Phenotype expansion in rare disorders

What is phenotype expansion?

By doing genetic testing through high-throughput Next Generation Sequencing, more specifically by doing whole exome sequencing and whole genome sequencing, patients affected by a well defined syndrome may be found to harbor a pathogenic mutation in a gene previously known to be associated with a different phenotype. Similarly, a patient with a certain syndrome caused by a mutation in a known gene may suddenly show new signs or symptoms which were unknown so far. Those two cases perfectly describe the concept of phenotype expansion in rare disorders. To make it clearer, we'll give later a couple of clinical examples. The concept of phenotype expansion is very important and we think it should be added in any Medical Genetics book, alongside other well known genetic principles such as variable expressivity, incomplete penetrance, allelic and genetic heterogeneity, pleiotropism, etc.

Why does phenotype expansion happen?

Different parts of a gene encode different parts of a protein. Furthermore, pathogenic mutations may be of very distinct types, leading to gain or loss of protein function. Finally, genes are immersed within a molecular universe of thousands of other genes, which may modulate gene expression in various ways. These are probably the most likely cause of the phenomenon of phenotype expansion, i.e. these are the reasons why new types of mutations (or mutations in different parts of gene) may cause new, so far unknown, clinical signs, or even a completely new syndrome.

How do we recognize a case of phenotype expansion?

This is probably the most difficult question to answer. Because patients and physicians need a clear and correct answer from genetic testing, medical reports must be based on acquired knowledge and should be generally quite conservative (at least this how we think it should be in any good genetic testing lab). So, when we find a variant of uncertain significance (VUS) or even a likely pathogenic mutation in a gene of which associated phenotype does not overlap with the patient's clinical features, it may be very difficult to go in the right direction of the clinical interpretation. If the patient shows at least some of the cardinal clinical signs of a certain syndrome, beside showing completely unexpected ones, it's easier for the Medical Geneticist to venture into a likely diagnosis with the possibility of phenotype expansion. Much more difficult is the case of a patient who does not show any of the expected clinical signs of a known gene-syndrome association, because even the apparently worst mutation (e.g. a nonsense or a frameshift mutation) always comes with the possibility of being a neutral variant. So, a likely disrupting mutation in a gene which is not expected to cause the phenotype of our patient must be considered with extreme caution. However, also in this case, hints may be given to the treating physician and the patient to guard such mutation for the future, when newly acquired scientific knowledge may explain its real clinical significance (or even confirm the diagnosis!).

Some examples of phenotype expansion: COL12A1 and SMARCA2

Let's come to a couple of examples, which may help us to better understand the meaning of phenotype expansion in Medical Genetics. We'll consider two genes: COL12A1 and  SMARCA2.

In a study by Punetha et al., 2019 (PMID: 27348394), the authors suggest expanding the clinical picture of COL12A1-related congenital myopathies as they found a heterozygous missense mutation in a patient with an intermediate phenotype between the known associated milder Bethlem-like myopathy and a severe congenital form with failure to attain ambulation. The authors concluded that their case expands the phenotypic spectrum for COL121A1 disorder. Again, in another study on the COL12A1 gene (Mohassel et al., 2019, PMID: 31509352), the authors highlight that the full phenotypic spectrum of the COL12A1-related disease is not yet delineated.

Coming now to SMARCA2: heterozygous mutations in the SMARCA2 gene have been so far associated with Nicolaides-Baraitser syndrome, which is characterized by severe mental retardation, early-onset seizures, short stature, dysmorphic facial features, and sparse hair. Recently, it has been published that mutations in the SMARCA2 gene that clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability, with the distinctive trait of blepharophimosis (PMID: 32694869).

Suspicion of phenotype expansion: what to do next.

OK, you have found a very interesting mutation in a fantastic gene! However, your patient's feature seems to be (very) far from the clinical phenotype known to be associated with that gene. So, you think now that this could be a case of phenotype expansion. What to do next?

At this point, we think you should ask yourself at least two questions:

  1. Does the patient have at least some of the cardinal clinical features of the syndrome associated to this gene?
  2. Is there sufficiently strong evidence to consider the mutation likely pathogenic or at least a "strong" VUS?

If you can answer "yes" to both questions, then there is a given likelihood that this may really be a case of phenotype expansion and both the treating physician and the patient should be informed accordingly.

If you must answer "no" to both questions, then you should probably go ahead and look at other patient's variants in other genes.

If you can answer "yes" to only one of the two questions, then it might still be worth remembering this mutation for the future, mostly to stay open to newly acquired medical evidence which may help variant re-interpretation.


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Posted in Academia, Last Update, Medical Genetics.

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