Inverted tandem ("mirror") duplications in human chromosomes: -nv dup 8p, 4q, 22q

We have studied 4 patients with inverted tandem duplications of parts of chromosomes, a hitherto rarely identified form of a structural rearrangement involving a single chromosome in man. In patients 1 and 2, the duplication involved parts of the short arm of chromosome 8 (regions 8p12 leads to 8p23 and 8p21 leads to 8p23, respectively). Both patients manifested certain characteristics of the mosaic trisomy 8 syndrome. Elevated levels of glutathione reductase (GSR) in their erythrocytes supported the interpretation of a partial duplication of chromosome 8 and indicated a regional localization for the GSR gene locus. In Partient 3, the distal half of the long arm of chromosome 4 was duplicated (region 4q23 leads to 4q35). Clinical evidence supported this interpretation, as Patient 3 resembled phenotypically the 13 reported cases with duplication of the distal 4q. The cytogenetic findings in Patient 4 suggested a possibly inverted duplication of 22q. The clinical correlation was less convincing due to the lack of a well-defined phenotype for trisomy 22. These chromosome aberrations had occurred de novo in all 4 cases. Although they involved different chromosomal regions, they might well have arisen by the same mechanism. Possible modes of origin that are discussed in detail include unequal exchange between homologous chromosomes, between chromatids of 1 chromosome or between strands of 1 DNA duplex.     

Partial 8p trisomy due to interstitial duplication: karyotype: 46, XX, inv dup(8) (p21.1→p22)

A 24-year-old female with severe mental retardation, congenital malformations and dysmorphic features is described. 8p trisomy due to a de novo inv dup(8) (p21.1----p22) was found in her karyotype. Other published cases with 8p trisomy are reviewed.     

De novo inverted interstitial (“mirror”) duplication of chromosome 8(q13→q24.1) in a liveborn male

We report on a newborn boy with a de novo inverted interstitial duplication of chromosome 8(q13→q24.1). This form of cytogenetic abnormality, in which a mirror image interstitial duplication has occurred, is exceedingly rare. Review of the literature and mechanisms to explain the origin of this type of chromosome aberration are presented. A review of the findings from individuals with partial dup(8q) demonstrate remarkable similarity to the infant we describe.     

Inv dup del (1)(pter→q44::q44→q42:) with the classical phenotype of trisomy 1q42–qter

We report on a girl with a trisomy 1q42–q44 due to an inverted duplication of this region, associated with a terminal deletion of the long arm of the rearranged chromosome 1. Both the large duplication (more than 30 cM) and the small deletion were detected by FISH. Complete karyotype was: (46,XX, inv dup(1)(q44q42).ish(dup del 1)(q44q42)(D1S446×2, D1S423×2, tel1q‐). The phenotype of the patient is characterized by macrocephaly with prominent forehead, downslanting palpebral fissures, micrognathia, and psychomotor retardation. All these clinical features are the same as observed for the typical trisomy 1q42–qter syndrome. The phenotypic effects of the inversion and the terminal deletion of 1q in addition to the trisomy are discussed here. © 2001 Wiley‐Liss, Inc.     

Unbalanced karyotype with normal phenotype in a family with translocation (8;13) (p21;q22)

We describe a family with translocation (8;13) (p21;q22), in which both unbalanced products of adjacent-1 segregation occurred. Two members of the family have partial trisomy 8p with partial monosomy 13q; two others have partial monosomy 8p with partial trisomy 13q. The latter are both phenotypically normal, which is a highly unusual observation. One of these is, in addition, a carrier of a de novo balanced translocation between chromosomes 2 and 19. The risk for unbalanced progeny is discussed.     

Duplication 8q syndrome due to familial chromosome ins(10;8)(q21;q212q22)

We describe a kindred in which an ins(10;8)(q21;q212q22) chromosome rearrangement has been segregating for at least four generations. The risk for balanced carriers to have offspring with duplication of 8q212→8q22 is about 0.31. Individuals with unbalanced chromosomes are mildly to moderately mentally retarded and have a similar unusual appearance. Other manifestations include highly arched or cleft palate (8/9), micrognathia (6/9), sloped shoulders (4–6/9), convulsions (4/9), camptodactyly (3/9), pectus excavatum (2/9), elbow contractures (1/9), and postaxial polydactyly (1/9). The appearance and habitus resemble the mosaic trisomy 8 syndrome, although other anomalies of mosaic trisomy 8, such as vertebral, patellar, and renal defects, were not demonstrated.     

Inv(8)(p23q22) and recombinant derivative in a Sicilian family

A family with inv8(p23q22), in which one girl with a derivative chromosome 8 showed the characteristic phenotype, is reported. Our case differs from the 32 known families with inv8(p23q22), being the first of apparently non-Hispanic descent. The anomaly may, however, have its origins in the Spanish domination of Sicily.     

Thymus deficiency in an infant with a chromosome t(18;22)(q12.2;p11.2)pat rearrangement

The finding of an unbalanced t(18;22)pat chromosome rearrangement in a boy with multiple anomalies including apparent absence of the thymus is described. The observation is of interest because of the reported association of chromosome 22 rearrangements with the DiGeorge sequence. In contrast to previous reports of this association, the deletion involving chromosome 22 is confined to the short arm.     

Partial 18q trisomy and 18p monosomy resulting from a maternal pericentric inversion,inv(18)(p11.2q21.3)

A 7-year-old boy with dysmorphic features was found to have a recombinant chromosome 18, rec(18), resulting from meiotic recombination of a maternal pericentric inversion, inv(18) (p11.2q21.3), as defined by high-resolution banding. He was trisomic for the long arm (q21.3-qter) and monosomic for the short arm (p11.2-pter) of chromosome 18. His clinical features were compared with those in other rec(18) cases, and also those in monosomy 18p, trisomy 18qter and full trisomy 18 syndromes. The risk of recombinant formation for inv(18) carriers was also discussed.     

High risk for unbalanced segregation of some reciprocal translocations: A large pedigree containing distal 4q trisomy from t(4;7)(q28;p22)

We report on a familial t(4;7)(q28;p22) with 2:2 adjacent‐1 unbalanced segregation producing duplication of 4q28→qter in multiple offspring. Within the large four‐generation pedigree, a carrier had a reproductive outcome that was approximately equal for 1) the balanced translocation, 2) normal chromosomes, and 3) viable 4q trisomy or pregnancy loss. The three individuals with chromosomal confirmation of trisomy 4q28→qter (comprising approximately 1.8% of the haploid autosomal length) had similar mental and developmental retardation, hypotonia, restricted speech, seizures, and facial anomalies but no cardiac, renal, or skeletal anomalies. It is suggested that these latter severe malformations, associated with the classic 4q2 to 3 group of anomalies, were from an imbalance outside 4q28→qter and were not necessarily related to the relatively large size of the trisomic segment. Multiple different chromosomes are reported to be rearranged with 4q in the production of distal 4q trisomy. The incidence of 4q rearrangement remains unexplained, but once it is present in a family, viability of a large trisomy in 4q seems to explain the number of affected individuals reported. © 2001 Wiley‐Liss, Inc.     

Partial trisomy 4p resulting from a balanced intrachromosomal insertion, 4(q313p14p16)

Partial trisomy 4p was found in a child with dysmorphic features. Cytogenetic investigations in the parents revealed an intrachromosomal insertion in the mother, 46,XX,ins (4) (q313p14p16). The proband was trisomic for 4p(p14p16) as a result of a recombination event in the mother's chromosome 4 at meiosis. The clinical features of the proband are compared with those found in the literature.     

Five generations of t(4;8)(q35;q13) leading to a case of partial 8q trisomy with consideration of potential pregnancy outcomes from translocation carriers

We describe a female infant with partial trisomy 8q who has rnicrophthalmia, a cleft palate, micrognathia and a heart defect. Her dysmorphogenetic features closely resemble the characteristic pattern seen in the 17 cases thus far reported in the literature. Her chromosomal defect was caused by an unbalanced translocation, inherited through her father, and found to have been transmitted through at least 5 generations. Recently developed models designed to predict the most probable mode of unbalanced segregation from the meiotic quadrivalent and the likelihood that a chromosomally unbalanced fetus will survive to term are applied to this family's translocation. Also, the frequencies of potential reproductive outcomes from carriers of this translocation generated from empiric data are considered as a requisite aid to genetic counseling.     

Case report of rec(7)dup(7q)inv(7)(p22q22) and a review of the recombinants resulting from parental pericentric inversions on any chromosomes

We report a rare case of duplication for 7q22 → 7qter and deletion for 7p22 → 7pter, resulting from a meiotic recombination of a paternal pericentric inversion, inv(7)(p22q22). The newborn boy had the 7q trisomy syndrome. In addition, the diagnosis of chondrodysplasia punctata was made from lumbar and hand X-ray films taken soon after birth. Only two cases of rec(7)dup(7q), both in a single family, have been reported previously. We review 133 offspring with recombinations resulting from pericentric inversions on any chromosomes reported between 1981 and 1995. Of the 133 cases, 110 had a long-arm duplication and short-arm deletion, while only 23 had a short-arm duplication and long-arm deletion. In 85 of the 133 cases, the mother was an inversion carrier (five carriers had two affected offspring), and in 46, the carrier was a father (one carrier had three affected offspring). Kaiser [Hum Genet 1984;68:1–47] reviewed 63 offspring with recombinations derived from a parental pericentric inversion reported between 1972 and 1981. In both surveys, recombinations resulting from pericentric inversions of chromosomes 1, 12, 19, and Y were not found. Am. J. Med. Genet. 73:290–295, 1997. © 1997 Wiley-Liss, Inc.     

Meiotic segregation in familial reciprocal translocation t(8q;22q)

We studied the chromosomes of a mentally retarded boy with minor anomalies and of his parents using a G-band stained high-resolution chromosome method. This documented dup (8q24.1 → 8qter) and dup(22pter → 22q11.2) in the boy due to a maternal balanced reciprocal translocation of chromosomes 8 and 22 and 3:1 disjunction during meiosis I. The karyotype of the boy is 47, XY, + der(22) (22pter → 22q11.2::8q24.1 → 8qter). The der(22) was involved in satellite associations and stained positively with AgNO₃ in mother and child. The case is compared to similar cases in the literature and the function of the small acrocentric marker chromosome during meiosis is discussed.     

Pericentric inversion of chromosome 14 and the risk of partial duplication of 14q (14q31 → 14qter)

Cytogenetic analysis after conventional staining and Q-banding demonstrated a pericentric inversion of chromosome 14 in the mother of a child with a mental retardation/multiple congenital abnormality syndrome and an abnormal chromosome 14. The proposita's partial duplication for the distal segment of 14q is apparently the result of crossing over within the inverted segment during meiosis. An attempt is made at assessing the risk that a carrier of the described pericentric inversion faces of having an abnormal child. The estimate of the risk depends on two factors: 1) the probability of a crossover occurring within the inverted segment during meiosis, and 2) the probability of a child with either of the two possible unbalanced recombinant chromosomes being born alive. An explanation is offered as to why some pericentric inversions confer a significant risk while others are so benign and occur with such a high frequency that they can be considered normal chromosomal variants, rather than chromosome aberrations.     

Trisomy 1q42→qter in a sister and brother: Further delineation of the “trisomy 1q42→qter Syndrome”

We report on a 22-year-old woman and her 21-year-old brother with mild mental retardation, long face, prominent forehead, retrognathia, and (relative) macrocephaly. At birth they were small for date, their length is now below the 10th centile. Chromosome analysis demonstrated a nearly pure trisomy 1q42→qter in both patients due to unbalanced segregation of a paternal reciprocal balanced translocation 46,XY,t(1;15) (q42;p11). This is the second report of a nearly pure trisomy 1q42→qter. When comparing the manifestations of our patients with those of other reported cases we conclude that the most characteristic clinical manifestations of this syndrome are macrocephaly, prominent forehead, micro/retrognathia, large fontanelle, intrauterine growth retardation, postnatal growth retardation, and mental retardation. © 1995 Wiley-Liss, Inc.     

Partial trisomy 6q, due to balanced maternal translocation (6;22) (q21; p13) or (q21; pter)

We report a stillborn infant with partial trisomy 6q who had several major congenital malformations not previously associated with this chromosomal aberration. These included occipital encephalocele, ambiguous genitalia with imperforate anus, omphalocele and unilateral hydronephrosis. The infant's karyotype was 46, XY,-22, der(22), t(6;22)(q21; p13) or (q21;pter)mat. The mother and maternal grandmother are balanced translocation carriers.     

Segregation of a familial balanced (12;10) insertion resulting in dup(10)(q21.2q22.1) and del(10)(q21.2q22.1) in first cousins

An interchromosomal insertion in 3 generations of a family was ascertained through two developmentally delayed first cousins. Cytogenetic analysis using G-banding and chromosome painting showed an apparently balanced direct insertion of chromosome 10 material into chromosome 12, ins(12;10)(q15;q21.2q22.1), in the mothers and grandfather of these children. The proposita inherited only the derivative 10 chromosome, resulting in deletion of 10q21.2 → 22.1 while her cousin inherited only the derivative 12, resulting in duplication of 10q21.2 → 22.1. A comparison of the proposita with published deletion cases suggests a pattern of anomalies attributable to deletion of the 10q21 → q22 region: developmental delay, hypotonia, a heart murmur, telecanthus, broad nasal root and ear abnormalities. This is the first report of a nontandem duplication of the 10q21 → q22 region. The phenotype of the cousin with the duplication does not overlap greatly with published tandem 10q duplications. Finally, this report reaffirms the importance of obtaining family studies of patients with interstitial chromosomal abnormalities. Am J. Med. Genet. 69:188–193, 1997. © 1997 Wiley-Liss, Inc.     

Deficiency of chromosome 8p21.1→8pter: Case report and review of the literature

The clinical manifestations and cytogenetic changes of a patient with 46,XY,del(8)(p21.1) are compared with those of nine other patients with a similar deficiency of chromosome 8. Patients with this chromosome anomaly have a syndrome of postnatal growth retardation, microcephaly, mental retardation, epicanthal folds, posteriorly angulated and malformed ears, short neck, relatively increased internipple distance, and congenital heart defect. A short and broad nose, a wide and flat nasal bridge, and a small jaw are observed in young patients but tend to become less apparent with increasing age. In most instances, the syndrome has been associated with a de novo chromosome abnormality. Levels of glutathione reductase in our patient were normal—a finding consistent with localization of the gene coding for this enzyme to the proximal part of band 8p21.1 if gene dosage studies are reliable.