De novo variants and recombination at 4q35: Hints for preimplantation genetic testing in facioscapulohumeral muscular dystrophy

Pini, Sara; Napoli, Floriana Maria; Tagliafico, Enrico; Marca, Antonio La; Bertucci, Emma; Salsi, Valentina; Tupler, Rossella

doi:10.1111/cge.14250

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…Based on genetic distance, the calculated recombination events within the panel established in this study were 3.29%. However, previous research found a 14% recombination rate within 550 kb upstream of the D4Z4 region (Pini et al, 2023), which is higher than expected. In our study, 87 SNPs were found to be located within this high recombination region, with the nearest SNP being only 64 kb from D4Z4, minimizing the inference of recombination events.…”

Section: Discussioncontrasting

confidence: 70%

“…Wu et al demonstrated the feasibility of amplicon sequencing for NIPD by designing 20-30 amplicons flanking related pathogenic variants in seven different diseases (Wu et al, 2022). In consideration of the high recombination rate upstream of the DUX4 gene (Pini et al, 2023), we increased the number of SNPs to 402, which enabled more accurate detection of recombination events. The knowledge and experience gained from this study can be extended to the design of other panels.…”

Section: Discussionmentioning

confidence: 99%

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First‐trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP‐based amplicon sequencing: An earlier, rapid and safer way

Fu,

Zhao,

Kong

et al. 2024

American J of Med Genetics Pt A

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The study is to explore the feasibility and value of SNP‐based noninvasive prenatal diagnosis (NIPD) for facioscapulohumeral muscular dystrophy type 1 (FSHD1) in early pregnancy weeks. We prospectively collected seven FSHD1 families, with an average gestational age of 8+6. Among these seven couples, there were three affected FSHD1 mothers and four affected fathers. A multiplex‐PCR panel comprising 402 amplicons was designed to selective enrich for highly heterozygous SNPs upstream of the DUX4 gene. Risk haplotype was constructed based on familial linkage analysis. Fetal genotypes were accurately inferred through relative haplotype dosage analysis using Bayes Factor. All tests were successfully completed in a single attempt, and no recombination events were detected. NIPD results were provided within a week, which is 4 weeks earlier than karyomapping and 7 weeks earlier than Bionano single‐molecule optical mapping (BOM). Ultimately, five FSHD1 fetuses and two normal fetuses were successfully identified, with a 100% concordance rate with karyomapping and BOM. Therefore, SNP‐based NIPD for FSHD1 was demonstrated to be feasible and accurate in early weeks of gestation, although the risk of recombination events cannot be completely eliminated. In the future, testing of more cases is still necessary to fully determine the clinical utility.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

First‐trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP‐based amplicon sequencing: An earlier, rapid and safer way

Fu,

Zhao,

Kong

et al. 2024

American J of Med Genetics Pt A

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“…In itself, the D4Z4 array structure impedes direct testing in preimplantation genetic diagnosis [50], and the highly recombinogenic nature of the 4q and 10q subtelomeres obstacles the use of alternative markers for PGD [51]. More recently, molecular combing [52–54] and optical mapping techniques (OGM) [55,56] have emerged to estimate the size of the array.…”

Section: Resultsmentioning

confidence: 99%

The FSHD jigsaw: are we placing the tiles in the right position?

Salsi,

Vattemi,

Tupler

2023

Current Opinion in Neurology

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Purpose of reviewFacioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our purpose was to summarize the main objectives of the scientific community on this topic and the moving trajectories of research from the past to the present. Recent findingsTo date, research is mainly oriented toward deciphering the molecular and pathogenetic basis of the disease by investigating DUX4-mediated muscle alterations. Accordingly, FSHD drug development has been escalating in the last years in an attempt to silence DUX4 or to block its downstream effectors. Breakthroughs in the field include the awareness that new biomarkers and outcome measures are required for tracking disease progression and patient stratification. The need to develop personalized therapeutic strategies is also crucial according to the phenotypic variability observed in FSHD subjects.

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A human pan-genomic analysis reconfigures the genetic and epigenetic make up of facioscapulohumeral muscular dystrophy

Salsi

Chiara

Pini

et al. 2023

Preprint

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Background: Facioscapulohumeral muscular dystrophy (FSHD) is the only human disease associated with epigenetic changes at a macrosatellite array. Alleles with fewer than 10 D4Z4 elements at 4q35 are found in 95% of FSHD cases; remaining cases carrying D4Z4 alleles with 11 or more repeats bear mutations in chromatin remodeling factors. Reduced D4Z4 CpG methylation is used for the molecular diagnosis of FHSD, but D4Z4-like sequences dispersed in the genome can generate ambiguous results. Results: Using an original analytical approach based on complete haplotype level assemblies from the T2T-CHM13 human genome and the human pangenome project, which includes 86 haploid genomes, we uncovered the extensive number of D4Z4-like elements and their widespread inter- and intra-individual variability, which were not represented in the GRCh38 reference. Bisulfite-treated DNAs from 44 subjects (29 FSHD index cases, 15 relatives) were analyzed through high-depth methylation sequencing assaying 82 CpGs spanning the D4Z4 repeat. Samples stratified in three groups with low, intermediate, and high CpG methylation. Low D4Z4 methylation was associated with variants in the chromatin remodeling factor SMCHD1, but not with the patients'clinical phenotypes. Conclusions: This is the first study showing the relevance of the pangenome and T2T assemblies for investigating the genotype-phenotype correlation in genetic diseases. The extension and the variability of D4Z4-like elements scattered throughout the human genome and the variable phenotypes advocate for a critical revision of FSHD diagnostic tests based on D4Z4 CpG methylation assays and indicate that they must be complemented by family studies for the proper interpretation of results.

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De novo variants and recombination at 4q35: Hints for preimplantation genetic testing in facioscapulohumeral muscular dystrophy

Cited by 4 publications

References 19 publications

First‐trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP‐based amplicon sequencing: An earlier, rapid and safer way

First‐trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP‐based amplicon sequencing: An earlier, rapid and safer way

The FSHD jigsaw: are we placing the tiles in the right position?

A human pan-genomic analysis reconfigures the genetic and epigenetic make up of facioscapulohumeral muscular dystrophy

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