Mutation-genetic disease paradigm: a bewitching picture without a frame

The world of human genetics is wonderfully complex. Next-generation sequencing technologies implemented in genetic testing for rare disorders are impressive tools for searching throughout the whole human genome and singling out mutations causing mendelian diseases. However, although mendelian inheritance may look simple, its mechanisms is usually tangled in a wide range of biological phenomena that we need to take into account. Here we describe some of the most frequent “snags” a scientist has to face up in routinary analyses of whole-exome and whole-genome sequencing, especially when the pathogenicity of the variant is questionable and the working diagnosis does not point to any well-defined clinical picture.


Do you know that an individual can have the mutation but not the related disease? The penetrance is the percentage of individuals who have the mutation and exhibit the pathological phenotype and all individuals with such mutation. There are diseases with a penetrance of 100% like tanatophoric dysplasia or Huntington disease with full mutation, but more often the penetrance is incomplete (like several forms of primary immundeficiencies, hypertrophic cardiomyopathies or mental retardation).

According to the degree of penetrance, the relationship between mutations and disease can also be considered as a form of susceptibility. For example, genes related to susceptibility to familial breast cancer can be divided in high-penetrance genes (including BRCA1 and BRCA2, which account for about 20-25% of hereditary breast and ovarian cancer cases), moderate penetrance genes (like CHEK2, ATM) and low penetrance genes (RAD51C, RAD51D).

With very low penetrance it can be even difficult to distinguish between genetic and environmental factors.

The penetrance can refer also to the type of mutation and it can be also related to the age (Huntington disease) or can be sex-dependent (like dilated cardiomyopathy caused by truncating variants in the TTN gene).

The penetrance may explain why genetic diseases are occasionally inherited by unaffected parents, and why healthy individuals can carry potentially pathogenic variants without showing any clinical sign of the disease.

Hypomorphic alleles

When we observed a reduced penetrance of a mutation in the context of deleterious loss-of-function effects on a gene product, we run into a hypomorphic allele, that cause only a partial loss of gene function. In this case the pathological phenotype is expressed, or more severely expressed, only when a hypomorphic allele is in trans with a more severe loss-of-function allele.

Thrombocytopenia-absent radius syndrome is an autosomal recessive disease caused by mutations in the RBM8A gene. Two low-frequency polymorphisms in the 5’-UTR reduce the activity of the RBM8A promoter with a hypomorphic mechanism, so that only in combination with a severe loss-of-function mutation on the other allele, as the common 200-kb deletion, they can cause the disease.

Out of the single gene

Sometimes a true mutation in one gene is not sufficient, as another mutation in another gene, biochemically related to the first one, is still needed to cause the disease. The digenic inheritance is observed, for example, in some forms of Usher syndrome, retinitis pigmentosa or in Rotor type hyperbilirubinemia, where simultaneous homozygous mutation in both SLCO1B3 and SLCO1B1 are needed to cause the disease.

All these factors show clearly that the motto “mutations of genetic diseases are always rare” is misleading. Many mutations can have higher frequency than one can gather from the frequency of the observed cases of people affected by the corresponding disorder.

Furthermore, we know that many human traits depend on a polygenic model, in which the burden of a single gene for a certain trait can be only approximated to various degrees by complex statistical mathematic models. In these cases, the mendelian laws still work, but in a more complex way, as the effect of a gene involved in a certain trait is influenced by the interaction of effects of all other involved genes.

From the clinics: expressivity and anticipation

Many disorders can complicate a diagnosis because of their variable presentation, especially when the geneticist has just a bunch of variants of uncertain significance at hand! The expressivity is the degree to which the pathological phenotype is expressed by an individual carrying the mutation. Different individual with the same mutation for the same genetic disease can show small or big differences in severity and variety of clinical signs (like Van der Woude syndrome and neurofibromatosis). That’s another factor continually observed in clinical diagnostics work, and sometimes it can be so significant that a disorder can be underdiagnosed.
We can also observe an increased severity or a decreased age of on-set of genetic disorders in subsequent generations. This phenomenon is called anticipation and it is observed, for example, in Huntington disease (more common with paternal transmission of the disease) or myotonic dystrophy caused by mutations in the DMPK gene (more common with maternal transmission of the disease).

… puzzling a mosaic out!

A somatic variant is a change of the DNA that occurs in any cell of the human organism except the germline cells. They can be significant if they occur in very early stages of post-zygotic development, involving a cell which is an ancestor of a significant fractions of the organism. For instance, McCune-Albright syndrome, which is a disease affecting skin, bony skeleton and the endocrine system, is caused by early embrionic potzygotic somatic activating mutatios in the GNAS gene. All patients affected by McCune-Albright syndrome are a mosaic of mutated and wild-type cell lines in the affected tissues, because it is thought that the presence of this type of GNA mutations in all cells of the organism are presumably lethal to the embryo. In fact, family transmission has never been observed.

In those cases, the correct detection of the somatic mutation depends on the level of mosaicism in the tissue from which the DNA sample is extracted and by the fine-tuning of the sensitivity of the sequencing technique.

Furthermore, somatic mutations are also involved in the pathogenesis of cancers, and understanding how germline and somatic variants contribute towards tumorigenesis is pivotal in oncology.

Beyond DNA: from epigenetics to environment

Imprinting is an epigenetic phenomenon that results in gene expression according to a certain parental inheritance. Some disorders are expressed only when the related mutations are inherited from a particular parent. For example, Beckwith–Wiedemann syndrome is a growth disorder that is expressed only when the patient inherited the mutation from the mother. The maternal mutation is usually an abnormal methylation of two imprinting centers on chromosome 11p15, or a heterozygous mutation in the CDKN1C gene. But the loss of an active maternal allele can also be due to paternal uniparental disomy.

Finally, we cannot ignore that during all our run through the labyrinth of these complications, the environment factors work always behind the scenes, with the possibility to impact the biological pathways in which the gene product operates. The web weaved by polygenic and environmental factors, for example, cannot be ignored in the newest frontiers of most complicated current neurodevelopmental studies, like neuropsychiatric disorders (e.g.: ADHD and autism).

We can now understand that the mutation-genetic disease paradigm is not so simple as it appears. “We got the mutation, we got the diagnosis” can sound more as a bewitching but empty magic spell, if we do not pay attention to the context of these biological events which need to be defined as more precise as possible.

How do we deal with it?

At Breda Genetics we always keep an eye on all the afore-mentioned molecular and clinical aspect when we have to decide whether a variant of interest may be pathogenic or not. Therefore, even in our most difficult cases of diagnostic odissey, our routinary tasks include a review of the available and up-to-date literature, in order to define more accurately as possible the frame inside which we can correctly understand the genetics of rare diseases. We provide the most complete result and extensive comments in our reports, to support the physician and make test results fully clear to the patient.

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Kellermayer et al., 2019, PMID: 30919088
Mahdavi et al., 2019, PMID: 30552672
Wang et Chiang, 2018, PMID: 30385887
Albers et al., 2012, PMID: 22366785
Bird, 2020, PMID: 20301344
Caron et al., 2020, PMID: 20301482
Shuman et al., 2016, PMID: 20301568
Taeubner et al., 2018, PMID: 30352675
OMIM # 237450, OMIM # 174800
Ngeow et Eng, 2016, PMID: 29263804
Haldeman-Englert et al., 2017, PMID: 29072892


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