Parental origin of deletions and duplications – about the necessity to check for cryptic inversions

Abstract

BackgroundCopy number variants (CNVs) are the genetic bases for microdeletion/ microduplication syndromes (MMSs). Couples with an affected child and desire to have further children are routinely tested for a potential parental origin of a specific CNV either by molecular karyotyping or by two color fluorescence in situ hybridization (FISH), yet. In the latter case a critical region probe (CRP) is combined with a control probe for identification of the chromosome in question. However, CNVs can arise also due to other reasons, like a recombination-event based on a submicroscopic, cryptic inversion in one of the parents.ResultsSeventy-four patients with different MMSs and overall 81 CNVs were studied here by a novel three color FISH approach. The way how three locus-specific probes are selected (one is the CRP and two are flanking it in a distance of 5-10 Mb) enables to detect or exclude two possible parental conditions as origins of the CNV seen in the index: (i) direct parental origin of the CNV (deletion or duplication) or (ii) a parental cryptic inversion. Thus, for overall 51/81 CNVs (63%) a parental origin could be determined. 36/51 (70.5%) inherited the CNV directly from one of the parents, but 15/51 (29.5%) were due to an exclusively by three color FISH detectable parental inversion. A 2:1 ratio of maternal versus paternal inheritance was found. Also almost two times more male than female were among the index patients.ConclusionThe new, here suggested three color FISH approach is suited for more comprehensive parental studies of patients with MMS. The detection rate for parental origin was increased by 140% in this study. Still, for 30/81 cases (37%) no reason for the ‘de novo’ MMS in the affected index patient could be found by the here suggested FISH-probe set.Electronic supplementary materialThe online version of this article (10.1186/s13039-018-0369-1) contains supplementary material, which is available to authorized users.

Recombinant Chromosomes Resulting From Parental Pericentric Inversions—Two New Cases and a Review of the Literature

“…As preferential maternal origin of recombinant chromosomes was already shown by Ishii et al (1997) this was not recapitulated in the present study. Similar effects are well known for small supernumerary marker chromosomes (Liehr 2006) and passing on of other kinds of chromosomal aberrations in human (Liehr et al, 2018). For clinical impact and impact of large and small to submicroscopic paracentric inversions, the latter being part of normal variance in humans, see Pettenati et al (1995); Liehr et al (2018) and database of genomic variants ().…”

The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay

“…Besides being a well-established routine test for the rapid detection of suspected microdeletion syndromes, FISH analysis can identify the position of duplicated loci in microduplication syndromes. Using specific locus probes, it is possible to identify cryptic balanced inversions in parents, resulting in CNVs arising in the offspring following meiotic recombination within the inversion segment of the carrier parent [42][43][44]. Thus, due to the wide range in its diagnostic capacity, array-CGH is a standard method in routine diagnostic multistep algorithm, where it serves as a first-tier test, confirmatory test or test following conventional G-banding karyotyping as well.…”

Chromosomes in the DNA era: Perspectives in diagnostics and research

“…For constitutional genetics, it has recently been shown that FISH is the only routine diagnostic approach capable of detecting the parental origin of disease-causing submicroscopic inversions relevant for the offspring. Such submicroscopic events may lead to microdeletion or microduplication in the putative progeny of such inversion carriers [16]. Nonetheless, patients with a suspected microdeletion syndrome (including subtelomeric imbalances) are nowadays tested using molecular karyotyping rather than combination with cytogenetics.…”

“…One example is the identification of recurrent microdeletion and -duplication syndromes by CMA collected in several databases (e. g., Decipher, ISCA, ECRUCA) and the identification of the underlying pathomechanism of nonhomologous recombination triggered by low copy repeats. Subsequently, predisposing rearrangements such as inversions were discovered in parents of affected individuals and are now the subject of evaluation in routine FISH diagnostics to estimate the recurrence risk for those families [16]. Even combining all available standard approaches in human genetic diagnostics may be insufficient to solve the disease-causing gene.…”