Clinical and molecular overlap between Nucleotide Excision Repair (NER) disorders and DYRK1A haploinsufficiency syndrome

Nadege Calmels ^1,2* Nicolas Le May ² Jérémie Courraud ³ Imene Boujelbene ¹ Cathy Obringer ² Tomoo Ogi ⁴ Alan R Lehman ⁵ Fanny Laffargue ⁶ Daphné Lehalle ⁷ Seiji Mizuno ⁸ Shehla Mohammed ⁹ Clothilde Ormières ¹⁰ Marjolaine WILLEMS ¹¹ Vincent Laugel ^12,2 Amélie Piton ^1,3

• ¹ Laboratory of Genetic Diagnostics, University Hospitals of Strasbourg, Strasbourg, Alsace, France
• ² INSERM U1112 Laboratoire de Génétique Médicale, Strasbourg, Alsace, France
• ³ Equipe Génétique et physiopathologie de maladies neurodéveloppementales et épileptogènes, IGBMC, Illkirch, France
• ⁴ Departement of genetics, Departement of genome repair, Nagasaki University, Nagasaki, Japan
• ⁵ Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom
• ⁶ Service de génétique médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France
• ⁷ Département de génétique, Hôpitaux Universitaires Pitié Salpêtrière, Paris, France
• ⁸ Central Hospital, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, Japan
• ⁹ Genetics Clinic, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
• ¹⁰ Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hopitaux De Paris, Paris, France
• ¹¹ Equipe Maladies Génétiques de l'Enfant et de l'Adulte, CHU de Montpellier, Montpellier, France
• ¹² Service de pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

Nucleotide excision repair (NER) disorders are genetic conditions caused by defects in the pathway responsible for repairing DNA lesions due to UV radiation. These defects lead to a variety of heterogeneous disorders, including Cockayne syndrome (CS) and trichothiodystrophy (TTD).In this study, we report eleven patients initially suspected of having CS or TTD who were ultimately diagnosed with DYRK1A haploinsufficiency syndrome using high-throughput sequencing.Comparing clinical presentations, we observed that DYRK1A symptoms overlapped with CS, with shared features such as intellectual disability and microcephaly, systematically present in both disorders and other common symptoms including feeding difficulties, abnormal brain imaging, ataxic gait, hypertonia, and deep-set eyes. However, distinctive features of DYRK1A syndrome, such as severely impaired language, febrile seizures, and autistic behaviour or anxiety, helped differentiate it from CS, which typically manifests with severe growth delay, bilateral cataracts, and pigmentary retinopathy.Among the cohort, three patients carried novel DYRK1A variants, including two truncating and one inframe variant p.Val237_Leu241delinsGlu whose pathogenicity have been confirmed through functional analysis of DYRK1A protein.While previous research has implicated DYRK1A in DNA repair, with DYRK1A being one of the most downregulated genes in CS cells, our study found that DYRK1A patient-derived cell lines did not exhibit NER defects and did not share the CS transcriptomic signature. These findings suggest that if clinical symptoms overlap stems from common molecular disruptions, DYRK1A is involved downstream of the CS genes. This research highlights the importance of considering DYRK1A haploinsufficiency syndrome in the differential diagnoses for NER disorders.