Identification of a de novo HDAC8 pathogenicvariant in a patient with suspected angel mansyndrome

Abstract

A 2-year-old female presented with prenatal onset microcephaly, global development delay, short stature, mild intermittent convergent strabismus, ataxia, hyperkinesis, and dysmorphic facial features without an underlying clinical diagnosis. Normal prior investigations included a cerebral MRI scan, EEG, transferrin isoforms, microarray, and urine metabolic screen. Although an atypical presentation, Angelman syndrome (AS) was considered. AS is neurodevelopmental disorder characterized by moderate/severe developmental delay, absent speech, gait ataxia, microcephaly, and seizures. Aberrations of the maternally inherited UBE3A gene result in AS. In this patient, copy number and methylation studies of 15q11-q13 and UBE3A sequencing were normal. These results did not support a diagnosis of AS. Subsequent whole exome sequencing (WES) identified a de novo variant in the HDAC8 gene. Pathogenic HDAC8 variants are rare and were initially reported in patients with a clinical diagnosis of Cornelia de Lange syndrome (CdLS). HDAC8 is a component of the cohesion complex responsible for sister chromatid cohesion during cell division. Mutations in various components of the cohesion complex cause CdLS and related cohesinopathies. HDAC8 is located on the X chromosome, and phenotypes associated with pathogenic variants in this gene are highly variable. Males are severely affected, while females have more variable phenotypes that are thought to be partially due to X-inactivation. The phenotypic overlap and convergent pathways in CdLS, AS, and other related neurodevelopmental disorders are discussed. This case advocates the use of WES (or whole genome sequencing) as the primary method for investigating neurodevelopmental disorders with unclear clinical phenotypes following routine microarray testing.L6200018732018-01-03 <br />