Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomy
Objective·To investigate the genetic etiology of a rare and complex case clinically suspected to be methylmalonic acidemia (MMA), but with negative whole exome sequencing (WES) results, using a multi-omics sequencing approach.Methods·DNA and RNA samples were extracted from the peripheral blood of th...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | zho |
| Published: |
Editorial Office of Journal of Shanghai Jiao Tong University (Medical Science)
2025-06-01
|
| Series: | Shanghai Jiaotong Daxue xuebao. Yixue ban |
| Subjects: | |
| Online Access: | https://xuebao.shsmu.edu.cn/article/2025/1674-8115/1674-8115-2025-45-6-800.shtml（ |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850080831292309504 |
|---|---|
| author | HUO Xiaoyan LUO Xiaomei YE Xiantao SUN Yu YU Yongguo LIANG Lili FAN Yanjie |
| author_facet | HUO Xiaoyan LUO Xiaomei YE Xiantao SUN Yu YU Yongguo LIANG Lili FAN Yanjie |
| author_sort | HUO Xiaoyan |
| collection | DOAJ |
| description | Objective·To investigate the genetic etiology of a rare and complex case clinically suspected to be methylmalonic acidemia (MMA), but with negative whole exome sequencing (WES) results, using a multi-omics sequencing approach.Methods·DNA and RNA samples were extracted from the peripheral blood of the proband and both parents. Targeted MMA-related gene Panel sequencing and WES were first performed. Subsequently, RNA sequencing (RNA-seq) and whole genome sequencing (WGS) were conducted to comprehensively analyze the child's genetic variants, their origins and potential inheritance patterns.Results·No pathogenic variants associated with the patient's phenotype were identified through the MMA Panel or standard WES analysis. Extended analysis of WES suggested the possibility of uniparental disomy (UPD) of chromosome 4. WGS revealed a homozygous splice-site variant (c.-66+2T>C) in the non-coding region of the metabolism of cobalamin associated A (MMAA) gene. The variant was located in the 5' untranslated region (5'UTR), specifically at the second base downstream of the splice donor site of exon 1 (reference sequence: NM_172250). In genomic coordinates (hg19), the variant was located at base 146540561 on chromosome 4 (chr4:146540561). Sanger sequencing confirmed that the mother was heterozygous for this variant, while the father did not carry it. RNA-seq showed no detectable expression of the MMAA gene on chromosome 4 in the patient. This was further confirmed by reverse transcription real time quantitative PCR, indicating nearly absent mRNA expression, suggesting that the non-coding splice-site variant affected transcriptional expression.Conclusion·A homozygous splice-site variant (c.-66+2T>C) in the non-coding region of the MMAA gene—outside the coverage of WES—is likely the pathogenic cause in this case, presumably resulting from maternal UPD of chromosome 4. |
| format | Article |
| id | doaj-art-e06c672248784d439c8004664d7fe895 |
| institution | DOAJ |
| issn | 1674-8115 |
| language | zho |
| publishDate | 2025-06-01 |
| publisher | Editorial Office of Journal of Shanghai Jiao Tong University (Medical Science) |
| record_format | Article |
| series | Shanghai Jiaotong Daxue xuebao. Yixue ban |
| spelling | doaj-art-e06c672248784d439c8004664d7fe8952025-08-20T02:44:52ZzhoEditorial Office of Journal of Shanghai Jiao Tong University (Medical Science)Shanghai Jiaotong Daxue xuebao. Yixue ban1674-81152025-06-0145680080610.3969/j.issn.1674-8115.2025.06.0161674-8115（2025）06-0800-07Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomyHUO Xiaoyan0LUO Xiaomei1YE Xiantao2SUN Yu3YU Yongguo4LIANG Lili5FAN Yanjie6Department of Pediatric Genetics and Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute of Pediatric Research, Shanghai 200092, ChinaDepartment of Pediatric Genetics and Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute of Pediatric Research, Shanghai 200092, ChinaMedical Genetics Center, Jiangxi Maternal and Child Health Hospital, Nanchang 330000, ChinaDepartment of Pediatric Genetics and Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute of Pediatric Research, Shanghai 200092, ChinaDepartment of Pediatric Genetics and Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute of Pediatric Research, Shanghai 200092, ChinaDepartment of Pediatric Genetics and Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute of Pediatric Research, Shanghai 200092, ChinaDepartment of Pediatric Genetics and Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute of Pediatric Research, Shanghai 200092, ChinaObjective·To investigate the genetic etiology of a rare and complex case clinically suspected to be methylmalonic acidemia (MMA), but with negative whole exome sequencing (WES) results, using a multi-omics sequencing approach.Methods·DNA and RNA samples were extracted from the peripheral blood of the proband and both parents. Targeted MMA-related gene Panel sequencing and WES were first performed. Subsequently, RNA sequencing (RNA-seq) and whole genome sequencing (WGS) were conducted to comprehensively analyze the child's genetic variants, their origins and potential inheritance patterns.Results·No pathogenic variants associated with the patient's phenotype were identified through the MMA Panel or standard WES analysis. Extended analysis of WES suggested the possibility of uniparental disomy (UPD) of chromosome 4. WGS revealed a homozygous splice-site variant (c.-66+2T>C) in the non-coding region of the metabolism of cobalamin associated A (MMAA) gene. The variant was located in the 5' untranslated region (5'UTR), specifically at the second base downstream of the splice donor site of exon 1 (reference sequence: NM_172250). In genomic coordinates (hg19), the variant was located at base 146540561 on chromosome 4 (chr4:146540561). Sanger sequencing confirmed that the mother was heterozygous for this variant, while the father did not carry it. RNA-seq showed no detectable expression of the MMAA gene on chromosome 4 in the patient. This was further confirmed by reverse transcription real time quantitative PCR, indicating nearly absent mRNA expression, suggesting that the non-coding splice-site variant affected transcriptional expression.Conclusion·A homozygous splice-site variant (c.-66+2T>C) in the non-coding region of the MMAA gene—outside the coverage of WES—is likely the pathogenic cause in this case, presumably resulting from maternal UPD of chromosome 4.https://xuebao.shsmu.edu.cn/article/2025/1674-8115/1674-8115-2025-45-6-800.shtml（non-coding variantgenomic sequencingtranscriptome sequencingmethylmalonic acidemia (mma) |
| spellingShingle | HUO Xiaoyan LUO Xiaomei YE Xiantao SUN Yu YU Yongguo LIANG Lili FAN Yanjie Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomy Shanghai Jiaotong Daxue xuebao. Yixue ban non-coding variant genomic sequencing transcriptome sequencing methylmalonic acidemia (mma) |
| title | Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomy |
| title_full | Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomy |
| title_fullStr | Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomy |
| title_full_unstemmed | Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomy |
| title_short | Multi-omics analysis of methylmalonic acidemia caused by a non-coding region variant in MMAA gene combined with uniparental disomy |
| title_sort | multi omics analysis of methylmalonic acidemia caused by a non coding region variant in mmaa gene combined with uniparental disomy |
| topic | non-coding variant genomic sequencing transcriptome sequencing methylmalonic acidemia (mma) |
| url | https://xuebao.shsmu.edu.cn/article/2025/1674-8115/1674-8115-2025-45-6-800.shtml（ |
| work_keys_str_mv | AT huoxiaoyan multiomicsanalysisofmethylmalonicacidemiacausedbyanoncodingregionvariantinmmaagenecombinedwithuniparentaldisomy AT luoxiaomei multiomicsanalysisofmethylmalonicacidemiacausedbyanoncodingregionvariantinmmaagenecombinedwithuniparentaldisomy AT yexiantao multiomicsanalysisofmethylmalonicacidemiacausedbyanoncodingregionvariantinmmaagenecombinedwithuniparentaldisomy AT sunyu multiomicsanalysisofmethylmalonicacidemiacausedbyanoncodingregionvariantinmmaagenecombinedwithuniparentaldisomy AT yuyongguo multiomicsanalysisofmethylmalonicacidemiacausedbyanoncodingregionvariantinmmaagenecombinedwithuniparentaldisomy AT lianglili multiomicsanalysisofmethylmalonicacidemiacausedbyanoncodingregionvariantinmmaagenecombinedwithuniparentaldisomy AT fanyanjie multiomicsanalysisofmethylmalonicacidemiacausedbyanoncodingregionvariantinmmaagenecombinedwithuniparentaldisomy |