A spectrum of clinical severity of recessive titinopathies in prenatal
Variants in TTN are associated with a broad range of clinical phenotypes, from dominant adult-onset dilated cardiomyopathy to recessive infantile-onset myopathy. However, few foetal cases have been reported for multiple reasons. Next-generation sequencing has facilitated the prenatal identification...
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.1064474/full |
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| author | Yiming Qi Yiming Qi Xueqi Ji Xueqi Ji Hongke Ding Hongke Ding Yunan Wang Yunan Wang Xin Liu Yan Zhang Aihua Yin Aihua Yin |
| author_facet | Yiming Qi Yiming Qi Xueqi Ji Xueqi Ji Hongke Ding Hongke Ding Yunan Wang Yunan Wang Xin Liu Yan Zhang Aihua Yin Aihua Yin |
| author_sort | Yiming Qi |
| collection | DOAJ |
| description | Variants in TTN are associated with a broad range of clinical phenotypes, from dominant adult-onset dilated cardiomyopathy to recessive infantile-onset myopathy. However, few foetal cases have been reported for multiple reasons. Next-generation sequencing has facilitated the prenatal identification of a growing number of suspected titinopathy variants. We investigated six affected foetuses from three families, completed the intrauterine course of the serial phenotypic spectrum of TTN, and discussed the genotype-phenotype correlations from a broader perspective. The recognizable prenatal feature onset at the second trimester was started with reduced movement, then contracture 3–6 weeks later, followed with/without hydrops, finally at late pregnancy was accompanied with polyhydramnio (major) or oligohydramnios. Two cases with typical arthrogryposis-hydrops sequences identified a meta-only transcript variant c.36203-1G>T. Deleterious transcriptional consequences of the substitution were verified by minigene splicing analysis. Case 3 identified a homozygous splicing variant in the constitutively expressed Z-disc. It presented a milder phenotype than expected, which was presumably saved by the isoform of corons. A summary of the foetal-onset titinopathy cases implied that variants in TTN present with a series of signs and a spectrum of clinical severity, which followed the dosage/positional effect; the meta-only transcript allele involvement may be a prerequisite for the development of fatal hydrops. |
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| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-10T20:20:51Z |
| publishDate | 2023-01-01 |
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| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-448de3df1d364a50992c1240352205c82023-01-25T17:16:51ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-01-011310.3389/fgene.2022.10644741064474A spectrum of clinical severity of recessive titinopathies in prenatalYiming Qi0Yiming Qi1Xueqi Ji2Xueqi Ji3Hongke Ding4Hongke Ding5Yunan Wang6Yunan Wang7Xin Liu8Yan Zhang9Aihua Yin10Aihua Yin11Prenatal Diagnosis Centre, Guangdong Women and Children Hospital, Guangzhou, ChinaMaternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, ChinaPrenatal Diagnosis Centre, Guangdong Women and Children Hospital, Guangzhou, ChinaGuangzhou Medical University, Guangzhou, ChinaPrenatal Diagnosis Centre, Guangdong Women and Children Hospital, Guangzhou, ChinaMaternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, ChinaPrenatal Diagnosis Centre, Guangdong Women and Children Hospital, Guangzhou, ChinaMaternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, ChinaAegicare, Shenzhen, ChinaMaternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, ChinaPrenatal Diagnosis Centre, Guangdong Women and Children Hospital, Guangzhou, ChinaMaternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, ChinaVariants in TTN are associated with a broad range of clinical phenotypes, from dominant adult-onset dilated cardiomyopathy to recessive infantile-onset myopathy. However, few foetal cases have been reported for multiple reasons. Next-generation sequencing has facilitated the prenatal identification of a growing number of suspected titinopathy variants. We investigated six affected foetuses from three families, completed the intrauterine course of the serial phenotypic spectrum of TTN, and discussed the genotype-phenotype correlations from a broader perspective. The recognizable prenatal feature onset at the second trimester was started with reduced movement, then contracture 3–6 weeks later, followed with/without hydrops, finally at late pregnancy was accompanied with polyhydramnio (major) or oligohydramnios. Two cases with typical arthrogryposis-hydrops sequences identified a meta-only transcript variant c.36203-1G>T. Deleterious transcriptional consequences of the substitution were verified by minigene splicing analysis. Case 3 identified a homozygous splicing variant in the constitutively expressed Z-disc. It presented a milder phenotype than expected, which was presumably saved by the isoform of corons. A summary of the foetal-onset titinopathy cases implied that variants in TTN present with a series of signs and a spectrum of clinical severity, which followed the dosage/positional effect; the meta-only transcript allele involvement may be a prerequisite for the development of fatal hydrops.https://www.frontiersin.org/articles/10.3389/fgene.2022.1064474/fullTTN metatranscript-onlyhydrops fetalisarthrogryposisprenatal diagnosticstitinopathies |
| spellingShingle | Yiming Qi Yiming Qi Xueqi Ji Xueqi Ji Hongke Ding Hongke Ding Yunan Wang Yunan Wang Xin Liu Yan Zhang Aihua Yin Aihua Yin A spectrum of clinical severity of recessive titinopathies in prenatal Frontiers in Genetics TTN metatranscript-only hydrops fetalis arthrogryposis prenatal diagnostics titinopathies |
| title | A spectrum of clinical severity of recessive titinopathies in prenatal |
| title_full | A spectrum of clinical severity of recessive titinopathies in prenatal |
| title_fullStr | A spectrum of clinical severity of recessive titinopathies in prenatal |
| title_full_unstemmed | A spectrum of clinical severity of recessive titinopathies in prenatal |
| title_short | A spectrum of clinical severity of recessive titinopathies in prenatal |
| title_sort | spectrum of clinical severity of recessive titinopathies in prenatal |
| topic | TTN metatranscript-only hydrops fetalis arthrogryposis prenatal diagnostics titinopathies |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.1064474/full |
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