［病例讨论］（19）44,XY，两条13,14染色体均发生罗氏易位的生育问题
病例来源：
2017-7-14
遗传诊断大师群（一）
王静 中山大学附一院：
请问老师们，男性，两条13，14染色体均发生了罗氏易位，后代是什么情况呢？正常概率是多少呢？
杨锴 北京海淀妇幼：
@王静-中山大学附一院，是两份rob（13；14）？查父母了吗？
王静 中山大学附一院：
不是，是男方自己一个人的13，14都相互易位了，剩44条染色体了。这个人想要孩子。
杨锴 北京海淀妇幼：
个人认为机会是可以的！可以尝试自然妊娠，做产前诊断。这个患者是因为什么查出来这个核型的呢？
王静 中山大学附一院：
以前怀过2次都流产了，做试管要求PGD。这种情况是不是最好的结果就是罗氏易位携带了？
杨锴 北京海淀妇幼：
有过不良孕史吗？我们是觉得，正是因为发生了double罗氏，给了他更多生育表型正常后代的机会。如果他的配偶不是相关染色体罗氏易位携带者，他们的孩子经过常规产检又查不出问题，那孩子基本上就只能是罗氏易位携带者。当然，做试管也可以，看个人选择了。
高勇 北京希望组：
👍 👍 请看之前一个类似的报道：http://genetics.thetech.org/original_news/news124
His chromosomes are arranged in a stableway that could be passed on if he met a nice girl who had 44 chromosomes too.And this would certainly be possible in the future given his family history.
Note added in Proof: Here are some olderpapers that I missed that have very similar findings:
Translocation t(13;14) in nine generationswith a case of translocation homozygosity.
Homozygosity for a Robertsoniantranslocation (13q14q) in three offspring of heterozygous parents.
黄尚志 医学遗传，北京协和医学院：
两个rob是一样的，成“同源染色体”了，减数分裂应该没障碍，就是子代是rob（13;14）杂合子。这个男性有不育吗？他rob（13;14）纯合子耶。产前诊断是防其他核型异常，胎儿肯定是rob（13；14）。
刘平：
这是两条罗氏染色体的纯合型个体。能建议让这位男性父母查一下染色体核型吗？了解一下是新发的还是从父母来源。如果怀孕了查一下子代核型，应该是个携带者了。可以暂时不做PGD，产前诊断必须做。
高勇 北京希望组：
一个相似的病例报告如下：http://genetics.thetech.org/original_news/news124
The 44Chromosome Man
And What He Reveals About Our GeneticPast
February 26, 2010
Many people have trouble believing thatchromosome number can change and stay changed in a species. Their first thoughtis often of Down syndrome or the other problems that usually come with missingor extra chromosomes. It can be hard to imagine how a living thing could end upwith a new chromosome number without these problems.
And yet it happens all the time increatures as varied as yeast, corn, butterflies, voles and even mice. And nowit has been seen in people.
In a recent article, a doctor in Chinahas identified a man who has 44 chromosomes instead of the usual 46. Except forhis different number of chromosomes, this man is perfectly normal in everymeasurable way.
His chromosomes are arranged in a stableway that could be passed on if he met a nice girl who had 44 chromosomes too.And this would certainly be possible in the future given his family history.
No chromosome 15 but perfectly fine.
A partialkaryotype of a Chinese patient with only 44 chromosomes.
But why doesn't he have any problems? Aloss of one let alone two chromosomes is almost always fatal because so manyessential genes are lost.
In this case, he has fewer chromosomesbut is actually missing very few genes. Instead, he has two chromosomes stuckto two other chromosomes. More specifically, both his chromosome 14's are stuckto his chromosome 15's.
So he has almost all the same genes asany other person. He just has them packaged a bit differently.
This is an important finding because it tells us about akey genetic event in human prehistory. All the evidence points to humans, like theirrelatives the chimpanzees, having 48 chromosomes a million or so years ago.Nowadays most humans have 46.
What happened to this 44 chromosome manshows one way that the first step in this sort of change might have happened inour past. Scientists could certainly predict something like this. But now thereis proof that it can actually happen.
Note added in Proof: Here are some older papers that Imissed that have very similar findings:
1. Translocation t(13;14) in nine generations with a case oftranslocation homozygosity.
2. Homozygosity for a Robertsonian translocation (13q14q) inthree offspring of heterozygous parents.
And the current one:
Case Report: Potential Speciation inHumans Involving Robertsonian Translocations.
His Story
So how did this man end up with 44chromosomes? It is a story of close relatives having children together. And achromosomal rearrangement called a balanced translocation.
A balanced translocation is when onechromosome sticks to another. Because no genes are lost in this process, itusually doesn't have any effect. Until these folks try to have kids that is.
Usually around 2/3 of pregnanciesinvolving one person with a balanced translocation will end in miscarriage.This has to do with how chromosomes separate when eggs and sperm are made.Thisprocess is called meiosis.
Remember, humans (and most other livingthings) have two copies of each chromosome. So they have two copies ofchromosome 1, two copies of chromosome 2, etc. Only one chromosome from eachpair gets put into any one sperm or egg. That way, when the sperm fertilizesthe egg, the fetus has the right number of chromosomes.
This is where the problem starts forpeople with a balanced translocation. They have one unpaired chromosome and apair with an extra chromosome. Here is what can happen in this situation:
The top row represents two potential parents. The parenton the right has a balanced translocation. There are two possible ways for thefused chromosome to line up.
In the figure, only two chromosomes areshown. Numbers 14 and 15 were chosen because these are the two that are fusedin the 44 chromosome man.
The parent with the balancedtranslocation can make 4 different kinds of sperm or egg (the second row). Asthe figure shows, when the eggs and sperm combine, 1/2 of the time the fetusends up with an extra or missing chromosome. Unless this chromosome is the X, Yor number 21, the usual result is miscarriage or being born with severeproblems.
In this case it would almost certainlyresult in miscarriage. In fact, the 44 chromosome man's family has a longhistory of miscarriages and spontaneous abortions.
To get two of the same balancedtranslocations, both parents need to have the same balanced translocation. Thisis incredibly rare. Except when the parents are related.
In this case, both parents are firstcousins and they share the same translocation. When these parents try to have kids,they run into the same kinds of problems that can happen with one balancedtranslocation. Except that the problems are doubled. This makes for the manypossibilities outlined below:
This very complicated table shows the 36 possibleoutcomes when two parents with the same balanced translocation attempt to havea child.
In this representation, the father'spossible sperm are shown on the top and the mother's eggs on the side. Eachpregnancy has only an 8 in 36 chance for success. And 1 out of 36 would havetwo of the same balanced translocation (the circled possibility).
Theoretically the 44 chromosome manshould have fewer problems having children than his parents did. As this figureshows, there are no unpaired chromosomes when he and a woman with 46 chromosomeshave children. But all of their kids would have a balanced translocation:
So this is how he came to have 44chromosomes. This might also be how humans started on the road to 46chromosomes a million or so years ago.
More Information
Balanced translocations and Down syndrome
No chromosome 15 but perfectly fine.
A partial karyotype of a Chinese patient with only 44 chromosomes.
History
Humans and chimpanzees have a differentnumber of chromosomes. Humans have 46 while chimpanzees (and many other greatapes) have 48.
Current theories say that humans andchimpanzees had a common ancestor around 6-8 million years ago. This commonancestor must have had a certain number of chromosomes.
So why don't humans and chimpanzees havethe same number of chromosomes now? Because about a million years ago, in ahuman somewhere, two chromosomes fused. Over time, people with 46 chromosomeswon out over people with 48.
A close look at human and chimpanzee DNAshows that human chromosome 2 is very similar to chromosomes 12 and 13 ofchimpanzees. At some point, chromosomes 12 and 13 fused together in humanancestors to create chromosome 2. It probably happened in a similar way to whathappened with the 44 chromosome man.
What scientists don't know yet is how 46chromosomes came to win out over 48. As the 44 chromosome man shows, this sortof change starts out pretty rare. Right now having this particular set ofchromosomes is probably a 1 in 7 billion sort of thing.
There are a couple of obvious ways that46 chromosomes might take over. One is if there was some sort of advantage tohaving this number of chromosomes.
There is almost certainly no advantagein how the DNA is packaged. If anything, having a different number ofchromosomes hurts someone in terms of having the most babies possible.
It might be that where the twochromosomes fused together, some new helpful gene was created. Maybe one thatlet our ancestor communicate more effectively or walk upright. Unfortunately,there is no evidence to support this.
An alternative is that dumb luck allowed the 46chromosome humans to win. Perhaps people with 46 chromosomes were in anisolated community somewhere and the rest of humanity was wiped out. Certainlyhumanity has had near death experiences before. The most recent one wasprobably 75,000 or so years ago.
If by chance 46 chromosome humans werespared, then we have our current number of chromosomes by chance. And ifsomething similar were to happen in the near future and only descendants of the44 chromosome man survived, then humans would end up with 44 chromosomes.
王静 中山大学附一院：
谢谢老师们的指点，今天遇到这个病例又上了一课。多看多见才能不断积累经验，有了这个平台我们这些小辈就能第一时间向各位大咖们请教了。太棒了！