IllnessAngelman syndrome, differential diagnosis

• Step-by-step diagnosis, 1. PWS/AS MLPA-UPD, then if necessary UBE3A gene analyses...
• 70% maternal deletion of chromosomes 15q11.2-q13

NGS +

[Sanger]

Angelman syndrome (AS; "happy puppet") is an inconsistent genetic disorder with delayed development (after 6-12 months), intellectual disability, severe speech impairment, often ataxia, epilepsy, and microcephaly. Affected children are often hyperactive, smile and have sleep difficulties. Adult patients exhibit intellectual deficits with speech disorders, seizures, and coarsened facial features. Deficient expression or function of the maternally inherited UBE3A allele causes AS in 80% of cases by deletion, uniparental disomy (UPD) or an imprinting defect. Very rarely, patients have cytogenetic aberrations. Mutations in the UBE3A gene are present in at least 10% of individuals. In the remaining 10% of individuals with AS, the genetic mechanisms are unknown. Mutations in more than a dozen other genes can cause similar disease symptoms and must be considered in the differential diagnosis. In more than 70% of families, the familial recurrence risk is low because of a regional deletion on chromosome 15 but may reach 50% in >10% of cases with maternal UBE3A mutations. Negative cytogenetic and DNA results do not exclude a clinical diagnosis of AS.

(Core/basic diagnostic genes: ###; additional genes: ###).

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1144/

• Alias: Happy puppet syndrome (UBE3A)
• Allelic: Alpha-thalassemia myelodysplasia syndrome, somatic /ATRX)
• Allelic: Alpha-thalassemia/mental retardation syndrome (ATRX)
• Allelic: Autism susceptibility, XL 3 (MECP2)
• Allelic: Chromosome 5q14.3 deletion syndrome (MEF2C)
• Allelic: Corneal dystrophy, Fuchs endothelial, 3 (TCF4)
• Allelic: Cortical dysplasia-focal epilepsy syndrome (CNTNAP2)
• Allelic: Encephalopathy, neonatal severe (MECP2)
• Allelic: Neural tube defects, susceptibility to (MTHFR)
• Allelic: Schizophrenia, susceptibility to (MTHFR)
• Allelic: Skin/hair/eye pigmentation 1, blond/brown hair (HERC2)
• Allelic: Skin/hair/eye pigmentation 1, blue/nonblue eyes (HERC2)
• Allelic: Thromboembolism, susceptibility to (MTHFR)
• Allelic: Vascular disease, susceptibility to (MTHFR)
• Adenylosuccinase deficiency (ADSL)
• Angelman syndrome (UBE3A)
• Angelman/Pitt Hopkins syndrome-like disorder (STXBP1)
• Desanto-Shinawi syndr.: developm. delay, abnormal behavior, facial dysmorph., ocular abnormal. (WAC)
• Epileptic encephalopathy, early infantile, 2 (CDKL5)
• Epileptic encephalopathy, early infantile, 4 (STXBP1)
• Homocystinuria due to MTHFR deficiency (MTHFR)
• Kleefstra syndrome 1 (EHMT1)
• Kleefstra syndrome 2 (KMT2C)
• Mental retardation, AD 1 (MBD5)
• Mental retardation, AD 5 (SYNGAP1)
• Mental retardation, AR 38 (HERC2)
• Mental retardation, XL syndromic, Christianson type (SLC9A6)
• Mental retardation, XL syndromic, Lubs type (MECP2)
• Mental retardation, XL, syndromic 13 (MECP2)
• Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations (MEF2C)
• Mental retardation-hypotonic facies syndrome, XL (ATRX)
• Mowat-Wilson syndrome (ZEB2)
• Pitt-Hopkins like syndrome 1 (CNTNAP2)
• Pitt-Hopkins syndrome (TCF4)
• Pitt-Hopkins-like syndrome 2 (NRXN1)
• Rett syndrome (MECP2)
• Rett syndrome, atypical (MECP2)
• Rett syndrome, congenital variant (FOXG1)
• Rett syndrome, preserved speech variant (MECP2)