1 - Serviço de Genética Médica, área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2 - Serviço de Neurologia Pediátrica, Área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
3 - CGPP – Centro de Genética Preditiva e Preventiva, IBMC – Instituto de Biologia Molecular e Celular, i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Reunião internacional - European Society of Human Genetics (ESHG) Conference, sob a forma de poster
Background/Objectives: CHD4 is a chromatin remodeler involved in epigenetic regulation of gene transcription. Pathogenic variants in CHD4 gene are associated with Sifrim-Hitz-Weiss syndrome (OMIM#617159), a well described chromatinopathy characterized by global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Additional abnormalities include hypogonadism, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. Recently, missense variants in CHD4 were identified in patients with a milder phenotype consisting of epilepsy with sinus arrhythmia.
Methods: We report a case of a novel missense variant in CHD4 that presented with an intermediate phenotype, aiming to contribute to the clinical and genotypic spectrum characterization. Results: A 9-year-old boy was referred for developmental delay/mild intellectual disability and epilepsy evaluation. He was the oldest son of a non-consanguineous healthy couple. Prenatal and neonatal history were unremarkable. At our observation, he had no dysmorphisms nor congenital anomalies. FRAXA and microarray were normal. A WES-based gene panel identified a missense variant in the CHD4 gene, NM_001273:c.2660G>A (p.Arg887Gln). The variant was not previously described in literature, nor in gnomAD population. It occurs at a position that is conserved across species, in the same codon as a known pathogenic variant, and in silico analysis predicts a probably deleterious effect in protein. Finally, familial studies showed a de novo origin.
Conclusion: This report contributes to the expansion of the phenotypic spectrum of CHD4-related disorders. It highlights it can be a less obvious diagnosis since there is a wide phenotypic heterogeneity, without known genotypic-phenotypic correlations.
Palavras Chave: Cromatinopathy, CHD4 gene variants