Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD

Vasale, Jessica; Boyar, Fatih Z; Jocson, Michael; Sulcova, Vladimira; Chan, Patricia; Liaquat, Khalida; Hoffman, Carol; Meservey, Marc; Chang, Isabell; Tsao, David; Hensley, Kerri; Liu, Yan; Owen, Renius; Braastad, Corey; Sun, Weimin; Walrafen, Pierre; Komatsu, Jun; Wang, Jia‐Chi; Bensimon, Aaron; Anguiano, Arturo; Jaremko, Malgorzata; Wang, Zhenyuan; Batish, Sat Dev; Strom, Charles M.; Higgins, Joseph

doi:10.1016/j.nmd.2015.08.008

Cited by 36 publications

(37 citation statements)

References 39 publications

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“…Furthermore, our data support the added value of MC compared with SB for the primary diagnosis of the disease but also for the elucidation of complex cases such as rearrangements or unresolved genotypes and the systematic detection of 4qA/qB and 10q alleles. Overall, our results, together with a recent study (Vasale et al., ), show that MC has a lower false‐negative rate compared with SB and thus can be reliably used for molecular diagnosis of FSHD in general but also for the resolution of complex cases in clinical practice, the most undisputable feature in the disease being the clinical phenotype unifying FSHD1, FSHD2, and more complex cases (Figure ).…”

Section: Discussionsupporting

confidence: 74%

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

et al. 2017

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International audienceFacioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As molecular diagnosis relying on Southern blot (SB) might be challenging in some cases, molecular combing (MC) was recently developed as an additional technique for FSHD diagnosis and exploration of the genomic organization of the 4q35 and 10q26 regions. In complement to the usual SB, we applied MC in a large cohort of 586 individuals with clinical FSHD. In 332 subjects, the two 4q alleles were normal in size, allowing exclusion of FSHD1 while we confirmed FSHD1 in 230 patients. In 14 patients from 10 families, we identified a recurrent complex heterozygous rearrangement at 4q35 consisting of a duplication of the D4Z4 array and a 4qA haplotype, irresolvable by the SB technique. In five families, we further identified variations in the SMCHD1 gene. Impact of the different mutations was tested using a minigene assay and we analyzed DNA methylation after sodium bisulfite modification and NGS sequencing. We discuss the involvement of this rearrangement in FSHD since all mutations in SMCHD1 are not associated with D4Z4 hypomethylation and do not always segregate with the disease

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Section: Discussionsupporting

confidence: 74%

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

et al. 2017

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“…Comparative genomic hybridization (CGH)‐array studies confirmed 18p terminal deletion (de novo, as absent in the asymptomatic parents) encompassing the SMCHD1 gene (arr18p11.32‐p11.21.148.96314.081.888)×1(hg37)) (Figure , Panels 3 and 4). The D4Z4 array on chromosome 4 had either 19 and 20 repeat units (Panel 5), and two 4qA161 haplotypes were confirmed as previously described (Lemmers et al, ; Vasale et al, ). Severe hypomethylation (average CpG‐methylation 9%) of D4Z4 repeats (an epigenetic hallmark of FSHD) by bisulfite sequencing was observed (Figure , Panel 6), supporting the diagnostic hypothesis of inflammatory FSHD2 associated with 18p‐ syndrome (Gaillard et al, ; Hartweck et al, ).…”

Section: Textsupporting

confidence: 61%

Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome

Renard

Taïeb

Garibaldi

et al. 2018

American J of Med Genetics Pt A

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Facioscapulohumeral muscular dystrophy (FSHD) has been shown to be related to genetic and epigenetic derepression of DUX4 (mapping to chromosome 4), a gene located within a repeat array of D4Z4 sequences of polymorphic length. FSHD type 1 (FSHD1) is associated with pathogenic D4Z4 repeat array contraction, while FSHD type 2 (FSHD2) is associated with SMCHD1 variants (a chromatin modifier gene that maps to the short arm of chromosome 18). Both FSHD types require permissive polyadenylation signal (4qA) downstream of the D4Z4 array.

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“…The genetic diagnosis of FSHD1 is very difficult, because of the special DNA structural features involved in the genetics of this disease: (1) Multiple (11‐100) small (3.3 KB) D4Z4 repeated elements in chromosome region 4q35.2 are present on the normal chromosome, while pathogenic deletions associated with FSHD1 result in many fewer D4Z4 repeats (1‐10) ; (2) the downstream pathogenic 4qA allele must be distinguished from the non‐pathogenic 4qB allele; (3) The D4Z4 repeats are highly homologous and difficult to distinguish from 10q26.3 region . There are two methods of FSHD1 genetic diagnosis currently in use: Southern Blot and molecular combing. Recently, the Bionano optical mapping technique has been used for FSHD1 gene diagnosis .…”

Section: Discussionmentioning

confidence: 99%

Rapid prenatal diagnosis of Facioscapulohumeral Muscular Dystrophy 1 by combined Bionano optical mapping and karyomapping

Zheng

Kong

et al. 2019

Prenatal Diagnosis

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Purpose To explore the feasibility of performing rapid prenatal diagnoses of FSHD1 using a combination of Bianano optical mapping and linkage‐based karyomapping. Methods DNA specimens from a family that had been previously diagnosed with FSHD1 using Southern Blot analysis were used for this study. Genetic diagnosis of the proband, fetus chorionic amniotic fluid, and aborted fetal tissue was performed using Bianano optical mapping (BOM) together with linkage‐based karyomapping. Results BOM analysis showed that the proband's 4q35.2 region contained four D4Z4 repeats and the 4qA permissible allele, consistent with the previous FSHD1 diagnosis obtained by Southern Blotting. BOM analysis of the fetus' 4q35.2 region was consistent with that of the proband. Karyomap analysis revealed that the fetus inherited the affected chromosome segment from the proband. After genetic counseling, the couple choose termination of pregnancy, and we performed gene diagnosis of the abortus tissue by BOM. Conclusions Bianano optical mapping can determine the number of D4Z4 repeats and exclude interference of the 10q26.3 homologous region, and in combination with karyomapping, can be used for rapid and accurate prenatal diagnosis of FSHD1.

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Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD

Cited by 36 publications

References 39 publications

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome

Rapid prenatal diagnosis of Facioscapulohumeral Muscular Dystrophy 1 by combined Bionano optical mapping and karyomapping

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