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Review
. 2024 Jul;106(1):13-26.
doi: 10.1111/cge.14533. Epub 2024 Apr 29.

Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines

Emiliano Giardina  1   2 , Pilar Camaño  3   4 , Sarah Burton-Jones  5 , Gina Ravenscroft  6 , Franclo Henning  7 , Frederique Magdinier  8 , Nienke van der Stoep  9 , Patrick J van der Vliet  10 , Rafaëlle Bernard  8   11 , Pedro J Tomaselli  12 , Mark R Davis  13 , Ichizo Nishino  14   15 , Piraye Oflazer  16 , Valerie Race  17 , Venugopalan Y Vishnu  18 , Victoria Williams  19 , Cláudia F R Sobreira  12 , Silvere M van der Maarel  10 , Steve A Moore  20 , Nicol C Voermans  21 , Richard J L F Lemmers  10
Affiliations
Review

Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines

Emiliano Giardina et al. Clin Genet. 2024 Jul.

Abstract

The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.

Keywords: facioscapulohumeral muscular dystrophy; genetic diagnosis; genotype phenotype correlation; guidelines; molecular diagnostic techniques; outcome assessment; trial readiness; worldwide consensus.

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Figures

Figure 1:
Figure 1:
Typical signs of FSHD. These do not occur in a predetermined order and are mostly asymmetric. Reproduced with permission of BMJ Publishers (8).
Figure 2:
Figure 2:
Maximum likelihood curves of the penetrance related to FSHD1 allele size (in units). These curves show the likelihood of an FSHD1 allele carrier experiencing symptoms of FSHD (A: Symptomatic) and of experiencing symptoms or showing signs of FSHD (B: Symptomatic + asymptomatic). Individuals with an FSHD1 allele of 9U have a likelihood of approximately 10% of reporting symptoms in middle adulthood (category A), whereas the likelihood of reporting symptoms or showing signs (category B) is approximately 50%. This leaves 50% who are still non-penetrant at that age. Reproduced with permission of Wolters Kluwer Health, Inc. (7).
Figure 3:
Figure 3:
Schematic representation of minimal criteria for genetic confirmation of FSHD.
See this image and copyright information in PMC

References

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