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Genotype phenotype analysis in a family carrying truncating mutations in the titin gene.

ABSTRACT: We report a family carrying a previously described truncating mutation, NM_001267550.2(TTN):c.107889del p.(Lys35963Asnfs*9) in exon 364, and a novel truncating mutation, NM_001267550.1:c.100704C > A p.(Tyr33568*) in exon 358 in the titin gene. The c.107889del mutation, which was maternally transmitted, has been previously described in patients from the Iberian Peninsula. The mother was of Peruvian descent suggesting a potential European ancestral origin of this mutation. In this family, a daughter, who is a compound heterozygote carrying both these mutations, developed a peripartum cardiomyopathy during her second pregnancy. Subsequently, she was diagnosed with a myopathy following electromyography testing and a muscle biopsy which showed fiber type disproportion. Her brother, who carries only the paternally inherited c.100704C > A mutation, developed a cardiomyopathy following a suspected viral illness. Their father, who transmitted this mutation, has no evidence of a cardiomyopathy. We hypothesize that the c.100704C > A mutation confers susceptibility to the development of cardiomyopathy which may be brought on by cardiovascular stress. Our study of this family expands the genotype and phenotype spectrum of disorders that can be associated with mutations in the titin gene.

SUBMITTER: Peddareddygari LR

PROVIDER: S-EPMC8033428 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder caused by truncating variants in the paternal allele of MAGEL2, located in the Prader-Willi critical region, 15q11-q13. Although the phenotypes of SYS overlap those of Prader-Willi syndrome (PWS), including neonatal hypotonia, feeding problems, and developmental delay/intellectual disability, SYS patients show autism spectrum disorder and joint contractures, which are atypical phenotypes for PWS. Therefore, we hypothesized that the truncated Magel2 protein could potentially produce gain-of-function toxic effects. To test the hypothesis, we generated two engineered mouse models; one, an overexpression model that expressed the N-terminal region of Magel2 that was FLAG tagged with a strong ubiquitous promoter, and another, a genome-edited model that carried a truncating variant in Magel2 generated using the CRISPR/Cas9 system. In the overexpression model, all transgenic mice died in the fetal or neonatal period indicating embryonic or neonatal lethality of the transgene. Therefore, overexpression of the truncated Magel2 could show toxic effects. In the genome-edited model, we generated a mouse model carrying a frameshift variant (c.1690_1924del; p(Glu564Serfs*130)) in Magel2. Model mice carrying the frameshift variant in the paternal or maternal allele of Magel2 were termed Magel2P:fs and Magel2M:fs, respectively. The imprinted expression and spatial distribution of truncating Magel2 transcripts in the brain were maintained. Although neonatal Magel2P:fs mice were lighter than wildtype littermates, Magel2P:fs males and females weighed the same as their wildtype littermates by eight and four weeks of age, respectively. Collectively, the overexpression mouse model may recapitulate fetal or neonatal death, which are the severest phenotypes for SYS. In contrast, the genome-edited mouse model maintains genomic imprinting and distribution of truncated Magel2 transcripts in the brain, but only partially recapitulates SYS phenotypes. Therefore, our results imply that simple gain-of-function toxic effects may not explain the patho-mechanism of SYS, but rather suggest a range of effects due to Magel2 variants as in human SYS patients.

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Genotype phenotype analysis in a family carrying truncating mutations in the titin gene.

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