New genotype-phenotype correlations and management recommendations for individuals with RERE variants.
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Curtis David, Zhao Xiaonan, Owen Nichole M, Azamian Mahshid S, Lalani Seema R, Keller Kierstin, Strong Alanna, Shen Joseph, DeFilippo Colette, Goel Himanshu, Schmalz Betsy, Chaudhari Bimal P, Joss Shelagh, Gucsavas-Calikoglu Muge, Shiloh-Malawsky Yael, Perilla-Young Yezmin, Thompson Olivia, Champaigne Neena, Chiriatti Luigi, Ferilli Marco, Tartaglia Marco, Priolo Manuela, Radio Francesca Clementina, El Achkar Christelle Moufawad, Valentine Rozalia, van Gassen Koen L I, Van den Boogaard Marie-José H, Roscioli Tony, Syryn Hannes, Cools Martine, De Baere Elfride, Repetto Gabriela M, Massey Hannah, Alanay Yasemin, Akgun-Dogan Ozlem, Josephi-Taylor Sarah, Bournazos Adam M, Cooper Sandra T, Faundes Victor, Scott Daryl A
Аннотация
METHODS: We assembled a cohort of 54 individuals with heterozygous pathogenic, likely pathogenic, and variants of uncertain significance in RERE, including 30 previously unreported cases. Individuals were classified into 5 subcohorts based on variant type and location: loss-of-function, missense variants inside and outside a specific histidine-rich region (HRR), and HRR in-frame deletions and duplications. Phenotypic features were analyzed and compared across groups. Protein modeling was performed to assess potential structural effects.
RESULTS: Developmental delay, intellectual disability, and/or autism spectrum disorder were prevalent across all groups. Loss-of-function variants are associated with fewer multisystem anomalies than missense variants and are more likely to be inherited from a mildly symptomatic or asymptomatic parent. In contrast, HRR-associated missense variants and in-frame HRR duplications were associated with more multisystem phenotypes and usually arise de novo. HRR missense variants were structurally stabilizing, suggesting a gain-of-function or dominant-negative mechanism.
CONCLUSION: These findings expand the clinical spectrum of RERE-related disorders, refine genotype-phenotype correlations, and support variant-specific approaches to management and genetic counseling.