Intricacies of aetiology in intrafamilial degenerative disease

Abstract

The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the disease trait in affected, but not unaffected, individuals. However, instances of intrafamilial etiological heterogeneity, where pathogenic variants in a culprit gene are not shared among all affected family members, continue to emerge and confound gene-discovery and genetic counselling efforts. Discordant intrafamilial cases lacking a mutation shared by other affected family members are described as disease phenocopies. This description often results in an over-simplified acceptance of an environmental cause of disease in the phenocopy cases, while the role of intrafamilial genetic heterogeneity, shared de novo mutations or epigenetic aberrations in such families is often ignored. On a related note, it is now evident that the same disease-associated variant can be present in individuals exhibiting clinically distinct phenotypes, thereby genetically uniting seemingly unrelated syndromes to form a spectrum of disease. Herein, we discuss the intricacies of determining complex degenerative disease aetiology and suggest alternative mechanisms of disease transmission that may account for the apparent missing heritability of disease.

Keywords: aetiology; inheritance; neurodegeneration; phenocopy; pleiotropy.

Graphical Abstract

Figure 1

Family 379. Unaffected individuals are represented by white diamonds. For simplicity and clarity, multiple unaffected individuals within a sibship are represented by a single diamond and spouses are omitted. All affected individuals in this pedigree have a clinical diagnosis of ALS. Affected individuals for which DNA samples were unavailable are represented by grey diamonds. Affected family members with a TAR DNA-binding protein 43 p. G298S mutation are represented by black diamonds. Affected individual III-6 (yellow diamond) harbours a heterozygous SOD1 p. D91A mutation. Affected individuals IV-30 and V-3 (red diamonds) lack a mutation in known ALS-associated genes. Individual IV-25 is a true obligate carrier of TAR DNA-binding protein 43 p. G298S. All other indicated obligate carriers, represented by a black circle within a diamond, are possible obligate carriers since DNA samples were unavailable to confirm the presence of a mutation or the affected individuals in subsequent generations lack a known mutation.

Figure 2

Family 1174. Unaffected individuals are represented by white diamonds. For simplicity and clarity, multiple unaffected individuals within a sibship are represented by a single diamond and spouses are omitted. Individuals affected with ALS for which DNA samples were unavailable are represented by grey diamonds. Individuals affected with ALS for which DNA samples are available are represented by black diamonds. Individual V-1, represented by a yellow diamond, presented with bilateral leg weakness at 45 years of age and has a clinical diagnosis of spastic paraparesis with lower extremity weakness. Their condition has been stable for 30 years. Individual V-6, represented by a green diamond, has a clinical diagnosis of probable Alzheimer Disease. Individual V-13, represented by a red diamond, has a clinical diagnosis of Paget Disease of Bone. SQSTM1 p. P392L-positive individuals are indicated by a ‘+’ sign. SQSTM1 p. P392L-negative individuals are indicated by a ‘−’ sign. Possible obligate carriers are represented by a black circle within a diamond.

Figure 3

A hypothetical pedigree depicting scenarios to consider when encountering cases of presumed discordant disease aetiology. We indicate three siblings with a clinically similar phenotype (black). Two of the three affected individuals (II-3 and II-4) harbour a candidate disease-causing variant W, whereas all others tested negative for variant W in blood. While the phenotype in individual II-5 may be the result of an environmental trigger (i.e. classical phenocopy), the apparent disconnect between genotype and phenotype may also be explained by intrafamilial genetic heterogeneity (variants W and X), chimerism, mosaicism or identification of a distinct shared disease-causing variant Y. Alternatively, variant Z may have pleiotropic functions, and therefore cause a clinically distinct phenotype (red and black). In situations where both parents appear healthy and/or test negative for the suspected disease-causing variant, one must consider the potential role of germline chimerism or germline mosaicism via DNMs or epimutations.