1 - Serviço de Genética Médica, Área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal
2 - 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 - American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting, sob a forma de poster
Background: Chromatinopathies are a molecularly heterogeneous group of neurodevelopmental syndromes with distinctive facial dysmorphisms related to congenital chromatin remodelling defects. The lysine‑specific demethylase 1A gene (KDM1A, OMIM*609132) encodes a histone demethylase involved in chromatin remodeling. Recently, de novo missense variants in KDM1A gene were linked to developmental delay/intellectual disability (DD/ID) with specific dysmorphisms (Tunovic, et al., 2014 and Chong et al., 2016. Kosmicki (2017) Nat Genet 49: 504 PubMed: 28191890). Thus, a new chromatinopathy is emerging, namely the Cleft Palate, Psychomotor Retardation and Distinctive Facial Features Syndrome (CPRF, OMIM#616728). To date, only three patients have been published in the literature, and clinical data remains scarce. Here, we report an additional patient with KDM1A‑related neurodevelopmental disorder aiming to contribute towards the characterization of this clinical entity.
Case presentation: A 19-year-old male was first referred to our Genetic Department at 6‑years‑old for evaluation of moderate to severe DD and dysmorphisms. He was the second child of a non-consanguineous couple with no relevant family history fort genetic diseases. Pregnancy and delivery were unremarkable. Neonatal period was complicated with respiratory distress, hypotonia and feeding difficulties. Additional clinical features included agenesis of the corpus callosum, congenital heart defect (perimembranous ventricular septal defect), and pes valgus. Global developmental delay was apparent from the infancy. At our first observation at 6‑years‑old, he was not collaborative and presented auto-aggressive behavior, stereotypies, and no language. Facial dysmorphisms included macrocrania, triangular face, prominent forehead, downslanted palpebral fissures, strabismus, anteverted nares, high palate, full lips with tented upper lip, open mouth, widely spaced teeth, and macrodontia of the upper incisors. Extensive investigation with karyotype, fluorescent in situ hybridization for locus 17p11.2, molecular study of FMR1 and NSD1 genes, and chromosomal microarray analysis were normal. Through clinical exome sequencing, a de novo missense variant in KDM1A NM_001009999.2:c.2353T>C, p.(Try785His), classified as likely pathogenic, was identified.
Conclusion: This specific missense variant was previously found in one of the 3 currently known patients, which may suggest a mutational hotspot in this gene. Since it does not affect a CpG island, its mutational mechanism and recurrence is still unexplained. Our case has significant overlap with the clinical features displayed by the other patients, including severe DD/ID, central nervous system anomalies, and distinctive facial features (prominent forehead, slanted palpebral fissures, palate anomalies, and widely spaced teeth). He also shows some hallmark features of other chromatinopathies such as Kabuki syndrome (widely spaced teeth) or KBG syndrome (macrodontia). This report adds further evidence towards a consistent neurological phenotype associated with KDM1A disease-causing variants. Additionally, it reinforces the concept that variants affecting the epigenetic machinery led to a shared molecular effect (chromatin remodelling), thus determining superimposable clinical conditions. We expect, as more patients are to be identified, that it will be possible to further delineate the genotypic and phenotypic aspects of KDM1A, ultimately contributing towards consistent genotype-phenotype correlations.
Palavras Chave: Chromatinopathies, KDM1A gene variants