Deciphering the Complexity of FSHD: A Multimodal Approach as a Model for Rare Disorders

Abstract

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients' care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype-phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up.

Keywords: FSHD; genotype–phenotype correlation; multidisciplinary approach; neuromuscular disorders; rare diseases.

Figure 1

High-throughput technologies for FSHD diagnosis. (A) Molecular combing (MC) [48]. (B) Long-read sequencing. (C) Optical genome mapping (OGM). (D) Short-read sequencing. The figure reports the advantages and disadvantages of the techniques. Each panel contains an example of the data plot for the secondary analysis provided by specific software and bioinformatic pipelines.

Figure 2

The multimodal approach for FSHD diagnosis. The integration of clinical and genetic data at different levels of the FSHD diagnostic path (corresponding to red arrows) is a pivotal component of the multimodal approach highlighted by the present work. Created with https://www.biorender.com (accessed on 24 July 2024). AI: Artificial intelligence.