Early detection of Angelman syndrome resulting from de novo paternal isodisomic 15q UPD and review of comparable cases

Emese Horváth,Gyurgyinka Gergev,János Szabó,László Sztriha,Márta Széll,Dóra Isaszegi,Nikoletta Nagy,Emőke Endreffy,Zsuzsanna Horváth

doi:10.1186/1755-8166-6-35

Emese Horváth, Gyurgyinka Gergev + Show 7 more

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https://doi.org/10.1186/1755-8166-6-35

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Abstract

BackgroundAngelman syndrome is a rare neurogenetic disorder that results in intellectual and developmental disturbances, seizures, jerky movements and frequent smiling. Angelman syndrome is caused by two genetic disturbances: either genes on the maternally inherited chromosome 15 are deleted or inactivated or two paternal copies of the corresponding genes are inherited (paternal uniparental disomy). A 16-month-old child was referred with minor facial anomalies, neurodevelopmental delay and speech impairment. The clinical symptoms suggested angelman syndrome. The aim of our study was to elucidate the genetic background of this case.ResultsThis study reports the earliest diagnosed angelman syndrome in a 16-month-old Hungarian child. Cytogenetic results suggested a de novo Robertsonian-like translocation involving both q arms of chromosome 15: 45,XY,der(15;15)(q10;q10). Molecular genetic studies with polymorphic short tandem repeat markers of the fibrillin-1 gene, located in the 15q21.1, revealed that both arms of the translocated chromosome were derived from a single paternal chromosome 15 (isodisomy) and led to the diagnosis of angelman syndrome caused by paternal uniparental disomy.ConclusionsAS resulting from paternal uniparental disomy caused by de novo balanced translocation t(15q;15q) of a single paternal chromosome has been reported by other groups. This paper reviews 19 previously published comparable cases of the literature. Our paper contributes to the deeper understanding of the phenotype-genotype correlation in angelman syndrome for non-deletion subclasses and suggests that patients with uniparental disomy have milder symptoms and higher BMI than the ones with other underlying genetic abnormalities.

Highlights

Angelman syndrome is a rare neurogenetic disorder that results in intellectual and developmental disturbances, seizures, jerky movements and frequent smiling
Analysis of polymorphic short tandem repeat (STR) markers of the fibrillin-1 gene, which is located in 15q21.1, revealed that both long arms of the aberrant chromosome 15 were inherited from the father (Figure 3), allowing a diagnosis of Angelman syndrome (AS) caused by paternal uniparental disomy (UPD)
The patient was homozygous at all loci for which his father was heterozygous, indicating that the rearrangement resulted from an isodisomic 15q

Summary

Introduction

Angelman syndrome is a rare neurogenetic disorder that results in intellectual and developmental disturbances, seizures, jerky movements and frequent smiling. Angelman syndrome is caused by two genetic disturbances: either genes on the maternally inherited chromosome 15 are deleted or inactivated or two paternal copies of the corresponding genes are inherited (paternal uniparental disomy). Angelman syndrome (AS; OMIM 105830) is a rare neurodevelopmental disorder characterized by severe mental and physical delay, limited speech, fine tremor, ataxia, excessive mouthing behavior, fascination with water, jerky limb movements, seizures, craniofacial abnormalities and unusually happy sociable behavior characterized by frequent episodes of inappropriate smiling [1,2]. We report a 16-month-old Hungarian child, who was referred to our genetic counseling unit with delayed psychomotor and speech development and dysmorphic features, including wide nasal bridge, low set ears, thick lips, wide mouth with protuberant tongue (Figure 1). The clinical phenotype of the patient suggested AS, molecular cytogenetic investigations were carried out to elucidate the genetic background of the presented case

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