Reproductive outcomes of paracentric inversion carriers: Report of a liveborn dicentric recombinant and literature review

Summary An abnormal infant had a dicentric chromosome 14 with an inverted tandem duplication [46,XY,inv dup(14) (pterq32.3::q24.2pter)], thus making him trisomic for the proximal two-thirds of chromosome 14. This abnormality was derived from a maternal paracentric inversion in chromosome 14 [46,XX,inv(14)(q24.2q32.3)]. To our knowledge, this is the first report of a liveborn infant carrying a stable, dicentric product of crossing over within a paracentric inversion loop. A review of the reproductive outcomes of paracentric inversion carriers in the literature suggests that they are at some risk for pregnancy wastage. The risk for liveborn recombinants is small but such births have occurred, at least to female carriers.     

Duplication deficiency as the result of meiotic segregation of a maternal InV (10)

Summary In a family a large pericentric inversion involving nearly 70% of the chromosome 10 has been segregating during three generations, giving several carriers and an affected male with the karyotype 46,XY,der(10)(10pter10q25::10p12 10pter) mat. The patient is trisomic for 10p except for a small segment near the centromere, and monosomic for the distal 10q26. A simple diagrammatic representation explains the behavior of the inv(10) in meiosis. The study of meiotic segregation in the present case, and the reviews of previously reported duplication-deficiencies, agree with established postulates and add some principles to the understanding of duplication deficiencies resulting from the meiotic behavior of inverted chromosomes.     

Intrachromosomal insertions: a case report and a review

Summary We describe the phenotype of a child having a recombinant chromosome 3 with a duplication 3q13.2 q25 derived from a paternal inv ins(3)(p25.3q25q13.2). A review of 27 reported cases of intrachromosomal insertions has revealed that for a carrier of intrachromosomal insertion the risk of a child with an unbalanced karyotype is 15%. This risk may be higher for particular insertions. The recombinant chromosome can have a duplication or a deletion of different segments depending on whether the insertion is direct or inverted, paracentric or pericentric, and whether there is meiotic crossing over in the inserted or the interstitial non-inserted segment. Several of the insertions have been difficult to interpret and some of them have been mistaken for paracentric inversions. Caution is therefore indicated in interpreting parental karyotypes of a child with a deletion or a duplication, particularly if it is interstitial. This is because, whereas a risk of recurrence of a child with an unbalanced karyotype is low in de novo cases and for carriers of paracentric inversions, it is high for carriers of insertions.     

Paracentric inversion in the short arm of chromosome 1. Report of a family and review of the literature

In general, carriers of paracentric inversions are phenotypically normal, although individual reports describe like occurrence of infertility, miscarriages and mental retardation in inversion carriers. We present a family with paracentric inversion of 1p [karyotype: 46,XY/XY, inv(1)(p13.2p36.2)] in 7 of the 12 investigated family members. The index patient, a four year-old boy was referred for motor and mental retardation. The possible relationship between the paracentric inversion and the MR/MCA syndrome in the index patient of this family is briefly discussed.     

Paracentric inversion of chromosome 15(q15q24): description of three families

Three unrelated families with paracentric inversion of chromosome 15(q15q24) are reported. An additional pericentric inversion of chromosome 9 with breakpoints in p11.2q13 was also observed in one of the three families. Reproductive problems, such as stillbirths, spontaneous abortions and two live-born children with multiple abnormalities, were present.     

Cytogenetic recombinants from a female carrying a paracentric inversion of the short arm of chromosome number 5

Summary We present a family, identified through a girl with Cri-du-chat syndrome, in which two different types of recombinants exist [del(5)(qterp14:) and dup(5)(p13)]. They are due to a 5p paracentric inversion of maternal origin [inv(5) (pter p13)]. We discuss the relationship between the breakpoints and segregation of the inversion carrier, as well as the origin and the identification of the recombinants.     

A large pericentric inversion of human chromosome 8.

A large pericentric inversion, inv(8) (p11q24), was ascertained in a male investigated because his wife had had repeated miscarriages. The inversion segregated in 3 generations of the family, and no chromosomally unbalanced offspring were detected. The miscarriage and the inversion could not be causally related.     

Inv(10)(p11.2q21.2), a variant chromosome

We present 33 families in which a pericentric inversion of chromosome 10 is segregating. In addition, we summarise the data on 32 families in which an apparently identical inv(10) has been reported in the literature. Ascertainment was through prenatal diagnosis or with a normal phenotype in 21/33 families. In the other 12 families, probands were ascertained through a wide variety of referral reasons but in all but one case (a stillbirth), studies of the family showed that the reason for referral was unrelated to the chromosome abnormality. There has been, to our knowledge, no recorded instance of a recombinant chromosome 10 arising from this inversion and no excess of infertility or spontaneous abortion among carriers of either sex. We propose that inv(10)(p11.2q21.2) can be regarded as a variant analogous to the pericentric inversion of chromosome 2(p11q13). We conclude that prenatal chromosome analysis is not justified for inv(10) carriers. In addition, family investigation of carrier status is not warranted in view of the unnecessary concern this may cause parents and other family members. Received: 7 July 1997 / Accepted: 4 August 1997     

The significance of pericentric inversions of chromosome 2

Summary Thirteen new cases of a pericentric inversion 2 collected from different laboratories are reported. In addition 41 cases of a pericentric inversion 2 were reviewed from the literature. The pooled data were analysed using Weinberg's proband method to evaluate the risk of a carrier for either children with congenital anomalies or reproductive wastage. In the corrected sample of 166 lifeborn offspring of carriers of a pericentric inversion 2 there were five who showed phenotypic anomalies and two died a few hours after delivery. The reported anomalies are heterogeneous and probably reflect the basic risk of any couple for abnormal lifeborn offspring. There has been no observation of a lifeborn who inherited an unbalanced recombination of a parental pericentric inversion 2. A carrier of a pericentric inversion 2 obviously has an increased risk for reproductive wastage. This is indicated by (1) an increase of the rate of spontaneous abortions and (2) an increase of the rate of index patients ascertained because of previous miscarriages. The risk of a carrier of a pericentric inversion 2 for a spontaneous abortion or a stillbirth may be about twice the basic risk of the general population.     

Meiotic analysis of a pericentric inversion, inv(7) (p22q32), in the father of a child with a duplication-deletion of chromosome 7

In a family in which a large pericentric inversion of chromosome 7 is segregating, two of the four progeny of inversion heterozygotes show severe psychomotor retardation and have the karyotype 46,XX,rec(7),dup q,inv(7)(p22q32), derived from crossing-over within the inversion. Meiotic analysis in one of the heterozygotes revealed no evidence of inversion loops in well-spread pachytene cells. In approximately 20% of cells in diakinesis, the presumptive bivalent 7 had only one chiasma. Two alternatives to the reversed loop mode of meiotic pairing of inversions are proposed. Review of the literature supports the view that "small" pericentric inversions have a much better genetic prognosis than "large" pericentric inversions.     

Preferential maternal derivation in inv dup(15)

Summary Eight patients are reported with a de nov extra inverted duplicated chromosome 15. The abnormal chromosome was considered to be the same in all cases, but its precise delineation remained uncertain and was defined as either 15qter15q12::15q1215pter or 15pter15q11::15q1315pter. Analysis with various techniques of the satellite regions of the bisatellited chromosomes demonstrated maternal derivation in six and paternal derivation in one of the seven families. A nonsister chromatid exchange between the two homologous chromosomes 15 is considered a likely origin of the inv dup(15) in the cases with maternal derivation; in the only case of paternal derivation, however, the abnormal chromosome originated from one single chromosome 15. The clinical findings confirm that patients with inv dup(15) have mental and developmental retardation and are frequently affected by seizures, while severe physical malformations are absent.     

A new type of inversion of a human Y chromosome

Summary Using chromosome banding techniques, a phenotypically normal male was found to have an abnormal banding pattern of the Y chromosome. By the constitutive heterochromatin staining method, a darkly stained band was located on the short arm and the proximal region of the long arm. The quinacrine staining method also showed a similar abnormal banding pattern: a brightly fluorescing band was seen on the short arm and the proximal region of the long arm. By the conventional Giemsa staining method, however, no specific morphological abnormality was detected in the aberrant Y. On detailed karyotype analyses no recognizable abnormality of banding patterns of any other chromosome was found aside from the abnormal Y. The abnormality was determined to be a complex inversion of the Y chromosome, which is described as 46,X,inv(Y)(pterp11::q11q12::cen::q12qter).     

Three large Danish families with a paracentric inversion in the short arm of chromosome N. 5

A paracentric inversion in the short arm of chromosome 5 [inv(5p)] was segregating through at least four generations in three large danish families. All inversion carriers were phenotypically normal, and no adverse effects on reproduction were observed.     

Familial pericentric inversion (3)(p12q24)

Summary A large kindred with a familial pericentric inversion of chromosome 3, (p12q24), was found after an investigation initiated by a young female with three spontaneous first-trimester abortions. Altogether 22 (33%) inversion carriers were discovered, 9 females and 13 males. 6 women and 9 men were included in the fertility and segregation analyses because they were all either sexually mature or past maturity. The abortion frequency was below the average European rate in both the inversion carrier group and the cytogenetically normal relative group; 6%: 3%, respectively. The mean numbers of pregnancies and live births (1.8–3.1) did not vary significantly in the two comparison groups. The segregation analysis among the inversion carriers showed a good correspondence to the theoretical 11 ratio (1613). Males and females contributed equally. No duplication/deletion syndromes have been found in the kindred; all family members are phenotypically normal. We report a balanced familial pericentric inversion with no adverse effects. This chromosome aberration could be an example of a harmless chromosome polymorphism.     

Genetic counseling in balanced chromosomal inversions

The genetic counseling given at carriers of equilibrated chromosomal inversions is in relation with the type of the inversion. The risk for carriers of pericentric inversions concerning euchromatic regions depends on many factors, i.e. the length of the inserted segment in relation with the total length of the chromosome involved, the sex of the carrier and the way of assortment. In contrast, the carriers of pericentric inversions concerning the heterochromatic regions, as well as of paracentric inversions, have not a particular risk for their descendance.     

Disruption of DMD and deletion of ACSL4 causing developmental delay, hypotonia, and multiple congenital anomalies

We have studied a male patient with significant developmental delay, growth failure, hypotonia, girdle weakness, microcephaly, and multiple congenital anomalies including atrial (ASD) and ventricular (VSD) septal defects. Detailed cytogenetic and molecular analyses revealed three de novo X chromosome aberrations and a karyotype 46,Y,der(X)inv(X) (p11.4q11.2)inv(X)(q11.2q21.32 approximately q22.2)del(X)(q22.3q22.3) was determined. The three X chromosome aberrations in the patient include: a pericentric inversion (inv 1) that disrupted the Duchenne muscular dystrophy (DMD) gene, dystrophin, at Xp11.4; an Xq11.2q21.32 approximately q22.2 paracentric inversion (inv 2) putatively affecting no genes; and an interstitial deletion at Xq22.3 that results in functional nullisomy of several known genes, including a gene previously associated with X-linked nonsyndromic mental retardation, acyl-CoA synthetase long chain family member 4 (ACSL4). These findings suggest that the disruption of DMD and the absence of ACSL4 in the patient are responsible for neuromuscular disease and cognitive impairment.     

Familial pericentric inversion of the X chromosome [inv(X)(p11q28)]

A familial pericentric inversion of the X chromosome [46,X,inv(X)(p11q28)] and [46,inv(X)(p11q28), Y] is reported. The carriers of the inv(X) presented no clinical symptoms. Either the inverted or the normal X chromosome may be late replicating.     

A fetus with recombinant of chromosome 8 inherited from her carrier father

Summary A pericentric inversion of chromosome 8, inv(8)(p23q22), in a male carrier resulted in an unbalanced recombinant, rec(8)dup q, inv(8)(p23q22), which was diagnosed prenatally. The features seen in the aborted fetus resembled the features seen in a previously affected child who received the identical recombinant from her carrier mother. In this particular inversion involving chromosome 8, both male and female carriers risk producing an unbalanced progeny. Different familial pericentric inversions are reviewed for the presence or absence of unbalanced recombinants.     

Genetic analysis of meiotic recombination in humans by use of sperm typing: reduced recombination within a heterozygous paracentric inversion of chromosome 9q32-q34.3.

To investigate patterns of genetic recombination within a heterozygous paracentric inversion of chromosome 9 (46XY inv[9] [q32q34.3]), we performed sperm typing using a series of polymorphic microsatellite markers spanning the inversion region. For comparison, two donors with cytogenetically normal chromosomes 9, one of whom was heterozygous for a pericentric chromosome 2 inversion (46XY inv[2] [p11q13]), were also tested. Linkage analysis was performed by use of the multilocus linkage-analysis program SPERM, and also CRI-MAP, which was adapted for sperm-typing data. Analysis of the controls generated a marker order in agreement with previously published data and revealed no significant interchromosomal effects of the inv(2) on recombination on chromosome 9. FISH employing cosmids containing appropriate chromosome 9 markers was used to localize the inversion breakpoint of inv(9). Analysis of inv(9) sperm was performed by use of a set of microsatellite markers that mapped centromeric to, telomeric to, and within the inversion breakpoints. Three distinct patterns of recombination across the region were observed. Proximal to the centromeric breakpoint, recombination was similar to normal levels. Distal to the telomeric breakpoint, there was an increase in recombination found in the inversion patient. Finally, within the inversion, recombination was dramatically reduced, but several apparent double recombinants were found. A putative model explaining these data is proposed.     

Pericentric inversion in chromosome 2 without phenotypic effect

A subject with pericentric inversion of chromosome 2: 46, XY, inv(2) (p11q13) is described. All the family members which present the same inversion are clinically normal