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Unusual association of a unique CAG interruption in 5′ of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism |
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| Authors: | Stéphanie Tomé Alexis Bertrand David Geneviève Yann Péréon DM contraction study group Marie Simon Jean‐Paul Bonnefont Guillaume Bassez Geneviève Gourdon |
| Affiliation: | 1. Laboratory CTGDM, Inserm UMR1163, Paris, France;2. Institut Imagine, Université Paris‐Descartes‐Sorbonne Paris‐Cité, Paris, France;3. Molecular Genetic Laboratory, Necker Hospital, Paris, France;4. Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU Montpellier, Université Montpellier, Montpellier, France;5. Centre for Neuromuscular Diseases, H?tel‐Dieu Hospital, Nantes, France;6. Pauline Arnaud: Department of genetic, Bichat Hospital, Paris, France, Rapha?le Chasserieau: Centre for Neuromuscular Diseases, H?tel‐Dieu Hospital, Nantes, France, Pascal Cintas: Neuromuscular Reference Center, Purpan Hospital, Toulouse, France, Ana‐maria Cobo Esteban: Neuromuscular Reference Center, Marin Hospital, Hendaye, France, Marie‐Carmen Cruz: Neuromuscular Reference Center, Purpan Hospital, Toulouse, France, Dalil Hamroun: Centre Hospitalo‐Universitaire de Montpellier, Montpellier, France, Armelle Magot: Neuromuscular Reference Center, H?tel‐Dieu Hospital, Nantes, France, Alexandra Nadaj‐Pakleza Neuromuscular Reference Center, Larrey Hospital, Angers, France, Anne‐catherine Aube‐Gauthier Neuromuscular Reference Center, Larrey Hospital, Angers, France, Andoni Urtizberea: Neuromuscular Reference Center, Marin Hospital, Hendaye, France;7. Sorbonne Université, Inserm, UMRS974, Neuromuscular Reference center, AP‐HP, H?pital Pitié‐Salpêtrière, Paris, France |
| Abstract: | Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ～90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5′ of the CTG expansion in one family, whereas multiple 5′ CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet‐prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3′ of the interruptions for both families. |
| Keywords: | CTG contractions and 5′ single CAG interruption myotonic dystrophy type 1 triplet repeat instability |