It sounds like it could be a dominant trait that one of the parents is mosaic for. This sort of inheritence pattern suggests a de novo mutation occurred early in the development of one of the parents such that their gametes carry the mutation. This makes even more sense if it is an x-linked gene and the father is the carrier because he would pass it to all of his children. There is a precedent for this sort of inheritance with parental mosaicism in X-linked Charcot-Marie-Tooth syndrome (http://www.ncbi.nlm.nih.gov/pubmed/23912496). Of course 0.0039 isn't 0 - it is absolutely possible that this is an autosomal recessive trait. You would need more information to figure this out (family history, symptoms/severity, type of disease, etc would all be helpful). 

A working diagnosis was done based on the early evidence? Was it confirmed by the proper genetic testing? If a mutation had been detected and confirmed and the result can explain the pathological phenotype, I would say it is possible to suggest a confrimational diagnosis for that rare hereditary disease. I think that's the most important step. 

If the genetic testing confirms the working diagnosis and the inheritance pattern, and you know that the mother and the father are carriers, then the percentages we are looking for are the known 25% of being affected, 50% of being a carrier and 25% of being unaffected and not carriers. And 25% of being affected is not a so "unlikely" likelihood.

In my work I saw several families with more than 1 sibling affected by rare autosomal recessive disorders. I remember a case in which three siblings were affected and the genetic testing for the 4th sibling confirmed the diagnosis.

I think it's possible to happen, if both parents are carrier of the this gene. The chance should be 25% each time

Most of all I'd like to see the case report. However on the basis of "when you hear hoofbeats, it's more likely to be horses than zebras.." I'd say that Ahmed has the most likely answer (although Simon's is the most interesting). Each child is it's own probability event. If both parents are carriers then each child has a 25% chance of being affected - the probability doesn't change with the number of children.

Good luck

Grant

Firstly, for recessive rare disorder, it would be helpful to consider family history, 2ndly, each child has 25% chances of getting the disease so it's quite normal if all the children are carrying the disease. 

Another possible reason is, one of the parent is having the mutant gene but gene is masking its expression and that could be the reason but I am not very much sure about this point.

We have seen similar scenarios, especially in communities with high consanguinity rates, keeping in mind the results of array comparative genomic hybridization, which is very helpful in this state.

Yes, it is possible, but the probability (or chance) of having it exactly that way would be very low.

Some years ago we analyzed a family where all 5 kids are homozygous for a LPL mutation and therefore develop type I hypertriglyceridemia. Both parents are heterozygous for the mutation. The possibility is low but it still exist.

We also discovered a mutation homozygous in four out of four kids in a family, with both parents heterozygous. Although such families will be relatively rare in the entire population, they really stand out when clinicians treat them, so there is a very strong ascertainment bias of such families being identified. The typical family of four kids with only one affected by a recessive trait looks like a sporadic case and would not make the clinician automatically go looking for a genetics consult, unless the phenotype were already known to have a strong genetic component.

It could be  a case of consanguineous marriage where both parents are carriers. This is common in parts of the world where consanguinity is an accepted social phenomenon. 

Autosomal recessive inheritance is likely in situations where there is consanguinity or high inbreeding. Alternatively, certain ethnic tribes or communities may have high proportion of carriers of a particular rare disease. Mitochondrial inheritance is another possibility where an apparently healthy mother can transmit a disease to more than one child. An unusual case would be one parent having a non-penetrant dominant gene which is transmitted to the children who are manifesting.

Yes, it could be AR, althoug the risk for an autosomal recesive disease 25% (and it is repeated again in each cases , it should not be combined as you did) but in my practice there is a family with 6 children and 4 affected by CFTR mutations, 1 is carrier and 1 is wild type.

Other speciality of this case is the different parental mutations. Fater is df508 carrier and mother 1215 carrier, so the children has a bit different symtomps of CF.

Other two options: maternal inheritance where the grandma is affected by the disease and her grandchild got the symptoms (there is only a few proved cases such as grandchildless mutation).

MtDNA could be also an option. (see above)

Predomination is also an option, where the parental genes works perfectly in the same combination such as  +/+ or -/- but the heterogozytes +/- has problems.

In my opinion, you should make a karyogram, it could also fetal unbalanced (partial) translocation which was balanced in the parent. The added part with the chromosome is survivable condition but the deleted is lethal in utero or before, so each survivable pregnancy will be affected by an unbalaced translocation.

If you feel like mood to cooperate in this case, I could be glad to help you.

Many thanks for the interesting answers. In fact this family was just investigated clinically and their symptoms were similar to a reported rare AR disorder. Now we are going to perform linkage analysis to determine the genetic pattern. You can find the family pedigree as an attachment. Obviously, consanguineous marriage is the case but 4 patients in a family was very interesting for me.    

Symptoms? Rate of  sp. abortation?

Dear Sareh,

This high number of affected children is indeed due to the consanguinity in this family. You can expect a common mutation in the four children, at the homozygous state, because of the homozygosity by descent process. Here, you can suppose that the mutation was inherited from an ancestor at least 4 generations away (as there is an affected great-uncle, with a very likely additionnal consanguinity loop between the great-grand parents). Each parent is likely to possess  the mutation at the heterozygous state and this same mutation was transmitted to the affected children by both parents. The healthy daughter is either homozygous wild-type or heterozygous (healthy carrier).

This is highly reminiscent of a family that I studied, with the same type of family tree. We performed linkage analysis, and this was very helpful to narrow down the regions of interest and to find the causal gene. Try to include as many individuals in the genotyping/linkage analysis, and you could very well reach the Z=3 significant linkage, even with only one family. Then you could further refine the analysis with the haplotypes reconstruction. With a bit of luck, you could obtain a very little number of linkage regions, that wouldn't be too large because the common ancestor that transmitted the mutation is at least 4 generations away. The next steps will depend on the result of this linkage/haplotyping analysis. Either you have a single narrow region with an obvious candidate gene (one can dream :-D), then you can sequence it directly. Either you have several not-so-narrow regions, and you could go for exome sequencing.

Good luck with this study !

Dear Sandrine

Your comments were very helpful. I hope we can find the mutated gene in this family  especially because the affected male is going to marry and it is important for them. 

Thanks.

This is a typical AR pedigree. Would you please explain more about the clinical features?

Regards 

Once the first sibling is affected by an AR disease, consanguinity is irrelevant; we already know that the parents are both carriers. The probability of each subsequent sibling being affected is exactly 0.25, consanguinity or not. Since these probabilities are independent, you can simply multiply them: 0.25^4=0.00390625, or one in 256 families with a rare AR disease. There are surely many more than 256 consanguineous families with a rare disease around the globe.

If we suppose that the average medical geneticist sees about 50 families with rare phenotypes in their career, then one in five geneticists is bound to see such a family at some point in their lifetime.

I would only add to Constantin's explanation that his calculation applies to any recessive trait, disease or not. For heterozygous parents who have 4 children,  the probability that all four will exhibit the recessive phenotype is 1/256 and the probability than none will exhibit the phenotype is 81/256. Note that this calculation specifically applies for families with 4 children. Consanguinity increases the probability that both parents are carriers of the same mutation, it does NOT change the probability for each child to be affected once the parents are hets.

I agree with Constantin and Darius, my first sentence was not correct. Consanguinity indeed increases the probabilty of related parents to be carriers of the same mutation inherited from the common ancestor, not the probability of each child to inherit this mutation from both parents.

What could be said here is that, in populations where it is normal and traditional to marry between cousins, it is also frequent to have many children (although this is not always true). Then it would be more frequent to see families with several affected/homozygous children, but this is merely due to the number of siblings.

Thanks to Constantin and Darius for correcting me !

should be published!

remember that it is also possible for one of the parents to be a genetic mosaic, so the germline in one could be homozygous recessive. That would systematically up the chances of the rare event (by making them not independent).