Chromosome 3 duplication q21 leads to qter deletion p25 leads to pter syndrome in children of carriers of a pericentric inversion inv(3) (p25q21).

Close phenotypic similarity between two cases carrying a rec(3) dup q,inv(3) (p25q21), 12 additional infants from the same inv (3)(p25q21) kindred who lived less than 1 year, and eight cases studied in other medical centers has led us to postulate the existence of a distinct chromosome 3 duplication-deletion syndrome. In the presence of trisomy for (3)q21 leads to qter and monosomy for (3)p25 leads to pter, the facial dysmorphy is unique: a distorted head shape due to irregular cranial sutures, thick low eyebrows, long eyelashes, persistent lanugo, distended veins on the scalp, hypertelorism, oblique palpebral fissures, a very short nose with a broad depressed bridge and anteverted nares, protruding maxilla, thin upper lip, micrognathia, low-set ears, and a short webbed neck. Port-wine stains, congenital glaucoma, cloudy corneas, cleft palate and harelip also occur frequently. Each infant has difficulty sucking and swallowing. Congenital anomalies of the cardiovascular system, of midgut rotation, and of the urogenital system are noted for the infants who died neonatally. Most frequent is a ventricular septal defect, followed by atrial septal defect, patent ductus arteriosus, patent foramen ovale, and coarctation of the aorta. Omphalocele, umbilical hernia, hyperplastic kidneys, polycystic kidneys, double ureter, hydro-ureter, hydronephrosis, and undescended testes often occur. The extremities are short in proportion to the length of the trunk. Clinodactyly, coxa valga, talipes, and spina bifida are frequently observed.     

Segregation analysis in a man heterozygous for a pericentric inversion of chromosome 7 (p13;q36) by sperm chromosome studies.

We have analyzed 140 sperm chromosome complements from a subfertile man heterozygous for an inv(7)(p13;q36). Seventy-five percent of the chromosome complements were not recombinant: 37.9% contained the normal chromosome 7, and 37.1% contained the inverted chromosome 7. Twenty-five percent of the 140 were recombinant: 7.1% carried a recombinant chromosome 7 with a duplication p and deletion q, 17.1% carried a recombinant chromosome 7 with a duplication q and deletion p, and 0.7% carried both recombinant chromosomes. The frequency of structural chromosomal aberrations unrelated to the inversion was 11.4%, and the frequency of aneuploidy was 2.9%. Both frequencies were not significantly different from those in control donors. Two sperm complements with a second independent, contiguous inversion involving one of the original breakpoints (q36) were observed (1.4%). The risk of producing chromosomally abnormal offspring or spontaneous abortions would be 34.3%. The proportion of X-bearing and Y-bearing sperm was 46.8% and 53.2%, respectively, not significantly different from the expected 1:1 ratio.     

Risk assessment and segregation analysis in a pericentric inversion inv6p23q25 carrier using FISH on decondensed sperm nuclei

Fluorescent in situ hybridization (FISH) in decondensed sperm nuclei has been used to determine the percentage of normal/balanced or unbalanced spermatozoa produced by an inv(6)(p23q25) carrier, and the possible interchromosomal effect (ICE) of the reorganized chromosomes on other chromosome pairs. A dual color FISH with specific subtelomeric probes for the 6p and 6q regions was performed to determine the segregation pattern of the inverted chromosome. ICE on chromosomes 18, X and Y was assessed using a triple color FISH assay. In the segregation analysis 10,049 spermatozoa were analyzed, and only 45.7% of them were normal/balanced. The high number of unbalanced gametes in our carrier could be the consequence of the large size of the inverted segment. This situation could facilitate the formation of an inversion loop, where formation of an odd number of chiasmata (usually one) result in the production of 50% normal and 50% unbalanced sperm. Furthermore, an increase in the disomy rate for chromosome 6 was also observed. In the screening for ICE, 10,007 spermatozoa were analyzed. The disomy rate for the sex chromosomes and chromosome 18 were not significantly different from those found in our controls, suggesting no evidence of interchromosomal effects in this patient. The use of FISH in decondensed sperm nuclei has proved once more to be an accurate approach to determine the chromosome anomalies in sperm and could help to better establish a reproductive prognosis.     

Chromosome segregation in a man heterozygous for a pericentric inversion, inv(9)(p11q13), analyzed by using sperm karyotyping and two-color fluorescence in situ hybridization on sperm nuclei

Analysis of sperm karyotypes and two-color fluorescent in situ hybridization (FISH) on sperm nuclei were carried out in a man heterozygous for the pericentric inversion inv(9)(p11q13). Sperm chromosome complements were obtained after in vitro fusion of zona-free hamster oocytes and donor sperm. A total of 314 sperm complements was analyzed: 153 (48.7%) carried the inverted chromosome 9 and 161 (51.3%) carried the normal one. None of the sperm complements contained a recombinant chromosome 9, suggesting that no chiasmata were formed in the heterochromatic region. The frequency of structural chromosome aberrations unrelated to the inversion (8.3%) and the frequency of conservative aneuploidy (3.2%) were within the limits observed in our control donors. The proportions of X-bearing (47.3%) and Y-bearing sperm (52.7%) were not significantly different from the expected 1:1 ratio. The percentage of disomy for chromosome 21 was analyzed by two-color FISH in 10 336 sperm nuclei. The disomy rate for chromosome 21 (0.30%) was not significantly different from that found in our controls. These results suggest that the risk for this man of producing chromosomally abnormal offspring or spontaneous abortions was not increased, and do not support the existence of an interchromosomal effect for chromosome 21. Received: 28 October 1996     

Two Down syndrome patients with rec(21),dupq,inv(21)(p11;q2109) from a familial pericentric inversion

Aneusomie de recombinaison arose from a familial pericentric inversion of a chromosome 21. Two female patients had a typical Down syndrome; one of them had slight psychomotor retardation. There was partial trisomy 21q2109----qter in these two patients but ZnCu SOD activity was normal.     

Sperm chromosome analysis of a man heterozygous for a pericentric inversion of chromosome 3

Using a procedure in which human sperm were allowed to fertilize zona-free golden hamster (Mesocricetus auratus) eggs in vitro, the sperm chromosomes of a man heterozygous for inv(3) (p11q11) were analyzed. When the chromosomes were Q-banded, the inverted chromosome had the bright centromeric band on the short arm rather than on the long arm, as was seen in the normal No. 3. One hundred and eleven sperm chromosome spreads were examined, of which 64 contained the normal chromosome and 47 the inverted one. This was not significantly different from the expected 1:1 ratio. No sperm containing a chromosome imbalance caused by a crossover within the inversion were seen. Ten (8.1%) of the sperm contained chromosome abnormalities unrelated to the inversion. The ratio of X- to Y-bearing sperm was 55:45.     

Analysis of sperm chromosome complements from a man heterozygous for a pericentric inversion of chromosome 1

Human sperm chromosomes were studied in a man heterozygous for a pericentric inversion of chromosome (1)(p31q12). Q-banded pronuclear chromosomes were analyzed after in vitro penetration of golden hamster oocytes. A total of 159 sperm were examined: 54% bearing the inverted chromosome 1 and 46% the normal chromosome 1. These frequencies are not significantly different from the theoretical 11 ratio. There were no recombinant sperm with duplications or deficiencies, suggesting that a pairing loop failed to form or that crossing-over was suppressed. The frequency of abnormalities unrelated to the inversion was 5% for numerical, 8.8% for structural, 2.5% for numerical and structural, values not significantly different from control donors studied in our lab. The frequencies of X- and Y-bearing sperm were 46% and 54%, respectively, not significantly different from the expected value of 50%. This is the fifth pericentric inversion studied by human sperm chromosome analysis; recombinant chromosomes have been observed in two of the five cases. Some of the factors associated with an increased risk of recombinant sperm appear to be inversion size greater than 30% of the chromosome and chromosome breakpoints in G-light bands.     

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.     

Sperm chromosome analysis of a man heterozygous for a pericentric inversion of chromosome 20

Summary The sperm chromosomes of a man heterozygous for inv(20)(p13q11.2) were analyzed. Twenty-six sperm chromosome complements were examined, of which fourteen contained the normal chromosome, and twelve the inverted chromosome. None of the sperm complements contained a recombinant chromosome 20. The frequency of structural chromosomal aberrations unrelated to the inversion was 11.5% (3/26). Numerical aberrations were not observed. The percentages of X- and Y-bearing sperm were 56% and 44%, respectively, which was similar to the expected 11 ratio.     

Six cases of partial duplication-deficiency 21 syndrome: 21(dupq22delp23) due to maternal pericentric inversion: inv(21)(p12;q22). A family study

Six probands, apparently not related, with a minimal phenotype of Down's syndrome were investigated between 1970 and 1984 in our laboratory. We found in all of them an identical chromosomal abnormality 46,XX or XY,-21,+ der21(dupq22delp23). The der 21 was due to aneusomie de recombinaison, each mother having an abnormal chromosome 21: inv(21)(p12;q22). The fathers' caryotypes were normal. All parents were young and healthy. Pedigrees were established in order to find a relationship between these families. Four of our probands could be related. Familial investigations are still in progress for the last two cases; the ancestors being born in the same small geographical area (within 50 km2) we think that we shall be able to establish a relationship with the others families.     

Impact of pericentric inversion of Chromosome 9 [inv (9) (p11q12)] on infertility

BACKGROUND:

One of the frequent occurrences in chromosome rearrangements is pericentric inversion of the Chromosome 9; inv (9) (p11q12), which is consider to be the variant of normal karyotype. Although it seems not to correlate with abnormal phenotypes, there have been many controversial reports indicating that it may lead to abnormal clinical conditions such as infertility. The incidence is found to be about 1.98% in the general population.

MATERIALS AND METHODS:

We investigated the karyotypes of 300 infertile couples (600 individuals) being referred to our infertility clinic using standard GTG banding for karyotype preparation.

RESULTS:

The chromosomal analysis revealed a total of 15 (2.5%) inversions, among these, 14 male patients were inversion 9 carriers (4.69%) while one female patient was affected (0.33%). The incidence of inversion 9 in male patients is significantly higher than that of normal population and even than that of female patients (P< 0.05).

CONCLUSIONS:

This result suggests that inversion 9 may often cause infertility in men due to spermatogenic disturbances, which are arisen by the loops or acentric fragments formed in meiosis.     

Familial paracentric inversion inv(3)(q21q25.1). Case report and review of the literature

A second case of a paracentric inversion 3q is described. This anomaly was detected during prenatal analysis and found to be inherited from the father.     

Recombination aneusomy of subtelomeric regions of chromosome 5, resulting from a large familial pericentric inversion inv(5)(p15.33q35.3)

We present a family with three cases of recombination aneusomy rec(5)dup(5q) originating from a large parental pericentric inversion of chromosome 5. The proband--a 6-year-old girl with mental retardation, speech delay, microcephaly, and slight facial dysmorphism--was referred for subtelomere testing. FISH with a Multiprobe Chromoprobe T System (CytoCell) and with several BAC clones mapping to both subtelomere regions of chromosome 5, revealed a recombinant chromosome rec(5)dup(5q) originating from a paternal pericentric inversion inv(5)(p15.33q35.3). The same inversion was present in the proband's father's twin-brother and rec(5)dup(5q) was also identified in his two mentally retarded daughters. The distance of breakpoints from the telomere was: 0.234-1.4 Mb for 5p and 4.1-4.8 Mb for 5q. HR-CGH analysis confirmed the duplication of the 5q subtelomeric region but did not identify any concomitant deletion in the 5p subtelomere. Precise mapping of the aneusomic regions in the proband enabled mapping the cat cry and speech delay to 5p15.33, making the earlier localizations of these features more precise. Our family shows that the large pericentric inversion with both breakpoints at subtelomeric regions of chromosome 5 is associated with a high risk of rec(5)dup(5q) in the progeny.     

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.     

Paracentric inversion inv(11) (q21q23) in the Netherlands

Summary We report the result of investigations from 20 families with 72 carriers of the paracentric inversion inv(11)(q21q23) in the Netherlands. There is no increase in the rate of spontaneous abortions among carriers of the inversion or their partners. Also, so far, there are no children with recombinant chromosomes arising from the inversion. It is doubtful whether prenatal diagnosis would be helpful to carriers of this inversion. The results of the genealogy study and geographical distribution are discussed; it is suggested that all the families have arisen from a single mutation.     

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.     

Sperm chromosome analysis in a man heterozygous for a paracentric inversion of chromosome 7 (q11q22)

Summary Human sperm chromosomes were studied in a man heterozygous for a paracentric inversion of chromosome 7 (q11q22). The pronuclear chromosomes were analysed after in vitro penetration of golden hamster (Mesocricetus auratus) eggs. Ninety-four sperm chromosome spreads were examined, of which 34 contained the normal number 7 chromosome and 59 the inverted 6. This segregation was significantly different from the expected 1:1 ratio. The number of X- to Y-bearing sperm was 48 and 46 respectively. No sperm contained a recombinant chromosome caused by a crossover within the inversion. The frequency of chromosomal abnormalities in other chromosomes was 9.6%, which is not significantly different from the frequency observed in normal donors (8.9%) in our laboratory. These result suggest that the risk of chromosomally unbalanced sperm is not high for this paracentric inversion.     

A small one-band paracentric inversion inv (4) (p15.3p16.3).

A neonate with aniridia was found to have a one band paracentric inversion of the short arm of chromosome 4. This was initially difficult to interpret on high resolution banding. The inversion was present in three generations of the family.