A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability
Variants in <i>MFSD8</i> can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions h...
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MDPI AG
2022-02-01
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| author | Milda Reith Lena Zeltner Karin Schäferhoff Dennis Witt Theresia Zuleger Tobias B. Haack Antje Bornemann Michael Alber Susanne Ruf Ludger Schoels Katarina Stingl Nicole Weisschuh |
| author_facet | Milda Reith Lena Zeltner Karin Schäferhoff Dennis Witt Theresia Zuleger Tobias B. Haack Antje Bornemann Michael Alber Susanne Ruf Ludger Schoels Katarina Stingl Nicole Weisschuh |
| author_sort | Milda Reith |
| collection | DOAJ |
| description | Variants in <i>MFSD8</i> can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to cause <i>MFSD8</i>-associated diseases. We report two closely related subjects from a consanguineous Turkish family who presented classical features of NCLs but demonstrated marked intrafamilial variability in age at the onset and severity of symptoms. In fact, the difference in the onset of first neurologic symptoms was 15 years and that of ophthalmologic symptoms was 12 years. One subject presented an intellectual disability and a considerable cerebellar ataxia syndrome, while the other subject showed no intellectual disability and only a mild atactic syndrome. The diagnostic genetic testing of both subjects based on genome sequencing prioritized a novel, apparently synonymous variant in <i>MFSD8</i>, which was found in homozygosity in both subjects. The variant was not located within an integral part of the splice site consensus sequences. However, the bioinformatic analyses suggested that the mutant allele is more likely to cause exon skipping due to an altered ratio of exonic splice enhancer and silencer motifs. Exon skipping was confirmed in vitro by minigene assays and in vivo by RNA analysis from patient lymphocytes. The mutant transcript is predicted to result in a frameshift and, if translated, in a truncated protein. Synonymous variants are often given a low priority in genetic diagnostics because of their expected lack of functional impact. This study highlights the importance of investigating the impact of synonymous variants on splicing. |
| first_indexed | 2024-03-09T21:44:36Z |
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| last_indexed | 2024-03-09T21:44:36Z |
| publishDate | 2022-02-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f45ea98492ba4e8fb28d8d9a19b081d52023-11-23T20:22:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234227110.3390/ijms23042271A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial VariabilityMilda Reith0Lena Zeltner1Karin Schäferhoff2Dennis Witt3Theresia Zuleger4Tobias B. Haack5Antje Bornemann6Michael Alber7Susanne Ruf8Ludger Schoels9Katarina Stingl10Nicole Weisschuh11Centre for Ophthalmology, University Eye Hospital, University of Tübingen, 72076 Tübingen, GermanyDepartment of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, 72076 Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, GermanyCentre for Rare Diseases, University of Tübingen, 72076 Tübingen, GermanyDepartment of Neuropathology, University Hospital Tübingen, University of Tübingen, 72076 Tübingen, GermanyDepartment of Neuropaediatrics, Developmental Neurology, Social Paediatrics, University Children’s Hospital, 72076 Tübingen, GermanyDepartment of Neuropaediatrics, Developmental Neurology, Social Paediatrics, University Children’s Hospital, 72076 Tübingen, GermanyDepartment of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, 72076 Tübingen, GermanyCentre for Ophthalmology, University Eye Hospital, University of Tübingen, 72076 Tübingen, GermanyCentre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, GermanyVariants in <i>MFSD8</i> can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to cause <i>MFSD8</i>-associated diseases. We report two closely related subjects from a consanguineous Turkish family who presented classical features of NCLs but demonstrated marked intrafamilial variability in age at the onset and severity of symptoms. In fact, the difference in the onset of first neurologic symptoms was 15 years and that of ophthalmologic symptoms was 12 years. One subject presented an intellectual disability and a considerable cerebellar ataxia syndrome, while the other subject showed no intellectual disability and only a mild atactic syndrome. The diagnostic genetic testing of both subjects based on genome sequencing prioritized a novel, apparently synonymous variant in <i>MFSD8</i>, which was found in homozygosity in both subjects. The variant was not located within an integral part of the splice site consensus sequences. However, the bioinformatic analyses suggested that the mutant allele is more likely to cause exon skipping due to an altered ratio of exonic splice enhancer and silencer motifs. Exon skipping was confirmed in vitro by minigene assays and in vivo by RNA analysis from patient lymphocytes. The mutant transcript is predicted to result in a frameshift and, if translated, in a truncated protein. Synonymous variants are often given a low priority in genetic diagnostics because of their expected lack of functional impact. This study highlights the importance of investigating the impact of synonymous variants on splicing.https://www.mdpi.com/1422-0067/23/4/2271CLN7<i>MFSD8</i>synonymous substitutionmis-splicingexon skippingfunctional studies |
| spellingShingle | Milda Reith Lena Zeltner Karin Schäferhoff Dennis Witt Theresia Zuleger Tobias B. Haack Antje Bornemann Michael Alber Susanne Ruf Ludger Schoels Katarina Stingl Nicole Weisschuh A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability International Journal of Molecular Sciences CLN7 <i>MFSD8</i> synonymous substitution mis-splicing exon skipping functional studies |
| title | A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability |
| title_full | A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability |
| title_fullStr | A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability |
| title_full_unstemmed | A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability |
| title_short | A Novel, Apparently Silent Variant in <i>MFSD8</i> Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability |
| title_sort | novel apparently silent variant in i mfsd8 i causes neuronal ceroid lipofuscinosis with marked intrafamilial variability |
| topic | CLN7 <i>MFSD8</i> synonymous substitution mis-splicing exon skipping functional studies |
| url | https://www.mdpi.com/1422-0067/23/4/2271 |
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