Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report
Abstract Background Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataple...
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | BMC Neurology |
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| Online Access: | https://doi.org/10.1186/s12883-022-02921-w |
| _version_ | 1811319572064632832 |
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| author | João H. C. Campos Ana C. R. Aguilar Fernando Antoneli Giselle Truzzi Marcelo R. S. Briones Renata C. Ferreira Fernando M. S. Coelho |
| author_facet | João H. C. Campos Ana C. R. Aguilar Fernando Antoneli Giselle Truzzi Marcelo R. S. Briones Renata C. Ferreira Fernando M. S. Coelho |
| author_sort | João H. C. Campos |
| collection | DOAJ |
| description | Abstract Background Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1. Case presentation We present the case of a pair of 17-year-old male, monozygotic twins discordant for NT1. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. To describe the genetic background for the NT1 discordant manifestations in this case, we present the whole-genome analysis of this monozygotic twin pair. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). Conclusions The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease. |
| first_indexed | 2024-04-13T12:45:17Z |
| format | Article |
| id | doaj.art-2c909f8bb9a840e0a2de0e04f169a5b9 |
| institution | Directory Open Access Journal |
| issn | 1471-2377 |
| language | English |
| last_indexed | 2024-04-13T12:45:17Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
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| series | BMC Neurology |
| spelling | doaj.art-2c909f8bb9a840e0a2de0e04f169a5b92022-12-22T02:46:23ZengBMCBMC Neurology1471-23772022-11-012211810.1186/s12883-022-02921-wWhole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case reportJoão H. C. Campos0Ana C. R. Aguilar1Fernando Antoneli2Giselle Truzzi3Marcelo R. S. Briones4Renata C. Ferreira5Fernando M. S. Coelho6Center for Medical Bioinformatics, Escola Paulista de Medicina, UNIFESPDepartment of Neurology and Neurosurgery, Escola Paulista de Medicina, UNIFESPCenter for Medical Bioinformatics, Escola Paulista de Medicina, UNIFESPDepartment of Psychobiology, Escola Paulista de Medicina, UNIFESPCenter for Medical Bioinformatics, Escola Paulista de Medicina, UNIFESPDepartment of Neurology and Neurosurgery, Escola Paulista de Medicina, UNIFESPDepartment of Neurology and Neurosurgery, Escola Paulista de Medicina, UNIFESPAbstract Background Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1. Case presentation We present the case of a pair of 17-year-old male, monozygotic twins discordant for NT1. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. To describe the genetic background for the NT1 discordant manifestations in this case, we present the whole-genome analysis of this monozygotic twin pair. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). Conclusions The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease.https://doi.org/10.1186/s12883-022-02921-wNarcolepsy type 1Whole-genome analysisHLAAutoimmune diseaseDiscordant monozygotic twinsDiagnostics |
| spellingShingle | João H. C. Campos Ana C. R. Aguilar Fernando Antoneli Giselle Truzzi Marcelo R. S. Briones Renata C. Ferreira Fernando M. S. Coelho Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report BMC Neurology Narcolepsy type 1 Whole-genome analysis HLA Autoimmune disease Discordant monozygotic twins Diagnostics |
| title | Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report |
| title_full | Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report |
| title_fullStr | Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report |
| title_full_unstemmed | Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report |
| title_short | Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report |
| title_sort | whole genome analysis of monozygotic brazilian twins discordant for type 1 narcolepsy a case report |
| topic | Narcolepsy type 1 Whole-genome analysis HLA Autoimmune disease Discordant monozygotic twins Diagnostics |
| url | https://doi.org/10.1186/s12883-022-02921-w |
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