Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a neurobehavioral disorder manifested by infantile hypotonia and feeding difficulties in infancy, followed by morbid obesity secondary to hyperphagia. It is caused by deficiency of paternally expressed transcript(s) within the human chromosome region 15q11.2. PWS patients harboring balanced chromosomal translocations with breakpoints within small nuclear ribonucleoprotein polypeptide N (SNRPN) have provided indirect evidence for a role for the imprinted C/D box containing small nucleolar RNA (snoRNA) genes encoded downstream of SNRPN. In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology. In this study, we performed detailed phenotypic, cytogenetic, and molecular analyses including chromosome analysis, array comparative genomic hybridization (array CGH), expression studies, and single-nucleotide polymorphism (SNP) genotyping for parent-of-origin determination of the 15q11.2 microdeletion on an 11-year-old child expressing the major components of the PWS phenotype. This child had an ∼236.29 kb microdeletion at 15q11.2 within the larger Prader-Willi/Angelman syndrome critical region that included the SNORD116 cluster of snoRNAs. Analysis of SNP genotypes in proband and mother provided evidence in support of the deletion being on the paternal chromosome 15. This child also met most of the major PWS diagnostic criteria including infantile hypotonia, early-onset morbid obesity, and hypogonadism. Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis. Array CGH testing for genomic copy-number changes in cases with complex phenotypes is proving to be invaluable in detecting novel alterations and enabling better genotype-phenotype correlations.
Duker
Angela L
AL
Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan, Detroit, MI, USA.
Ballif
Blake C
BC
Bawle
Erawati V
EV
Person
Richard E
RE
Mahadevan
Sangeetha
S
Alliman
Sarah
S
Thompson
Regina
R
Traylor
Ryan
R
Bejjani
Bassem A
BA
Shaffer
Lisa G
LG
Rosenfeld
Jill A
JA
Lamb
Allen N
AN
Sahoo
Trilochan
T
D001483:Base Sequence; D002648:Child; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005220:Fathers; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D005810:Multigene Family; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000473:pathology; D020537:RNA, Small Nucleolar / Q000235:genetics*
D020537:RNA, Small Nucleolar