Interchromosomal insertions

Abstract

In five families with questionable chromosome rearrangements, we identified an interchromosomal insertion by fluorescent in situ hybridization (FISH). In case 1 with a dir ins (5;11)(p14;q14q24) in three generations, the mentally retarded and microcephalic proband showed a 5p14-->pter deletion. In case 2, a duplication (13)(q21.31--> q31.2) combined with a deletion (11)(q14-->q22) segregated from a reciprocal ins(11;13)(q14q122)(q21.32q31.2), causing a mixed phenotype with psychomotor retardation, caput quadratum, choanal atresia, and pes equinovarus. In case 3, a dir ins (18;5)(q21.3;p13.1p14) was associated with spontaneous abortions, in case 4, the proband with mental retardation, microcephaly, and a heart defect showed a pure trisomy of (12)(q13-->q15), which had segregated from a carrier of an ins (18;12)(p11.3;q13q15). In case 5, a duplication of (10)(q26.3-->q25.2) segregated from an inv ins(5;10)(q15;q26.3q25.2), which was passed on directly from a mother to her son,with mental retardation. In all families the elucidation of the insertional translocation (IT) considerably increased the associated genetic risks of carriers. For the review, we collected data from 81 articles on 87 IT probands on ascertainment, origin, familial transmittance, progeny, and genetic risks of IT carriers. We also discussed the recombinant chromosomes and complex rearrangements associated with ITs, and listed chromosome regions occurring solely as deletions, or solely as duplications, or as both to facilitate genotype/phenotype correlations. We conclude that ITs are rare chromosomal rearrangements with an 1:80,000 incidence, of which nearly 80% were referred because of congenital abnormalities and mental retardation. A maternal origin was seen in 59.5%, a paternal origin in 26.6%, and 13.9% were de novo. No notable difference in fertility between male and female IT carriers was noticed. Bias of ascertainment was excluded in 15 familial cases and led to an estimate of the genetic risks for IT carriers of 32.0-36.0%. The mean size of the inserted regions occurring solely as duplications (n=39) measures 0.96% of the haploid autosomal length (HAL), and of regions solely occurring as deletions (n=14) 0.47% HAL. In the families where both aneusomies occurred, the size of the insertions ranged between 0.22 and 1.21% HAL. Overall, the findings fit with the general idea that a surplus of genetic material is tolerated more easily than a deficiency.

Genomic Characterization of Chromosomal Insertions: Insights into the Mechanisms Underlying Chromothripsis

“…Unbalanced insertions also arise de novo. They are relatively rare CSRs, with an estimated incidence of about 1: 80,000 according to conventional cytogenetic techniques [Van Hemel and Eussen, 2000]. However, 3 recent cohort studies using high-resolution aCGH in conjunction with FISH found a higher incidence than previously estimated [Kang et al, 2010;Neill et al, 2011;Nowakowska et al, 2012].…”

“…Chromosomal insertion, also called insertional translocation, is one of several gross interchromosomal structural rearrangements [Van Hemel and Eussen, 2000]. Insertions involve a translocation of a segment from one chromosome and its insertion as an interstitial region into another nonhomologous chromosome [Weckselblatt and Rudd, 2015].…”

Male and female meiotic behaviour of an intrachromosomal insertion determined by preimplantation genetic diagnosis

“…Postnatal studies report no difference in fertility between male and female interchromosomal insertion carriers [14] and estimate the risk of having an abnormal child as being close to 32% for male carriers, compared to 36% for female carriers [3], whereas no reports have been made for intrachromosomal insertions.…”

Mechanisms for Complex Chromosomal Insertions

“…[2, 3] By cytogenetic techniques, the incidence of microscopically visible insertions was estimated to be 1 in 80,000 live births. [4] More recently, by array-comparative genomic hybridization (aCGH) in conjunction with fluorescence in situ hybridization (FISH) confirmation of the aCGH findings, insertion events were demonstrated to occur much more frequently, with estimated incidence of 1 in 500[1] or 1 in 563[5] individuals tested. Another study demonstrated that ~2.1% of apparently de novo , interstitial CNVs were actually consequences of imbalances resulted from parents with balanced insertions.…”