Challenging Occam's Razor: Dual Molecular Diagnoses Explain Entangled Clinical Pictures

Abstract

Dual molecular diagnoses are defined as the presence of pathogenic variants at two distinct and independently segregating loci that cause two different Mendelian conditions. In this study, we report the identification of double genetic disorders in a series of patients with complex clinical features. In the last 24 months, 342 syndromic patients have been recruited and clinically characterised. Whole Exome Sequencing analysis has been performed on the proband and on both parents and identified seven patients affected by a dual molecular diagnosis. Upon a detailed evaluation of both their clinical and molecular features, subjects are able to be divided into two groups: (A) five patients who present distinct phenotypes, due to each of the two different underlying genetic diseases; (B) two patients with overlapping clinical features that may be underpinned by both the identified genetic variations. Notably, only in one case a multilocus genomic variation was already suspected during the clinical evaluation. Overall, our findings highlight how dual molecular diagnoses represent a challenging model of complex inheritance that should always be considered whenever a patient shows atypical clinical features. Indeed, an accurate genetic characterisation is of the utmost importance to provide patients with a personalised and safe clinical management.

Keywords: dual molecular diagnosis; multilocus genomic variation; whole exome sequencing.

Figure 1

Dual molecular diagnoses patterns. (A). Dual molecular diagnoses with distinct phenotypes: patients present a blended phenotype due to the simultaneous presence of two Mendelian disorders caused by variants at two independently segregating loci. Each condition is characterised by a different and specific set of signs and symptoms, and they may be recognised as discrete upon reverse phenotyping. (B). Dual molecular diagnoses with overlapping phenotypes: patients’ clinical picture may be ascribed to either of the two underlying Mendelian disorders. In the exemplified cases, one condition is inherited from both patients in an autosomal recessive manner, and the other has a de novo origin in the proband; nevertheless, all inheritance patterns are possible.

Figure 2

Family pedigrees of patients affected by dual molecular diagnoses. The figure illustrates the main clinical features of each patient and the genes associated with their phenotypes. (A–G) indicate each of the seven patients described in this study. Half black filling of father and mother indicates healthy carrier parents. Three-quarters black filling of proband indicates that he/she is affected by an autosomal recessive condition. One-quarter or half chessboard filling of proband or parent indicates that subject is affected by an autosomal dominant disorder. Half diagonal-line filling of proband or parent indicates that subject is affected by another autosomal dominant disorder. Half vertical-line filling of a male proband indicates that he is affected by an X-linked disorder. Half vertical-line filling of a female subject indicates a healthy carrier of an X-linked condition.

Figure 3

Diagnostic work-up of patients presenting complex clinical pictures. The first step consists in a detail clinical characterisation that is achieved through an anamnesis collection, a dysmorphological examination, and ancillary laboratory and imaging investigations. This leads to the formulation of a diagnostic hypothesis, that could immediately consider the possible presence of a dual molecular diagnosis or, on the contrary, contemplate the existence of a single syndromic condition.