S, Kartalis G, Speletas M, Ritis K.MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet. 2007 May;71(5):458-67).
- I strongly agree with Dr. Luzzatto that the possibility of existence of MEFV mutations among healthy individuals should not be neglected; the total carrier rate of disease-causing MEFV mutations (M680I and M694V) among healthy individuals was 0.7% in Greeks.
- Turkish FMF patients are characterized by an increased genetic heterogeneity; thus, the regional origin is a crucial factor (Papadopoulos V, Mitroulis I, Giaglis S. MEFV heterogeneity in Turkish Familial Mediterranean Fever patients. Mol Biol Rep. 2010 Jan;37(1):355-8. doi: 10.1007/s11033-009-9779-9).
- Badges
- Science topic
- Similar topics
- Mathematics
- Statistics
- Sampling Design
- Sample Size