An increasing number of case studies now describe patients with only one variant of biallelic Mendelian diseases who display an intermediate phenotype somewhere on the continuum between affected, symptomatic patients and unaffected individuals. These case reports usually describe either a single individual or a whole family displaying various phenotype degrees while having a heterozygous symptomatic carrier status; however, in some cases larger cohorts have been reported ^[1][2][3][7,8,9]. The limiting factor is, however, the lack of full molecular analysis in most cases so that symptomatic heterozygosity is a hypothesis, and the most probable explanation is that the “second hit” has been missed. In most cases of symptomatic heterozygotes, symptoms are milder than in the disease state ^[4][10]. Often, the genetic status of symptomatic heterozygosity is first identified after re-examining the family member of an affected individual because the symptoms are so mild and unspecific that they are not noticed by the patient. Symptoms are usually located somewhere on the continuum between healthy individuals and patients carrying two variants. Correspondingly, symptomatic heterozygotes for genes related to neuromuscular disorders usually present with myalgias ^[5][6][5,6], mild muscular atrophy ^[7][11], and for hematological diseases with jaundice and mild symptoms of anemia ^[8][12] or familiar mild ptosis among the individuals with only one variant causative for congenital myasthenic syndrome (CMS), but where also cases of recessive CMS occurred ^[9][13]. In some cases, only some abnormalities in the laboratory tests may be detected ^[10][11][12][14,15,16]. This also suggests that it may be a disease phenotypic spectrum between heterozygous individuals and homozygous affected patients.

21. Disease Spectrum and Phenotypic Variability

Symptomatic carriers of autosomal diseases have been described for a wide range of disorders, including neuromuscular, neurological, hematological, and pulmonary diseases . Unfortunately, the current knowledge is still based mostly on case reports, and only the tip of the iceberg is revealed. Also, most of the cases reported as examples of “symptomatic heterozygosity” underwent only Sanger sequencing or whole-exome sequencing analysis (WES), which makes missing of the second hit variant the most probable hypothesis.

32. Dual Inheritance Mode vs. Symptomatic Heterozygous

For some diseases, both recessive and dominant inheritance patterns have been reported. These include myotonia congenita (Thomsen and Becker myotonia) ^[13][38], collagen 6- and 12-related muscle diseases (Bethlem myopathy and Ullrich congenital muscular dystrophy) ^[14][39]. The differences between dominant and recessive inheritance for the same gene and symptomatic heterozygotes may be fluent. However, symptomatic heterozygous inheritance is accepted to have only mild symptoms, whereas dominant and recessive inheritance show nearly the same severity for the affected state.

43. Population Studies and Phenotypic Spectrum

Interestingly, large population studies seem to confirm the existence of a spectrum of mild subclinical phenotypes related to disease at the population level. A study from the UK biobank encompassing 487,409 participants showed 102 significant associations, indicating that many disease-associated recessive variants can produce mitigated phenotypes in heterozygous carriers ^[15][3]. Other recent large biobank studies from a Finnish cohort confirmed these results and found a phenotypic effect in the Mendelian diseases, likely pathogenic heterozygous variants in 203 likely disease genes associated with recessive inheritance in a phenome-wide association study (pheWAS). The Finnish population shows a strong founder effect, so the enriched variants were chosen in order to reach a sufficient statistical study power. In particular, a heterozygous effect has been identified for the variants SERPINA1, NPHS1, CASP7, and GJB2 that are associated with biallelic disease ^[16][4]. The authors suggested that these be reclassified as “recessive, with rare expressing heterozygotes” and summarized that the inheritance of many known Mendelian variants cannot be adequately described by a conventional definition of dominant or recessive ^[16][4].

54. Molecular Background and Possible Influencing Factors

What is the molecular basis for symptomatic heterozygosity, and what other alternative diagnoses can be considered?

Types of Variants

Interestingly, in pseuedodomiant inheritance, most of the variants also appear to be null mutations ^[17][18][54,55], but missense variants have been described as well ^[19][20][56,57], highlighting the possibility that in symptomatic heterozygous individuals may indeed come to the pseudodominant inheritance.

(Deep) Splice Site Variants and Genetic Modifiers

The most obvious differential diagnostic possibility is that a second pathogenic variant has been missed. Several diseases are known in which the variant has been reported first as dominant, but further analysis revealed a second variant later in the diagnostic process. An example is the pseudo-dominant inheritance reported for titinopathies ^[21][22][58,59]. Usually, only the flanking regions around ±10 bp from the exon are sequenced, and even variants described as pathogenic but slightly further from the exon, such as −20 bp variants, are often missed ^[23][60].

Oligogenic Inheritance and Mutational Burden

Digenic/oligogenic inheritance has been identified in a number of disorders, including neurodevelopmental disorders, cardiac disorders, eye diseases, and rare multisystemic disorders, such as Bardet–Biedl syndrome ^[24][25][26][73,74,75]. Moreover, it was shown that some were heterozygous carriers for individual mutations in more than one gene involved in these functionally related pathways. In isolation, heterozygosity for each mutation was clinically irrelevant, but concurrent heterozygosity was synergistic, leading to clinically relevant biochemical derangements. This model of “synergistic heterozygosity” can be very useful for the understanding of complex phenotypes ^[27][28][76,77].

Epigenetic Factors

For approximately 5% of CpG sites, a significant (>30%) difference in DNA methylation can exist between the two alleles. Consequently, methylation of the wild-type allele can lead to symptoms in heterozygous individuals ^[29][30][81,82]. Genetic variation can also affect histone modifications, which can alter chromatin accessibility and result in allele-specific binding of transcription factors. This, in turn, can cause the expression of only the mutated allele in heterozygous individuals. In age-related diseases, including cancers, cardiovascular diseases, and neurodegeneration, the gene quite commonly will be expressed only from one allele. Phenotypic variation in the case of heterozygotes with autosomal diseases can be explained by random allelic expression (RAE) of many autosomal genes.

Environmental Factors

The influence of environmental factors can be a further factor triggering symptomatic heterozygosity and has been suggested for a number of diseases. For example, in FMF, other physiological, environmental, or unidentified conditions that could cause inflammation might also affect the protein threshold or the levels of pyrin required to fight the inflammation. The risk of lung disease may be increased in antitrypsin MZ heterozygotes depending on their environmental exposure, such as smoking and occupational exposure (including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes) ^[31][89]

The group of symptomatic heterozygotes, when compared to the heterozygous at the population level, is very small; thus, testing is not recommended, especially since the factors contributing to symptom occurrence are unknown. Detailed studies elucidating the mechanism of the symptomatic heterozygosity phenomenon are needed.