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

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.

Heterogeneity of a Constitutional Complex Chromosomal Rearrangement in 2q

“…Other authors suggest that the complexity of constitutional CCRs is the result of a single meiotic event [Houge et al, 2003;Beck et al, 2015]. In recent years, extraordinary 1-step catastrophic genomic events characterized by the shattering of one, or a few, chromosome segments followed by chaotic reassembly of the fragments to explain a CCR have been proposed [Kloosterman et al, 2011[Kloosterman et al, , 2012Stephens et al, 2011;Chiang et al, 2012;Genesio et al, 2013;Gu et al, 2013;Kloosterman and Cuppen, 2013;Zhang et al, 2013;Plaisancié et al, 2014;Wang et al, 2015]. In agreement with the definition, the present CCRs (originating from 1 to 8 breakpoints) involving only a small portion of the 2q region could be caused by these catastrophic events.…”

“…Today, multiple molecular techniques such as array-based comparative genomic hybridization (array-CGH), bacterial artificial chromosome (BAC) FISH analyses, SNP oligonucleotide microarray, qPCR and whole-genome sequencing are the most useful techniques in order to characterize CCRs [López-Expósito et al, 2008;Wang et al, 2014;Macera et al, 2015;Wang et al, 2015]. It has been described that certain chromosomes, such as 1, 2, 5, 16, and 18, are prone to cause constitutional CCR [Houge et al, 2003;Vera-Carbonell et al, 2010;Genesio et al, 2013;Gu et al, 2013;Plaisancié et al, 2014;Wang et al, 2014;Gamba et al, 2015].…”

“…However, new genome rearrangement mechanisms called chromosomal catastrophic events have been proposed to explain the CCRs frequently found in cancer cells [Stephens et al, 2011] and in patients with congenital disorders and/or intellectual disability [Kloosterman et al, 2011[Kloosterman et al, , 2012Liu et al, 2011;Chiang et al, 2012;Genesio et al, 2013;Gu et al, 2013;Kloosterman and Cuppen, 2013;Zhang et al, 2013Zhang et al, , 2015Nazaryan et al, 2014;Plaisancié et al, 2014;Gamba et al, 2015;Wang et al, 2015]. These mechanisms, produced in one unique event, are characterized by the shattering of one, or a few, chromosome segments followed by chaotic reassembly of the fragments resulting in a CCR affecting a limited portion of the genome, often a single chromosome or chromosome arm.…”

A germline chromothripsis event stably segregating in 11 individuals through three generations

“…In three of the cases, the G-CTH was transmitted in an unbalanced form from a healthy mother, giving rise to congenital malformations and developmental delay in the children. [11][12][13] In the fourth case, the G-CTH was also transmitted in…”

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

“…However, in the last decade, a combination of high-resolution platforms and conventional cytogenetics has substantially improved our capability to detect CCRs [e.g., Gu et al, 2013;Fukami et al, 2017]. In this report, an apparent 2-way translocation was reclassified as a 3-way translocation after microarray analysis of the genome of a severely affected toddler revealed the involvement of a new chromosome that was not previously identified by Gbanding in his phenotypically normal mother, i.e., an apparent t(1; 9) translocation turned out to be a t(1; 10; 9) CCR, which is unbalanced in the child and balanced in his mother.…”