Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis

Abstract

Angelman syndrome (AS) is a neurogenetic disorder caused by loss of expression of the maternal imprinted gene UBE3A on chromosome 15q11.2-q13. Clinical features of AS include severe intellectual disability, a happy disposition, ataxia, mandibular prognatism, and epilepsy. Our objectives were to examine the birth incidence of AS in Denmark and to characterize the size of the 15q11.2-q13 deletions with 1,000K array CGH. In addition, we analyzed genotype differences in regard to age at diagnosis and investigated the occurrence of deletions/duplications outside the 15q11.2-q13 regions. We identified 51 patients with genetically verified AS, which corresponded to a birth incidence of 1:24,580 (95%CI: 1:23,727-1:25,433). Thirty-six patients showed a deletion; 13 had a Class I deletion and 20 had a Class II deletion. There was bimodal distribution of the BP3 breakpoint. Three patients had larger and atypical deletions, with distal breakpoints telomeric to BP3. Five patients had paternal uniparental disomy (pUPD) of chromosome 15, and four had a verified UBE3A mutation. Additional deletions/duplications outside the 15q11.2-q13 areas were demonstrated in half the participants. Six harbored more than one CNV. Mean age at diagnosis was 21 months (95%CI: 17-23 months) for children with a deletion and 46 months (95%CI: 36-55 months) for children with pUPD or a UBE3A mutation (P < 0.01). The presence of a CNV outside 15q11.2-q13 did not have an impact on age at diagnosis.

Angelman syndrome in Hong Kong Chinese: A 20 years’ experience

“…The incidence of AS in this locality by this study was estimated to be approximately 1 per 22,305 live births, which was similar to other ethnic groups (Buckley et al, 1998;Clayton-Smith, 1993;Kyllerman, 1995;Petersen et al, 1995). In western populations (Dagli et al, 2011;Tan et al, 2011;Mertz et al, 2013;Thibert et al, 2013;Faundes et al, 2015), about 70e75% of AS were caused by maternal microdeletion, 2e7% by UPD15pat, 3e5% by IC defect and about 10% by UBE3A mutation. In our cohort, the prevalence of different molecular mechanisms were similar with 65.5% by maternal microdeletion, 10.9% by UPD15pat, 3.5% by IC defect and 14.5% by UBE3A mutation.…”

“…Although ascertainment bias cannot be excluded, genuine ethnic-specific difference in genomic architecture may also play a role in causing such a difference that further studies are needed to confirm this. The average age at diagnosis for AS in Hong Kong was 6.2 years old (95% C.I was 5.0e7.5 years old), which was far more older than western populations (Mertz et al, 2013). Lack of awareness for AS among medical health professionals and limited accessibility to genetic service were part of the reasons.…”

Angelman syndrome: a journey through the brain

“…Moreover, diagnosis confirmation by AS molecular testing is recommended. AS has been diagnosed in individuals of all ethnicities with an estimated number of the prevalence among children and young adults between 1 : 12 000 and 1 : 24 000 individuals .…”

Anxiety‐associated and separation distress‐associated behaviours in Angelman syndrome

“…Although the true prevalence of AS is not known, it is generally estimated to be approximately 1:15 000 births (Mertz et al . ). There are four molecular causes for the deficient expression of maternal UBE3A causing AS.…”

“…Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by a loss of function of the UBE3A gene on the maternal allele of chromosome 15q11.2-q13. Although the true prevalence of AS is not known, it is generally estimated to be approximately 1:15 000 births (Mertz et al 2013). There are four molecular causes for the deficient expression of maternal UBE3A causing AS.…”