Abstract
In this study, we investigated the sequence of (Structural Maintenance of Chromosomes flexible Hinge Domain containing 1) SMCHD1 gene in a cohort of clinically defined FSHD (facioscapulohumeral muscular dystrophy) patients in order to assess the distribution of SMCHD1 variants, considering the D4Z4 fragment size in terms of repeated units (RUs; short fragment: 1–7 RU, borderline: 8-10RU and normal fragment: >11RU). The analysis of SMCHD1 revealed the presence of 82 variants scattered throughout the introns, exons and 3’untranslated region (3′UTR) of the gene. Among them, 64 were classified as benign polymorphisms and 6 as VUS (variants of uncertain significance). Interestingly, seven pathogenic/likely pathogenic variants were identified in patients carrying a borderline or normal D4Z4 fragment size, namely c.182_183dupGT (p.Q62Vfs*48), c.2129dupC (p.A711Cfs*11), c.3469G>T (p.G1157*), c.5150_5151delAA (p.K1717Rfs*16) and c.1131+2_1131+5delTAAG, c.3010A>T (p.K1004*), c.853G>C (p.G285R). All of them were predicted to disrupt the structure and conformation of SMCHD1, resulting in the loss of GHKL-ATPase and SMC hinge essential domains. These results are consistent with the FSHD symptomatology and the Clinical Severity Score (CSS) of patients. In addition, five variants (c.*1376A>C, rs7238459; c.*1579G>A, rs559994; c.*1397A>G, rs150573037; c.*1631C>T, rs193227855; c.*1889G>C, rs149259359) were identified in the 3′UTR region of SMCHD1, suggesting a possible miRNA-dependent regulatory effect on FSHD-related pathways. The present study highlights the clinical utility of next-generation sequencing (NGS) platforms for the molecular diagnosis of FSHD and the importance of integrating molecular findings and clinical data in order to improve the accuracy of genotype–phenotype correlations.
Highlights
The application of molecular genetics strategies into the clinical practice highlighted the existence of a large gap between the genotype and phenotype in many human disorders [1,2]
It is important to remark that as many as 2% of the general population presents 8-10 Repeated Units (RU) without being affected [2]. These findings suggested that the etiopathogenesis of FSHD might not be due to the D4Z4 contraction on 4q35 alone, but to a combination of specific genetic and epigenetic signatures, which create a permissive background for the development of disease
The evaluation of frequency distribution and bioinformatics analysis indicated that 8 exonic variants were described as benign or likely benign, whereas 6 exonic variants were classified as Variants of Uncertain Significance (VUS) which need to be further investigated
Summary
The application of molecular genetics strategies into the clinical practice highlighted the existence of a large gap between the genotype and phenotype in many human disorders [1,2]. This is true for neuromuscular disorders which consist of a heterogenous group of pathologies characterized by progressive weakness and wasting of proximal and/or distal muscles [3,4]. Our group is one of the two Italian Reference Centers for the genetic characterization of Facioscapulohumeral muscular Dystrophy (FSHD, OMIM #158900). Patients experience a progressive weakness of scapular girdle, facial and humeral muscles in the initial stage of FSHD. The weakness can extend to the muscles of trunk and of lower-extremities, leading thereby to loss of ambulation in 20%
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