Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping
ObjectiveFacioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most common forms of autosomal-dominant muscular dystrophies characterized by variable disease penetrance due to shortened D4Z4 repeat units on 4q35. The molecular diagnosis of FSHD1 is usually made by Southern blotting, wh...
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2024.1258831/full |
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| author | Jieni Jiang Jieni Jiang Jieni Jiang Xiaotang Cai Xiaotang Cai Haibo Qu Haibo Qu Qiang Yao Qiang Yao Tiantian He Tiantian He Tiantian He Mei Yang Mei Yang Mei Yang Hui Zhou Hui Zhou Xuemei Zhang Xuemei Zhang Xuemei Zhang |
| author_facet | Jieni Jiang Jieni Jiang Jieni Jiang Xiaotang Cai Xiaotang Cai Haibo Qu Haibo Qu Qiang Yao Qiang Yao Tiantian He Tiantian He Tiantian He Mei Yang Mei Yang Mei Yang Hui Zhou Hui Zhou Xuemei Zhang Xuemei Zhang Xuemei Zhang |
| author_sort | Jieni Jiang |
| collection | DOAJ |
| description | ObjectiveFacioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most common forms of autosomal-dominant muscular dystrophies characterized by variable disease penetrance due to shortened D4Z4 repeat units on 4q35. The molecular diagnosis of FSHD1 is usually made by Southern blotting, which is complex, time-consuming, and lacks clinical practicality. Therefore, in this study, optical genome mapping (OGM) is employed for the genetic diagnosis of FSHD1. Furthermore, epigenetic heterogeneity is determined from methylation analysis.MethodsGenomic DNA samples from four members of the same family were subjected to whole-exome sequencing. OGM was used to identify structural variations in D4Z4, while sodium bisulfite sequencing helped identify the methylation levels of CpG sites in a region located distally to the D4Z4 array. A multidisciplinary team collected the clinical data, and comprehensive family analyses aided in the assessment of phenotypes and genotypes.ResultsWhole-exome sequencing did not reveal variants related to clinical phenotypes in the patients. OGM showed that the proband was a compound heterozygote for the 4qA allele with four and eight D4Z4 repeat units, whereas the affected younger brother had only one 4qA allele with four D4Z4 repeat units. Both the proband and her younger brother were found to display asymmetric weakness predominantly involving the facial, shoulder girdle, and upper arm muscles, whereas the younger brother had more severe clinical symptoms. The proband's father, who was found to be normal after a neurological examination, also carried the 4qA allele with eight D4Z4 repeat units. The unaffected mother exhibited 49 D4Z4 repeat units of the 4qA allele and a minor mosaic pattern with four D4Z4 repeat units of the 4qA allele. Consequently, the presence of the 4qA allele in the four D4Z4 repeat units strongly pointed to the occurrence of maternal germline mosaicism. The CpG6 methylation levels were lower in symptomatic patients compared to those in the asymptomatic parents. The older sister had lower clinical scores and ACSS and higher CpG6 methylation levels than that of her younger brother.ConclusionsIn this study, two siblings with FSHD1 with phenotypically normal parents were identified by OGM. Our findings suggest that the 4qA allele of four D4Z4 repeats was inherited through maternal germline mosaicism. The clinical phenotype heterogeneity is influenced by the CpG6 methylation levels. The results of this study greatly aid in the molecular diagnosis of FSHD1 and in also understanding the clinical phenotypic variability underlying the disease. |
| first_indexed | 2024-03-08T09:06:37Z |
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| last_indexed | 2024-03-08T09:06:37Z |
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| series | Frontiers in Neurology |
| spelling | doaj.art-9c8cd440307a4edfae57a7c9a20289ba2024-02-01T04:35:58ZengFrontiers Media S.A.Frontiers in Neurology1664-22952024-02-011510.3389/fneur.2024.12588311258831Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mappingJieni Jiang0Jieni Jiang1Jieni Jiang2Xiaotang Cai3Xiaotang Cai4Haibo Qu5Haibo Qu6Qiang Yao7Qiang Yao8Tiantian He9Tiantian He10Tiantian He11Mei Yang12Mei Yang13Mei Yang14Hui Zhou15Hui Zhou16Xuemei Zhang17Xuemei Zhang18Xuemei Zhang19Department of Medical Genetics and Prenatal Diagnosis Center, West China Second University Hospital, Sichuan University, Chengdu, ChinaDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaDepartment of Rehabilitation, West China Second University Hospital, Sichuan University, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaDepartment of Radiology, West China Second University Hospital, Sichuan University, Chengdu, ChinaDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaDepartment of Medical Genetics and Prenatal Diagnosis Center, West China Second University Hospital, Sichuan University, Chengdu, ChinaDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaDepartment of Medical Genetics and Prenatal Diagnosis Center, West China Second University Hospital, Sichuan University, Chengdu, ChinaDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaDepartment of Rehabilitation, West China Second University Hospital, Sichuan University, Chengdu, ChinaDepartment of Medical Genetics and Prenatal Diagnosis Center, West China Second University Hospital, Sichuan University, Chengdu, ChinaDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, ChinaObjectiveFacioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most common forms of autosomal-dominant muscular dystrophies characterized by variable disease penetrance due to shortened D4Z4 repeat units on 4q35. The molecular diagnosis of FSHD1 is usually made by Southern blotting, which is complex, time-consuming, and lacks clinical practicality. Therefore, in this study, optical genome mapping (OGM) is employed for the genetic diagnosis of FSHD1. Furthermore, epigenetic heterogeneity is determined from methylation analysis.MethodsGenomic DNA samples from four members of the same family were subjected to whole-exome sequencing. OGM was used to identify structural variations in D4Z4, while sodium bisulfite sequencing helped identify the methylation levels of CpG sites in a region located distally to the D4Z4 array. A multidisciplinary team collected the clinical data, and comprehensive family analyses aided in the assessment of phenotypes and genotypes.ResultsWhole-exome sequencing did not reveal variants related to clinical phenotypes in the patients. OGM showed that the proband was a compound heterozygote for the 4qA allele with four and eight D4Z4 repeat units, whereas the affected younger brother had only one 4qA allele with four D4Z4 repeat units. Both the proband and her younger brother were found to display asymmetric weakness predominantly involving the facial, shoulder girdle, and upper arm muscles, whereas the younger brother had more severe clinical symptoms. The proband's father, who was found to be normal after a neurological examination, also carried the 4qA allele with eight D4Z4 repeat units. The unaffected mother exhibited 49 D4Z4 repeat units of the 4qA allele and a minor mosaic pattern with four D4Z4 repeat units of the 4qA allele. Consequently, the presence of the 4qA allele in the four D4Z4 repeat units strongly pointed to the occurrence of maternal germline mosaicism. The CpG6 methylation levels were lower in symptomatic patients compared to those in the asymptomatic parents. The older sister had lower clinical scores and ACSS and higher CpG6 methylation levels than that of her younger brother.ConclusionsIn this study, two siblings with FSHD1 with phenotypically normal parents were identified by OGM. Our findings suggest that the 4qA allele of four D4Z4 repeats was inherited through maternal germline mosaicism. The clinical phenotype heterogeneity is influenced by the CpG6 methylation levels. The results of this study greatly aid in the molecular diagnosis of FSHD1 and in also understanding the clinical phenotypic variability underlying the disease.https://www.frontiersin.org/articles/10.3389/fneur.2024.1258831/fullfacioscapulohumeral muscular dystrophy 1optical genome mappingsibling patientlow-level mosaicismgermline mosaicismdisease penetrance |
| spellingShingle | Jieni Jiang Jieni Jiang Jieni Jiang Xiaotang Cai Xiaotang Cai Haibo Qu Haibo Qu Qiang Yao Qiang Yao Tiantian He Tiantian He Tiantian He Mei Yang Mei Yang Mei Yang Hui Zhou Hui Zhou Xuemei Zhang Xuemei Zhang Xuemei Zhang Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping Frontiers in Neurology facioscapulohumeral muscular dystrophy 1 optical genome mapping sibling patient low-level mosaicism germline mosaicism disease penetrance |
| title | Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping |
| title_full | Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping |
| title_fullStr | Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping |
| title_full_unstemmed | Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping |
| title_short | Case report: Identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping |
| title_sort | case report identification of facioscapulohumeral muscular dystrophy 1 in two siblings with normal phenotypic parents using optical genome mapping |
| topic | facioscapulohumeral muscular dystrophy 1 optical genome mapping sibling patient low-level mosaicism germline mosaicism disease penetrance |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2024.1258831/full |
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