Parental repeat length instability in myotonic dystrophy type 1 pre- and protomutations
| Autor: | Isis B.T. Joosten, Debby M.E.I. Hellebrekers, Catharina G. Faber, Monique M. Gerrits, Christine E. M. de Die-Smulders, Bianca T. A. de Greef, Hubert J.M. Smeets |
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| Přispěvatelé: | Klinische Neurowetenschappen, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA KG Lab Centraal Lab (9), RS: MHeNs - R3 - Neuroscience, MUMC+: KIO Kemta (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, RS: FHML MaCSBio, Klinische Genetica, MUMC+: DA KG Polikliniek (9), MUMC+: MA Med Staf Spec Neurologie (9) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Offspring Genetic counseling Biology HUNTINGTON-DISEASE CTG REPEAT Asymptomatic Myotonic dystrophy Article 03 medical and health sciences CAG REPEAT PATERNAL TRANSMISSION Genetics medicine Humans Myotonic Dystrophy HETEROGENEITY Allele ANTICIPATION Child Genetics (clinical) 0303 health sciences ORIGIN 030305 genetics & heredity Chromosome EXPANSION medicine.disease SIZE PRACTICE GUIDELINES Cohort Paternal Inheritance Female medicine.symptom Trinucleotide Repeat Expansion Trinucleotide repeat expansion Chromosomes Human Pair 19 |
| Zdroj: | Eur J Hum Genet European Journal of Human Genetics, 28(7), 956-962. Nature Publishing Group |
| ISSN: | 1018-4813 |
| DOI: | 10.1038/s41431-020-0601-4 |
| Popis: | Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide repeat expansion on chromosome 19q13.3. While DM1 premutation (36–50 repeats) and protomutation (51–80 repeats) allele carriers are mostly asymptomatic, offspring is at risk of inheriting expanded, symptom-associated, (CTG)n repeats of n > 80. In this study we aimed to evaluate the intergenerational instability of DM1 pre- and protomutation alleles, focussing on the influence of parental gender. One hundred and forty-six parent–child pairs (34 parental premutations, 112 protomutations) were retrospectively selected from the DM1 patient cohort of the Maastricht University Medical Center+. CTG repeat size of parents and children was determined by (triplet-primed) PCR followed by fragment length analysis and Southern blot analysis. Fifty-eight out of eighty-one (71.6%) paternal transmissions led to a (CTG)n repeat of n > 80 in offspring, compared with 15 out of 65 (23.1%) maternal transmissions (p < 0.001). Repeat length instability occurred for paternal (CTG)n repeats of n ≥ 45, while maternal instability did not occur until (CTG)n repeats reached a length of n ≥ 71. Transmission of premutations caused (CTG)n repeats of n > 80 in offspring only when paternally transmitted (two cases), while protomutations caused (CTG)n repeats of n > 80 in offspring in 71 cases, of which 56 (78.9%) were paternally transmitted. In conclusion, our data show that paternally transmitted pre- and protomutations were more unstable than maternally transmitted pre- and protomutations. For genetic counseling, this implies that males with a small DMPK mutation have a higher risk of symptomatic offspring compared with females. Consequently, we suggest addressing sex-dependent factors in genetic counseling of small-sized CTG repeat carriers. |
| Databáze: | OpenAIRE |
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