Li Kun, Quiat Daniel, She Fei, Liu Yuanwei, He Rong, Haghighi Alireza, Liu Fang, Zhang Rui, DePalma Steven Robert, Yang Ying, Wang Wen, Seidman Christine E, Zhang Ping, Seidman Jonathan G
Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
Department of Genetics, Harvard Medical School, Boston, MA.
Genet Med Open. 2024 Jan 29;2:101817. doi: 10.1016/j.gimo.2024.101817. eCollection 2024.
Facioscapulohumeral dystrophy type 1 (FSHD1) is a progressive, debilitating skeletal myopathy that requires a multimodal approach for complete molecular characterization of pathogenic genotypes. Here, we report genomic analyses of a family with suspected FSHD1. We first performed short-read genome sequencing, followed by parametric linkage analysis using rare variants to map the disease locus to a single 1.7 Mb interval on chromosome 4q35.2 with a logarithm of the odds score of 3.2. We then used ultra-long-read genome sequencing as a single molecular test to genotype a pathogenic FSHD allele containing a 4qA permissive haplotype and 5 KpnI repeat units at the D4Z4 locus. These results demonstrate that genome-wide rare variant-based linkage analysis is a powerful tool for mapping disease loci in families, and ultra-long-read genome sequencing is capable of genotyping pathogenic FSHD1 alleles.
1型面肩肱型肌营养不良症（FSHD1）是一种进行性、使人衰弱的骨骼肌病，需要采用多模式方法来全面分子表征致病基因型。在此，我们报告了一个疑似FSHD1家系的基因组分析。我们首先进行了短读长基因组测序，随后使用罕见变异进行参数连锁分析，将疾病位点定位到4号染色体q35.2上一个单一的1.7 Mb区间，对数优势分数为3.2。然后，我们使用超长读长基因组测序作为单一分子检测方法，对一个致病FSHD等位基因进行基因分型，该等位基因在D4Z4位点包含一个4qA许可单倍型和5个KpnI重复单元。这些结果表明，全基因组基于罕见变异的连锁分析是在家族中定位疾病位点的有力工具，超长读长基因组测序能够对致病FSHD1等位基因进行基因分型。
