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

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.

The first genetically confirmed cohort of Facioscapulohumeral Muscular Dystrophy from Northern India.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of hereditary myopathy. Sixty per cent of the world's population lives in Asia, so a significant percentage of the world's FSHD participants is expected to live there. To date, most FSHD studies have involved individuals of European descent, yet small-scale studies of East-Asian populations suggest that the likelihood of developing FSHD may vary. Here, we present the first genetically confirmed FSHD cohort of Indian ancestry, which suggests a pathogenic FSHD1 allele size distribution intermediate between European and North-East Asian populations and more asymptomatic carriers of 4 unit and 5 unit FSHD1 alleles than observed in European populations. Our data provides important evidence of differences relevant to clinical diagnostics and underscores the need for global FSHD participation in research and trial-ready Indian FSHD cohorts.