A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments
Abstract Background Meier–Gorlin syndrome (MGORS) is a rare autosomal inherited form of primordial dwarfism. Pathogenic variants in 13 genes involved in DNA replication initiation have been identified in this disease, but homozygous intronic variants have never been reported. Additionally, whether g...
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BMC
2024-12-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-024-03430-4 |
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| author | Qing Li Yichi Wu Fucheng Meng Zhuxi Li Di Zhan Xiaoping Luo |
| author_facet | Qing Li Yichi Wu Fucheng Meng Zhuxi Li Di Zhan Xiaoping Luo |
| author_sort | Qing Li |
| collection | DOAJ |
| description | Abstract Background Meier–Gorlin syndrome (MGORS) is a rare autosomal inherited form of primordial dwarfism. Pathogenic variants in 13 genes involved in DNA replication initiation have been identified in this disease, but homozygous intronic variants have never been reported. Additionally, whether growth hormone (GH) treatment can increase the height of children with MGORS is unclear. Methods The medical history data of a young girl were collected and reviewed. Whole-exome sequencing (WES) and bioinformatic analysis were performed to identify any variants and predict their pathogenicity. Minigene constructs were generated and transfected into HEK-293T cells for in vitro splicing assays. The literature was reviewed to explore the mutational spectrum and efficacy of GH treatment for this disease. Results A girl with microtia, hypoplastic patellae, and severe growth retardation carried a novel homozygous intronic variant (NM_030928.4: exon 3: c.352–30 A > C) in CDT1. The variant was predicted to break a branch point and alter splicing, and the minigene assay confirmed abnormal splicing with exon 3 skipping. The patient was treated with GH for 5 years, with an increase in growth velocity from 4.0 cm/year to an average of 6.2 cm/year. A literature review revealed that the most common variant type and inheritance state were missense and compound heterozygous, respectively. Additionally, the vast majority of children with MGORS treated with GH had normal insulin-like growth factor 1 (IGF-1) levels, and half of them responded positively to GH therapy. Conclusions We reported a novel pathogenic homozygous intronic variant (c.352–30 A > C) of CDT1 in a girl with MGORS, and this mutation extended the genetic spectrum of the disease. GH therapy may be beneficial for height outcomes in children with MGORS with normal IGF-1 levels. |
| format | Article |
| id | doaj-art-e8367324d8c74524810657a5ccb06d5e |
| institution | Kabale University |
| issn | 1750-1172 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-e8367324d8c74524810657a5ccb06d5e2025-01-12T12:39:37ZengBMCOrphanet Journal of Rare Diseases1750-11722024-12-0119111310.1186/s13023-024-03430-4A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatmentsQing Li0Yichi Wu1Fucheng Meng2Zhuxi Li3Di Zhan4Xiaoping Luo5Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Meier–Gorlin syndrome (MGORS) is a rare autosomal inherited form of primordial dwarfism. Pathogenic variants in 13 genes involved in DNA replication initiation have been identified in this disease, but homozygous intronic variants have never been reported. Additionally, whether growth hormone (GH) treatment can increase the height of children with MGORS is unclear. Methods The medical history data of a young girl were collected and reviewed. Whole-exome sequencing (WES) and bioinformatic analysis were performed to identify any variants and predict their pathogenicity. Minigene constructs were generated and transfected into HEK-293T cells for in vitro splicing assays. The literature was reviewed to explore the mutational spectrum and efficacy of GH treatment for this disease. Results A girl with microtia, hypoplastic patellae, and severe growth retardation carried a novel homozygous intronic variant (NM_030928.4: exon 3: c.352–30 A > C) in CDT1. The variant was predicted to break a branch point and alter splicing, and the minigene assay confirmed abnormal splicing with exon 3 skipping. The patient was treated with GH for 5 years, with an increase in growth velocity from 4.0 cm/year to an average of 6.2 cm/year. A literature review revealed that the most common variant type and inheritance state were missense and compound heterozygous, respectively. Additionally, the vast majority of children with MGORS treated with GH had normal insulin-like growth factor 1 (IGF-1) levels, and half of them responded positively to GH therapy. Conclusions We reported a novel pathogenic homozygous intronic variant (c.352–30 A > C) of CDT1 in a girl with MGORS, and this mutation extended the genetic spectrum of the disease. GH therapy may be beneficial for height outcomes in children with MGORS with normal IGF-1 levels.https://doi.org/10.1186/s13023-024-03430-4Meier–Gorlin syndromeCDT1Intronic mutationShort statureGrowth hormone treatment |
| spellingShingle | Qing Li Yichi Wu Fucheng Meng Zhuxi Li Di Zhan Xiaoping Luo A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments Orphanet Journal of Rare Diseases Meier–Gorlin syndrome CDT1 Intronic mutation Short stature Growth hormone treatment |
| title | A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments |
| title_full | A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments |
| title_fullStr | A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments |
| title_full_unstemmed | A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments |
| title_short | A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments |
| title_sort | novel homozygous intronic variant in cdt1 that alters splicing causes meier gorlin syndrome and a review of published mutations and growth hormone treatments |
| topic | Meier–Gorlin syndrome CDT1 Intronic mutation Short stature Growth hormone treatment |
| url | https://doi.org/10.1186/s13023-024-03430-4 |
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