TY - JOUR
T1 - Does parent of origin matter? Methylation studies should be performed on patients with multiple copies of the prader-willi/angelman syndrome critical region
AU - Aypar, Umut
AU - Brodersen, Pamela R.
AU - Lundquist, Patrick A.
AU - Brian Dawson, D.
AU - Thorland, Erik C.
AU - Hoppman, Nicole
N1 - Publisher Copyright:
© 2014 Wiley Periodicals, Inc.
PY - 2014/10
Y1 - 2014/10
N2 - Deletion of 15q11.2-q13 results in either Prader-Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region(PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent-oforigin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain.
AB - Deletion of 15q11.2-q13 results in either Prader-Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region(PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent-oforigin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain.
KW - 15q11.2-q13
KW - Array CGH
KW - Autism
KW - MSMLPA
KW - PWASCR
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U2 - 10.1002/ajmg.a.36663
DO - 10.1002/ajmg.a.36663
M3 - Article
C2 - 24975781
AN - SCOPUS:84908258341
SN - 1552-4825
VL - 164
SP - 2514
EP - 2520
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 10
ER -