What-was-it-again inheritance pattern. Something-or-the-other translocation. This-and-that Syndrome. You see these terms on your progress test and you promise yourself to look it up before the next one, but you never do. Well, do not despair! I have recently finished an internship at the clinical genetics department of the UMCG, so I am somewhat of a geneticist myself.
Autosomal inheritance patterns
We will kick off with something that was already covered in high school, and is probably the easiest part of clinical genetics to grasp: the different inheritance patterns. The two most famous ones everybody knows about are the autosomal recessive and autosomal dominant inheritance patterns. These patterns are autosomal in the sense that the genes can be found anywhere in chromosomes 1-44, but not in the sex chromosomes . An autosomal dominant gene is a gene which comes to expression, even if only one copy is present. So, if one parent has a certain trait, any child of theirs theoretically has a 50% chance of getting that trait (this will go up to 75-100% if both parents express the trait). Something you probably did not learn in high school is that the chance of getting the a certain condition is actually lower than 50% in reality, because of the concepts of reduced penetrance and variable expression. With reduced penetrance a certain trait which is known to be autosomal dominant, does not actually present itself even if the genetic basis is there. Variable expression is when a gene which causes one thing in one patient can cause something else in another. For example, the BRCA1 mutation causes breast cancer in most patients, but it can also only cause ovarian cancer (or more depressingly both). For autosomal recessive expression I would recommend looking at the picture on this page of the Punnett Square. Just draw it every time a question pops up about this during a progress test, and you should be fine.
Sex-linked inheritance patterns
Yeah, I get that all inheritance patterns are sex-linked, how very funny of you. This is clearly about traits linked to the sex chromosomes (so not autosomal). We will start with the Y-linked inheritance pattern, because it is actually the simplest inheritance pattern around. If a father has the trait then any son born to that man will have the condition and any daughters will not be affected. However, very few diseases are Y-linked. Y-linked infertility is one of the more common ones, which as you can guess from the name has some negative selection pressure. For X-linked diseases, the concepts of dominant and recessive return once more. The patterns have the same internal logic as the autosomal patterns but the male has only one X-chromosome. For X-linked dominant traits an affected father will always have affected daughters (except with reduced penetrance). For a mother with an X-linked dominant trait the rules are the same as with an autosomal dominant trait. X-linked recessive means that a carrier mother has a 50% chance of making a son express the trait and making a daughter a carrier. Affected fathers can make their daughters a carrier but their sons are safe. Again, if you feel confused, just draw a Punnett square to make it more clear.
Mitochondrial inheritance patterns
The final inheritance pattern is the mitochondrial one which, as the name implies, is based on the mitochondria. Mitochondria are all based on the mitochondrial DNA present in the lucky oocyte which is to be fertilised. This means that all children of the mother will have any traits present in that DNA. Her sons will never pass over any of the traits to their children but all her daughters will.
Cytogenetics
Cytogenetics, a term that could have come straight from a bad science fiction film, is the study of chromosomes and their abnormalities. It involves looking at pictures of sorted chromosomes, which have been stained to show structural abnormalities. Usually, you expect 46 chromosomes, 23 from your father and 23 from your mother all paired off and roughly the same. There are many diseases which are caused by abnormalities in the chromosomes. The most important abnormalities to remember are the loss or gain of entire chromosomes through nondisjunction (translation: chromosomes don’t separate during meiosis), translocations, and deletions.
Autosomal aneuploidies
The most common condition caused by aneuploidy (a different amount of chromosomes than normal) is of course trisomy 21 called Down syndrome (1/700 live births). It is so famous, I will immediately move to the other common aneuploidies. Trisomy 18 which is known as Edwards syndrome is the second most common autosomal aneuploidy (1/6000 live births), only about 5-8% of patients born alive with this syndrome live past 12 months and they are much more developmentally delayed than patients with Down syndrome. Patau syndrome, which comes from trisomy 13 is very rare (1/10000 live births), and similarly to Edwards syndrome, 95% die before 12 months of age. Now you are probably wondering about all the other trisomies. Well, sometimes they do occur but most of those abnormalities are incompatible with life, so they result in a spontaneous abortion.
Sex aneuploidies
I will not repeat the joke about sex being required for all aneuploidies, it would be childish. This is where a lot of progress test questions come from for some reason. First off is monosomy X (45, X) which is better known as Turner syndrome (1/5000 female births), which is exemplified by females with a short stature, a webbed neck and a broad, shield-like chest. Next is Klinefelter syndrome (1/1000 male births) which consists of a 47, XXY chromosomal configuration. This syndrome has the most subtle phenotype thus far with males who are tall with disproportionately long arms and legs with primary hypogonadism. Also, most of them are sterile. The last two sex aneuploidies are generally mild in presentation compared to the other aneuploidies. Trisomy X (1/1000 female births) produces sterile women with mild learning disability and 47, XYY (1/1000 male births) produces tall men with a lowered IQ (85).
Translocations
Translocations are when pieces of the arms of the chromosomes get switched around. It happens between 1/500 and 1/1000 live births, so it occurs quite frequently. There are two types of translocations, namely the reciprocal type and the Robertsonian type. In a reciprocal translocation two pieces of chromosomes get switched around with each other where both sides are technically wrong, but since no genetic material is lost the person has no consequences themselves. Basically the correct information is still there but it is in the wrong place. The problems will occur in the offspring, because it is possible that they get one misplaced piece and not the other, which causes an unbalanced amount of genetic material. This can cause a partial trisomy or a partial monosomy depending on the specific translocation and which misplaced piece was or was not included. For Robertsonian translocations, the short arms of one chromosome pair fuse and the long arms fuse. This leads to one tiny chromosome and one long chromosome. The tiny chromosome is lost, but it contains very little information which means the carrier remains unaffected. This carrier can, however, produce offspring children with monosomy and trisomy of the affected chromosome.