A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rare Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis

Heng Gu,Zheng Chen,Xin-Ming Son,Yang-Yu Huang,Xing-Sheng Dong,Jian-Ying Li,Jian-Hui Jiang,Ya-Nan Zhang,Xinyan Lu,Anthony W.I Lo

doi:10.1371/journal.pone.0076985

Abstract

Cri-du-Chat syndrome (MIM 123450) is a chromosomal syndrome characterized by the characteristic features, including cat-like cry and chromosome 5p deletions. We report a family with five individuals showing chromosomal rearrangements involving 5p, resulting from rare maternal complex chromosomal rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecular and cytogenetic analyses. Two probands, including a 4½-year-old brother and his 2½-year- old sister, showed no diagnostic cat cry during infancy, but presented with developmental delay, dysmorphic and autistic features. Both patients had an interstitial deletion del(5)(p13.3p15.33) spanning ∼26.22 Mb. The phenotypically normal mother had de novo CCRs involving 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn. In addition to these two children, she had three first-trimester miscarriages, two terminations due to the identification of the 5p deletion and one delivery of a phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identical maternal allele haplotype of 5p. Array CGH did not detect any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, in the unaffected daughter, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently reported as a mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate that the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further resulted in the interstitial 5p deletions in the unaffected daughter. Further high resolution sequencing based analysis is needed to determine whether chromothripsis is also present as a germline structural variation in phenotypically normal individuals in this family.

Highlights

Genomic imbalances such as chromosomal aberrations have been long recognized to be a major cause for genetic disorders, resulting in miscarriages, neonatal birth defects, postnatal developmental delay, autistic spectrum disorders and intellectual disability [1]
CDCs patients are diagnosed based upon the clinical manifestations, chromosome and/or Fluorescence in situ Hybridization (FISH) analyses, or molecular based testing such as multiplex ligation-dependent probe amplification (MLPA) or PCR
Several genotype-phenotype studies revealed that the size of chromosome 5p deletions could vary from a single chromosome cytogenetic band to the entire chromosome 5p, and the severity or spectrum of clinical phenotypes i.e. intellectual disability and microcephaly in CDCs or 5p syndromes are related to the size and the location of the deletions [6,29]

Summary

Introduction

Genomic imbalances such as chromosomal aberrations have been long recognized to be a major cause for genetic disorders, resulting in miscarriages, neonatal birth defects, postnatal developmental delay, autistic spectrum disorders and intellectual disability [1]. Chromosome 5p deletion or Cri-du-chat syndrome (CDCs, MIM 123450) was first described by Lejeune in 1963 [3] and it is the one of most common chromosomal deletion syndrome in humans [4]. The hallmark clinical features of CDCs include high-pitched cat-like monochromatic cry, microcephaly, a round face, hypertelorism, micrognathia, epicanthal folds, hypotonia, prominent nasal bridge, and severe psychomotor and intellectual disability [6]. Recurrent respiratory infections are frequently observed in CDCs and pneumonia is the major cause of neonatal or infantile death [4,7]

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