Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay.

Interstitial duplications of proximal 15q containing the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region have been found in patients with autism or atypical autism. In these cases with an abnormal phenotype, the duplications were maternally derived. Paternal origin of the duplication has been associated with a normal phenotype. We report on a patient who presented with nonspecific developmental delay and partial agenesis of the rostral corpus callosum. Fluorescence in situ hybridization (FISH) studies using probes specific for the PWS/AS region demonstrated a double signal on one chromosome 15, indicating the presence of an interstitial duplication of proximal 15q involving the PWS/ AS region in the patient. Parental chromosomes were normal with FISH studies. Methylation analysis at exon alpha of the SNRPN locus showed a maternal band at 4.2 kb and a paternal band of apparent double intensity at 0.9 kb, suggestive of one copy of the maternal allele and two copies of the paternal allele in the patient. Microsatellite analysis was informative at the GABRB3 locus in the family, which showed the inheritance of two different paternal alleles and a maternal allele in the patient consistent with the origin of this duplication from an unequal crossing over between the two chromosome 15 homologs in the father. This is the first report of an abnormal phenotype associated with a paternally derived duplication of proximal 15q shown to contain the PWS/AS region by molecular techniques.

[1]  G. Repetto,et al.  Interstitial duplications of chromosome region 15q11q13: clinical and molecular characterization. , 1998, American journal of medical genetics.

[2]  M. Cuccaro,et al.  Autism and maternally derived aberrations of chromosome 15q. , 1998, American journal of medical genetics.

[3]  D. Abeliovich,et al.  The mechanisms involved in formation of deletions and duplications of 15q11-q13. , 1998, Journal of medical genetics.

[4]  J. Barber,et al.  Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations. , 1997, American journal of human genetics.

[5]  S Schwartz,et al.  Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics. , 1997, American journal of medical genetics.

[6]  P. Patel,et al.  Recombination hot spots and human disease. , 1997, Genome research.

[7]  D. Ledbetter,et al.  Inter- and intrachromosomal rearrangements are both involved in the origin of 15q11-q13 deletions in Prader-Willi syndrome. , 1997, American journal of human genetics.

[8]  B. Leventhal,et al.  Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. , 1997, American journal of human genetics.

[9]  D. Ledbetter,et al.  Refined molecular characterization of the breakpoints in small inv dup(15) chromosomes , 1996, Human Genetics.

[10]  D. Ledbetter,et al.  Validation studies of SNRPN methylation as a diagnostic test for Prader-Willi syndrome. , 1996, American journal of medical genetics.

[11]  C. Truwit,et al.  The normal and abnormal genu of the corpus callosum: an evolutionary, embryologic, anatomic, and MR analysis. , 1996, AJNR. American journal of neuroradiology.

[12]  E. Zackai,et al.  Cytogenetic and molecular characterization of inverted duplicated chromosomes 15 from 11 patients. , 1994, American journal of human genetics.

[13]  N. Lindor,et al.  Form of 15q proximal duplication appears to be a normal euchromatic variant. , 1994, American journal of medical genetics.

[14]  D. Ledbetter,et al.  Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region , 1994, Nature Genetics.

[15]  S. Schwartz,et al.  Brief report: Duplication of chromosome 15q11-13 in two individuals with autistic disorder , 1994, Journal of autism and developmental disorders.

[16]  J. Corbett,et al.  Duplication of the 15q11‐13 Region in a Patient with Autism, Epilepsy and Ataxia , 1994, Developmental medicine and child neurology.

[17]  M. Pembrey,et al.  Duplication of chromosome 15 in the region 15q11-13 in a patient with developmental delay and ataxia with similarities to Angelman syndrome. , 1993, Journal of medical genetics.

[18]  D. Ledbetter,et al.  Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy. , 1993, Human molecular genetics.

[19]  R. Pauli,et al.  Absence of predictable phenotypic expression in proximal 15q duplications , 1991, Clinical genetics.

[20]  F. Beemer,et al.  Duplication in chromosome 15q in a boy with the Prader‐Willi syndrome; further cytogenetic confusion , 1984, Clinical genetics.

[21]  M. Lalande.  Parental imprinting and human disease. , 1996, Annual review of genetics.

[22]  J. P. Park.  Shared synteny of human chromosome 17 loci in Canids. , 1996, Cytogenetics and cell genetics.

[23]  M. Mattéi,et al.  Clinical Heterogeneity in 16 Patients with inv dup 15 Chromosome: Cytogenetic and Molecular Studies, Search for an Imprinting Effect , 1996, European journal of human genetics : EJHG.