Complex de novo chromosomal rearrangement at 15q11-q13 involving an intrachromosomal triplication in a patient with a severe neuropsychological phenotype: Clinical report and review of the literature

Chiara Castronovo, Milena Crippa, Ilaria Bestetti, Daniela Rusconi, Silvia Russo, Lidia Larizza, Roberto Sangermani, Maria Teresa Bonati, Palma Finelli

Research output: Contribution to journalArticle

Abstract

Interstitial triplications of 15q11-q13, leading to tetrasomy of the involved region, are very rare, with only 11 cases reported to date. Their pathogenicity is independent of the parental origin of the rearranged chromosome. The associated phenotype resembles, but is less severe, than that of patients bearing inv dup(15) marker chromosomes. Here, we describe a boy of 3 years and 9 months of age who exhibited very mild craniofacial dysmorphism (arched eyebrows, hypertelorism, and a wide mouth), developmental delay, generalized hypotonia, ataxic gait, severe intellectual disability, and autism. Array comparative genomic hybridization (CGH) analysis identified a heterozygous duplication of 1.1Mb at 15q11.2 (between low-copy repeats BP1 and BP2), and a heterozygous triplication of 6.8Mb at 15q11.2-q13.1 (BP2-BP4). Both acquisitions were de novo and contiguous. Microsatellite polymorphism analysis revealed the maternal origin of the triplication and the involvement of both maternal chromosomes 15. Furthermore, fluorescence in situ hybridization (FISH) analysis using BAC clones revealed that the rearrangement was complex, containing three differently sized tandem repeats of which the middle one was inverted. Our study confirms and extends the model proposed to explain the formation of intrachromosomal triplications through recombination events between non-allelic duplicons. The comparison of the proband's clinical presentation with those of previously described cases attests the existence of endophenotypes due to the parental origin of the 15q11-q13 triplicated segment and suggests a timetable for achievement of developmental milestones, thereby contributing to improved genotype-phenotype correlations.

Original languageEnglish
Pages (from-to)221-230
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume167
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

Fingerprint

Genomic Segmental Duplications
Tetrasomy
Mothers
Hypertelorism
Endophenotypes
Eyebrows
Phenotype
Chromosomes, Human, Pair 15
Muscle Hypotonia
Tandem Repeat Sequences
Comparative Genomic Hybridization
Genetic Association Studies
Autistic Disorder
Fluorescence In Situ Hybridization
Gait
Genetic Markers
Intellectual Disability
Microsatellite Repeats
Genetic Recombination
Virulence

Keywords

  • 15q11-q13 interstitial triplications
  • Array CGH
  • Autism
  • Low-copy repeat
  • NAHR
  • U-type exchange

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

@article{81d28f38d9724bf0a34e018f70a127db,
title = "Complex de novo chromosomal rearrangement at 15q11-q13 involving an intrachromosomal triplication in a patient with a severe neuropsychological phenotype: Clinical report and review of the literature",
abstract = "Interstitial triplications of 15q11-q13, leading to tetrasomy of the involved region, are very rare, with only 11 cases reported to date. Their pathogenicity is independent of the parental origin of the rearranged chromosome. The associated phenotype resembles, but is less severe, than that of patients bearing inv dup(15) marker chromosomes. Here, we describe a boy of 3 years and 9 months of age who exhibited very mild craniofacial dysmorphism (arched eyebrows, hypertelorism, and a wide mouth), developmental delay, generalized hypotonia, ataxic gait, severe intellectual disability, and autism. Array comparative genomic hybridization (CGH) analysis identified a heterozygous duplication of 1.1Mb at 15q11.2 (between low-copy repeats BP1 and BP2), and a heterozygous triplication of 6.8Mb at 15q11.2-q13.1 (BP2-BP4). Both acquisitions were de novo and contiguous. Microsatellite polymorphism analysis revealed the maternal origin of the triplication and the involvement of both maternal chromosomes 15. Furthermore, fluorescence in situ hybridization (FISH) analysis using BAC clones revealed that the rearrangement was complex, containing three differently sized tandem repeats of which the middle one was inverted. Our study confirms and extends the model proposed to explain the formation of intrachromosomal triplications through recombination events between non-allelic duplicons. The comparison of the proband's clinical presentation with those of previously described cases attests the existence of endophenotypes due to the parental origin of the 15q11-q13 triplicated segment and suggests a timetable for achievement of developmental milestones, thereby contributing to improved genotype-phenotype correlations.",
keywords = "15q11-q13 interstitial triplications, Array CGH, Autism, Low-copy repeat, NAHR, U-type exchange",
author = "Chiara Castronovo and Milena Crippa and Ilaria Bestetti and Daniela Rusconi and Silvia Russo and Lidia Larizza and Roberto Sangermani and Bonati, {Maria Teresa} and Palma Finelli",
year = "2015",
month = "1",
day = "1",
doi = "10.1002/ajmg.a.36815",
language = "English",
volume = "167",
pages = "221--230",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Complex de novo chromosomal rearrangement at 15q11-q13 involving an intrachromosomal triplication in a patient with a severe neuropsychological phenotype

T2 - Clinical report and review of the literature

AU - Castronovo, Chiara

AU - Crippa, Milena

AU - Bestetti, Ilaria

AU - Rusconi, Daniela

AU - Russo, Silvia

AU - Larizza, Lidia

AU - Sangermani, Roberto

AU - Bonati, Maria Teresa

AU - Finelli, Palma

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Interstitial triplications of 15q11-q13, leading to tetrasomy of the involved region, are very rare, with only 11 cases reported to date. Their pathogenicity is independent of the parental origin of the rearranged chromosome. The associated phenotype resembles, but is less severe, than that of patients bearing inv dup(15) marker chromosomes. Here, we describe a boy of 3 years and 9 months of age who exhibited very mild craniofacial dysmorphism (arched eyebrows, hypertelorism, and a wide mouth), developmental delay, generalized hypotonia, ataxic gait, severe intellectual disability, and autism. Array comparative genomic hybridization (CGH) analysis identified a heterozygous duplication of 1.1Mb at 15q11.2 (between low-copy repeats BP1 and BP2), and a heterozygous triplication of 6.8Mb at 15q11.2-q13.1 (BP2-BP4). Both acquisitions were de novo and contiguous. Microsatellite polymorphism analysis revealed the maternal origin of the triplication and the involvement of both maternal chromosomes 15. Furthermore, fluorescence in situ hybridization (FISH) analysis using BAC clones revealed that the rearrangement was complex, containing three differently sized tandem repeats of which the middle one was inverted. Our study confirms and extends the model proposed to explain the formation of intrachromosomal triplications through recombination events between non-allelic duplicons. The comparison of the proband's clinical presentation with those of previously described cases attests the existence of endophenotypes due to the parental origin of the 15q11-q13 triplicated segment and suggests a timetable for achievement of developmental milestones, thereby contributing to improved genotype-phenotype correlations.

AB - Interstitial triplications of 15q11-q13, leading to tetrasomy of the involved region, are very rare, with only 11 cases reported to date. Their pathogenicity is independent of the parental origin of the rearranged chromosome. The associated phenotype resembles, but is less severe, than that of patients bearing inv dup(15) marker chromosomes. Here, we describe a boy of 3 years and 9 months of age who exhibited very mild craniofacial dysmorphism (arched eyebrows, hypertelorism, and a wide mouth), developmental delay, generalized hypotonia, ataxic gait, severe intellectual disability, and autism. Array comparative genomic hybridization (CGH) analysis identified a heterozygous duplication of 1.1Mb at 15q11.2 (between low-copy repeats BP1 and BP2), and a heterozygous triplication of 6.8Mb at 15q11.2-q13.1 (BP2-BP4). Both acquisitions were de novo and contiguous. Microsatellite polymorphism analysis revealed the maternal origin of the triplication and the involvement of both maternal chromosomes 15. Furthermore, fluorescence in situ hybridization (FISH) analysis using BAC clones revealed that the rearrangement was complex, containing three differently sized tandem repeats of which the middle one was inverted. Our study confirms and extends the model proposed to explain the formation of intrachromosomal triplications through recombination events between non-allelic duplicons. The comparison of the proband's clinical presentation with those of previously described cases attests the existence of endophenotypes due to the parental origin of the 15q11-q13 triplicated segment and suggests a timetable for achievement of developmental milestones, thereby contributing to improved genotype-phenotype correlations.

KW - 15q11-q13 interstitial triplications

KW - Array CGH

KW - Autism

KW - Low-copy repeat

KW - NAHR

KW - U-type exchange

UR - http://www.scopus.com/inward/record.url?scp=84919684528&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919684528&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.36815

DO - 10.1002/ajmg.a.36815

M3 - Article

C2 - 25339188

AN - SCOPUS:84919684528

VL - 167

SP - 221

EP - 230

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 1

ER -