[Example of a genetic condition caused by an imprinting disorder: Angelman syndrome].

Abstract

An 18-months old boy was seen in a clinical genetics consultation with both his parents for a global developmental delay, hypotonia, post-natal microcephaly, as well as cognitive impairment including an absence of language acquisition. High throughput exome sequencing identified a pathogenic variant in the UBE3A gene that was inherited from his asymptomatic mother. This variant causes the child to lose the contribution of the maternal allele, through loss of UBE3A genetic expression. UBE3A is localized into a genomic imprinting region which undergoes transcriptional regulation based on parental origin, an epigenetic phenomenon described in certain specific regions of the human genome. Its expression is repressed on the paternal chromosome at locus 15q11-13. The truncating variant on the maternal allele then leads to a complete loss of UBE3A expression. This results in Angelman syndrome. Angelman syndrome is a genetic neurodevelopmental disorder whose transmission mode depends on the causative molecular mechanism, which consists of a lack of contribution from the maternal 15q11-q13 region. Angelman's phenotype and evolution varies according to causative molecular mechanism. Precise laboratory diagnosis is especially important for genetic counselling: in our patient's family, the recurrence risk amounts to 50 % in the event of a future pregnancy, and the family's relatives must me informed and offered medical counsel.