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      Association of 4qA-Specific Distal D4Z4 Hypomethylation With Disease Severity and Progression in Facioscapulohumeral Muscular Dystrophy

      research-article
      Author(s): , MD, , MD, , MD, , MD, , MD, , MD, , MD, , MD, , MD, , MD, , MD , , MD, PhD, , MD, , MD, PhD, , MD, PhD, , MD, PhD, , MD, PhD , , MD, PhD
      Publication date PMC-release:
      Journal: Neurology
      Publisher: Lippincott Williams & Wilkins

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          Abstract

          Background and Objectives

          The objective of this study was to examine whether the regional methylation levels at the most distal D4Z4 repeat units (RU) in the 4qA-permissive haplotype were associated with disease severity and progression in facioscapulohumeral muscular dystrophy type 1 (FSHD1).

          Methods

          This 21-year, retrospective, observational cohort study was conducted at the Fujian Neuromedical Center (FNMC) in China. Methylation levels of the most distal D4Z4 RU, including 10 CpGs, were assessed in all participants by bisulfite sequencing. Patients with FSHD1 were stratified into 4 groups based on methylation percentage quartiles, including LM1 (low methylation), LM2 (low to intermediate methylation), LM3 (intermediate to high methylation), and highest methylation (HM) levels. Patients received evaluations of motor function focusing on lower extremity (LE) progression at baseline and in follow-ups. FSHD clinical score (CS), age-corrected clinical severity scale (ACSS), and modified Rankin scale were used to assess motor function.

          Results

          The methylation levels of the 10 CpGs were significantly lower in all 823 patients with genetically confirmed FSHD1 than in 341 healthy controls (HCs). CpG6 methylation levels could distinguish the following: (1) patients with FSHD1 from HCs; (2) symptomatic from asymptomatic/unaffected patients; (3) patients with LE involvement from those without LE involvement, with AUCs (95% CI) of 0.9684 (0.9584–0.9785), 0.7417 (0.6903–0.7931), and 0.6386 (0.5816–0.6956), respectively. Lower CpG6 methylation levels were correlated with higher CS (r = -0.392), higher ACSS (r = -0.432), and earlier onset age of first-ever muscle weakness (r = 0.297). For the LM1, LM2, LM3, and HM groups, the respective proportions of LE involvement were 52.9%, 44.2%, 36.9%, and 23.4%; and onset ages of LE involvement were 20, 26.5, 25, and 26.5 years. Cox regression analysis—adjusted for sex, age at examination, D4Z4 RU, and 4qA/B haplotype—showed that the LM1, LM2, and LM3 groups (i.e., groups with lower methylation levels) had a higher risk of independent ambulation loss, with HRs (95% CI) of 3.523 (1.565–7.930), 3.356 (1.458–7.727), and 2.956 (1.245–7.020), respectively.

          Discussion

          4q35 distal D4Z4 hypomethylation is correlated with disease severity and progression to lower extremity involvement.

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          Most cited references26

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          Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale.

          J Wilson, Asha Hareendran, Marie Grant … (2002)
          The modified Rankin Scale is widely used to assess changes in activity and lifestyle after stroke, but it has been criticized for its subjectivity. The purpose of the present study was to compare conventional assessment on the modified Rankin Scale with assessment through a structured interview. Sixty-three patients with stroke 6 to 24 months previously were interviewed and graded independently on the modified Rankin Scale by 2 observers. These observers then underwent training in use of a structured interview for the scale that covered 5 areas of everyday function. Eight weeks after the first assessment, the same observers reassessed 58 of these patients using the structured interview. Interrater reliability was measured with the kappa statistic (weighted with quadratic weights). For the scale applied conventionally, overall agreement between the 2 raters was 57% (kappa(w)=0.78); 1 rater assigned significantly lower grades than the other (P=0.048). On the structured interview, the overall agreement between raters was 78% (kappa(w)=0.93), and there was no overall difference between raters in grades assigned (P=0.17). Rankin grades from the conventional assessment and the structured interview were highly correlated, but there was significantly less disagreement between raters when the structured interview was used (P=0.004). Variability and bias between raters in assigning patients to Rankin grades may be reduced by use of a structured interview. Use of a structured interview for the scale could potentially improve the quality of results from clinical studies in stroke.
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            Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype.

            E Ricci, G. Galluzzi, G Deidda … (1999)
            Genotype analysis by using the p13E-11 probe and other 4q35 polymorphic markers was performed in 122 Italian facioscapulohumeral muscular dystrophy families and 230 normal controls. EcoRI-BlnI double digestion was routinely used to avoid the interference of small EcoRI fragments of 10qter origin that were found in 15% of the controls. An EcoRI fragment ranging between 10 and 28 kb that was resistant to BlnI digestion was detected in 114 of 122 families (93%) comprising 76 familial and 38 isolated cases. Among the unaffected individuals, 3 were somatic mosaics and 7, carrying an EcoRI fragment larger than 20 kb, could be rated as nonpenetrant gene carriers. In a cohort of 165 patients with facioscapulohumeral muscular dystrophy we found an inverse correlation between fragment size and clinical severity. A severe lower limb involvement was observed in 100% of patients with an EcoRI fragment size of 10 to 13 kb (1-2 KpnI repeats left), in 53% of patients with a fragment size of 16 to 20 kb (3-4 KpnI repeats left), and in 19% of patients with a fragment size larger than 21 kb (>4 KpnI repeats left). Our results confirm that the size of the fragment is a major factor in determining the facioscapulohumeral muscular dystrophy phenotype and that it has an impact on clinical prognosis and genetic counseling of the disease.
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              Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.

              Jane Hewitt, Robert Lyle, Lorraine N Clark … (1994)
              The sequence of the tandem repeat sequence (D4Z4) associated with facioscapulohumeral muscular dystrophy (FSHD) has been determined: each copy of the 3.3 kb repeat contains two homeoboxes and two previously described repetitive sequences, LSau and a GC-rich low copy repeat designated hhspm3. By Southern blotting, FISH and isolation of cDNA and genomic clones we show that there are repeat sequences similar to D4Z4 at other locations in the human genome. Southern blot analysis of primate genomic DNA indicates that the copy number of D4Z4-like repeats has increased markedly within the last 25 million years. Two cDNA clones were isolated and found to contain stop codons and frameshifts within the homeodomains. An STS was produced to the cDNAs and analysis of a somatic cell hybrid panel suggests they map to chromosome 14. No cDNA clones mapping to the chromosome 4q35 D4Z4 repeats have been identified, although the possibility that they encode a protein cannot be ruled out. Although D4Z4 may not encode a protein, there is an association between deletions within this locus and FSHD. The D4Z4 repeats contain LSau repeats and are adjacent to 68 bp Sau3A repeats. Both of these sequences are associated with heterochromatic regions of DNA, regions known to be involved in the phenomenon of position effect variegation. We postulate that deletion of D4Z4 sequences could produce a position effect.
              Article 0 comments Cited 90 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Neurology
                Journal ID (iso-abbrev): Neurology
                Journal ID (hwp): neurology
                Journal ID (publisher-id): neur
                Journal ID (publisher-id): NEUROLOGY
                Title: Neurology
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0028-3878
                ISSN (Electronic): 1526-632X
                Publication date (Print): 18 July 2023
                Publication date PMC-release: 18 July 2023
                Volume: 101
                Issue: 3
                Pages: e225-e237
                Affiliations
                From the Department of Neurology and Institute of Neurology of First Affiliated Hospital (F.Z., L.Q., L.C., Y.Z., Xiaodan Lin, J.H., Xin Lin, Q.H., Yuhua Lin, L.L., L.W., F.L., K.Y., M.L., Yi Lin, Y.F., N.W., Z.W.), Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou; and Department of Neurology (L.Q., Xin Lin, F.L., M.L., Yi Lin, Y.F., N.W., Z.W.), National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
                Author notes
                Correspondence Dr. Wang fmuwzq@ 123456fjmu.edu.cn

                Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

                The Article Processing Charge was funded by the National Natural Science Foundation of China (81974193, Z.Q.W.); the Joint Funds (2020Y9016, Z.Q.W.) and (2021Y9133, L.L.Q.) for the Innovation of Science and Technology of Fujian Province.

                Submitted and externally peer reviewed. The handling editor was Associate Editor Anthony Amato, MD, FAAN.

                [*]

                These authors contributed equally to this work as first authors.

                Author information
                https://orcid.org/0000-0002-1983-3331
                Article
                Publisher ID: WNL-2023-000256
                DOI: 10.1212/WNL.0000000000207418
                PMC ID: 10382269
                PubMed ID: 37225433
                SO-VID: b880fe4f-a0ea-4d7a-bc62-944520a083cb
                Copyright © Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                Date received : 29 November 2022
                Date accepted : 31 March 2023
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