1 - Serviço de Genética Médica, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
2 - Serviço de Pediatria, Hospital de Vila Franca de Xira, Lisboa, Portugal
3 - Unidade de Endocrinologia Pediátrica, Departamento de Pediatria Médica, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
- poster - European Society of Human Genetics (ESHG) Conference 2023, 10-13 de junho 2023, Glasgow
Introduction: Menke-Hennekam syndrome 2 (MKHK2) is a recently recognized neurodevelopmental disorder that results from heterozygous missense mutations in exons 30/31 of EP300 gene, mainly known as a cause of Rubinstein-Taybi syndrome 2 (RSTS2). MKHK2 is characterised by developmental delay/intellectual disability, microcephaly, short stature, autism, epilepsy, feeding difficulties, vision and hearing impairment. Dysmorphims are largely different from RSTS2 and include short palpebral fissures, telecanthus, depressed nasal bridge, short nose, anteverted nares, short columella, and long philtrum. Here, we present a case that contribute to an increasing understanding of MKHK2.
Case presentation: A 1-year-old female was first referred to our outpatient genetic department with global developmental delay. At our observation, she showed facial dysmorphisms, syndactyly, short stature and post-natal microcephaly. Microarray was normal. A WES-based gene panel identified a missense variant in the EP300 gene, NM_001429.4:c.4783T>C p.(Phe1595Leu) in exon 30. The variant was not previously described in literature, nor in gnomAD population. It occurs at a conserved position across species, at the same position as another pathogenic missense change, and in silico analysis support a deleterious effect. Segregation studies revealed a de novo origin. Reverse phenotyping highlighted that our patient did not have typical RSTS2 characteristics, but rather shared the clinical features of MKHK2.
Conclusions: This case contributes to the expansion of the genotypic spectrum of MKHK2. It also emphasizes the wide clinical phenotype associated with EP300, and how reverse phenotyping is an important tool in the interpretation of Next-Generation Sequencing data.
Palavras Chave: EP300 gene, Menke-Hennekam syndrome 2, Rubinstein-Taybi syndrome 2