Phenotype–genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the absence of a maternal contribution to chromosome 15q11-q13. There are four classes of AS according to molecular or cytogenetic status: maternal microdeletion of 15q11-q13 (approximately 70% of AS patients); uniparental disomy (UPD); defects in a putative imprinting centre (IM); the fourth includes 20-30% of AS individuals with biparental inheritance and a normal pattern of allelic methylation in 15q11-q13. Mutations of UBE3A have recently been identified as causing AS in the latter group. Few studies have investigated the phenotypic differences between these classes. We compared 20 non-deletion to 20 age-matched deletion patients and found significant phenotypic differences between the two groups. The more severe phenotype in the deletion group may suggest a contiguous gene syndrome.

A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by an imprinting defect

“…In a study describing the phenotypical differences in AS patients of different molecular classes, Bürger et al 8 pointed out that microcephaly and hypopigmentation are less frequently observed in patients with imprinting mutations than in patients with deletions. Similar findings have been reported by Moncla et al 5 Our study confirms these aspects. 5,8,18 All patients described by us had a normal head circumference for their age and normal pigmentation.…”

“…Similar findings have been reported by Moncla et al 5 Our study confirms these aspects. 5,8,18 All patients described by us had a normal head circumference for their age and normal pigmentation. In addition, they had normal or larger birth sizes, and all but one lacked epilepsy.…”

“…6,7,8 Genotype-phenotype correlations in PWS and AS have revealed subtle clinical differences. 5 It appears as if microcephaly is less frequent in AS patients with an imprinting defect. 8 Furthermore, there are some case reports about AS patients with uniparental disomy and a milder phenotype.…”

“…5 Approximately 70% of patients with AS and PWS have a de novo maternally or paternally derived deletion in the chromosomal region 15q11-q13. Most of the other patients with PWS have two chromosomes 15 of maternal origin (uniparental maternal disomy), whereas uniparental paternal disomy occurs in only 1-2% of patients with AS.…”

Anaesthesia for an adult with Angelman syndrome

“…Deletion defects give rise to a more severe phenotype with earlier onset, refractory epilepsy, more profound motor and neurodevelopmental delay, and poorer speech and language than those with uniparental disomy, imprinting or lone UBE3A mutation Angelman syndrome. The greater severity may be due to the associated loss of genes encoding GABA A subunits [16][17][18][19][20], which is not a feature of non-deletion Angelman syndrome. It is not known if this poses any additional hazards for anaesthesia.…”