t(1;18)(q32.1;q22.1) associated with genitourinary malformations

We report a male infant who has impaired penile development, hypospadias, and mild developmental delay with a 46,XY,t(1;18)(q32.1;q22.1) karyotype. Fluorescent in situ hybridization (FISH) was performed to more precisely map the translocation breakpoint. The translocation breakpoint maps to a region that has been implicated in genitourinary malformations in the 18q- syndrome. This case report suggests that a gene involved in genitourinary development maps at or near the chromosome 18 translocation breakpoint.     

Genotype-phenotype mapping of chromosome 18q deletions by high-resolution array CGH: an update of the phenotypic map

Partial deletions of the long arm of chromosome 18 lead to variable phenotypes. Common clinical features include a characteristic face, short stature, congenital aural atresia (CAA), abnormalities of the feet, and mental retardation (MR). The presence or absence of these clinical features may depend on the size and position of the deleted region. Conversely, it is also known that patients whose breakpoints are localized within the same chromosome band may exhibit distinct phenotypes. New molecular techniques such as array CGH allow for a more precise determination of breakpoints in cytogenetic syndromes, thus leading to better-defined genotype-phenotype correlations. In order to update the phenotypic map for chromosome 18q deletions, we applied a tiling resolution chromosome 18 array to determine the exact breakpoints in 29 patients with such deletions. Subsequently, we linked the genotype to the patient's phenotype and integrated our results with those previously published. Using this approach, we were able to refine the critical regions for microcephaly (18q21.33), short stature (18q12.1-q12.3, 18q21.1-q21.33, and 18q22.3-q23), white matter disorders and delayed myelination (18q22.3-q23), growth hormone insufficiency (18q22.3-q23), and CAA (18q22.3). Additionally, the overall level of MR appeared to be mild in patients with deletions distal to 18q21.33 and severe in patients with deletions proximal to 18q21.31. The critical region for the 'typical' 18q-phenotype is a region of 4.3 Mb located within 18q22.3-q23. Molecular characterization of more patients will ultimately lead to a further delineation of the critical regions and thus to the identification of candidate genes for these specific traits.     

Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23

Fryns JP, Strømme P, van den Berghe H. Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23.
Clin Genet 1993: 44: 149–151. © Munksgaard, 1993
We report a 6-year-old, mentally retarded boy with typical clinical signs and symptoms of the blepharophimosis syndrome ( b lepharophimosis, p tosis, e picanthus inversus s yndrome (BPES)), born to normal parents. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q22.3—q23). This observation reinforces previous suggestions that the location of the BPES gene is at 3q2, i.e. 3q22.3-q23.     

A new deletion of 18q23 with few typical features of the 18q- syndrome.

We report on a patient with a deletion of 18q23. At both 2 and 4 years of age, she displayed few of the facial features or other clinical features associated with the 18q- syndrome. Fluorescent in situ hybridisation and microsatellite marker and RFLP analysis were performed to characterise the extent of the deletion, and a terminal deletion of 18q23 was confirmed. The deleted region includes the gene for myelin basic protein, suggesting that hemizygosity of this gene does not invariably lead to mental and developmental delay. The clinical presentation of this patient suggests that either she is not deleted for the genes involved in the 18q- clinical phenotype or this patient represents one end of the spectrum of the clinical variability seen with 18q terminal deletions.     

Chromosome 18q paracentric inversion in a family with mental retardation and hearing loss

We report on a mother and child with a paracentric inversion of the long arm of chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome. Am. J. Med. Genet. 76:372–378, 1998. © 1998 Wiley-Liss, Inc.     

Molecular and clinical characterization of a recurrent cryptic unbalanced t(4q;18q) resulting in an 18q deletion and 4q duplication

Recurrent constitutional non-Robertsonian translocations are very rare. We present the third instance of cryptic, unbalanced translocation between 4q and 18q. This individual had an apparently normal karyotype; however, after subtelomere fluorescence in situ hybridization (FISH), he was found to have a cryptic unbalanced translocation between 4q and 18q [ish der(18)t(4;18)(q35;q23)(4qtel+,18qtel-)]. Oligonucleotide array comparative genomic hybridization (aCGH) refined the breakpoints in this child and in the previously reported child and indicated that the breakpoints were within 20 kb of each other, suggesting that this translocation is, indeed, recurrent. A comparison of the clinical presentation of these individuals identified features that are characteristic of both 18q- and 4q+ as well as features that are not associated with either condition, such as a prominent metopic ridge, bitemporal narrowing, prominent, and thick eyebrows. Individuals with features suggestive of this 4q;18q translocation but a normal karyotype warrant aCGH or subtelomere studies.     

Genetic refinement and physical mapping of a chromosome 18q candidate region for bipolar disorder.

Recent genetic studies have implicated chromosome 18 in bipolar disorder (BP) with putative loci in the pericentromeric region and on 18q. We reported linkage to chromosome 18q21.33-q23 in a large family. In this study we typed additional markers in the family and were able to reduce the candidate region significantly. All affected family members are sharing alleles for markers spanning a genetic distance of maximal 8.9 cM. Haplotype analysis provided a marker order in agreement with published genetic and physical maps. Using yeast artificial chromosomes, we constructed a contig map that will help to identify positional candidate genes for bipolar disorder.     

A novel maternally-derived insertional translocation resulting in partial trisomy 4q13.2-q22.1 with complex translocation t(8;20) in a family with intellectual disability

We characterized the chromosomal aberration in family with intellectual disability, including two affected children and their affected mother. Initial standard karyotypes of the three individuals showed an apparently balanced translocation of chromosomes 8 and 20. Using molecular cytogenetic techniques, we observed complex structural chromosomal aberration comprising of reciprocal translocation between chromosomes 8 and 20 with pericentric inversion (8p11.12q22.3) and insertion of chromosome 4 segments into both der(8) and der(20). In particular, the insertion of chromosome 4 was complex. Two segments (4q13.2-q13.3 and 4q21.21-q22.1) were inserted into the der(8)t(8;20) breakpoint and one segment (4q13.3-q21.21) into the der(20)t(8;20) breakpoint. Both children inherited two normal chromosomes 4 from their parents and the der(8) and der(20) from the mother, resulting in partial trisomy of 4q13.2-q22.1. Interestingly, the mother, in addition to the same complex insertions and inversion, was founded to have a deletion of 4q13.2-q22.1 in one of her chromosomes 4, yielding no genetic imbalance but with potential disruption of intellectual dysfunction-related gene(s) at the breakpoints as the cause of her intellectual impairment. This family is the third case report of an insertional translocation mechanism causing partial trisomy 4q syndrome. Our study demonstrates that an insertion of an extra chromosomal segment, not primarily involving in translocation breakpoints, which results in partial trisomy, can be an unapparent cause of the abnormal phenotypes.     

Association of a novel constitutional translocation t(1q;3q) with familial renal cell carcinoma

Four cases of late onset clear cell renal cell carcinoma (RCC), a case of gastric cancer, and a case of exocrine pancreatic cancer were identified in a Japanese family. In order to elucidate the underlying mechanism for tumorigenesis in this family, extensive genetic studies were performed including routine and spectral karyotyping (SKY), fluorescence in situ hybridisation (FISH), comparative genomic hybridisation (CGH), loss of heterozygosity studies (LOH), and VHL mutation analysis. A germline translocation t(1;3)(q32-q41;q13-q21) was identified by karyotyping in five members of the family including all three RCC cases tested. The translocation was refined to t(1;3)(q32;q13.3) by FISH analysis using locus specific genomic clones, and the two breakpoints were mapped to a 5 cM region in 3q13.3 and a 3.6 cM region in 1q32. Both CGH and allelotyping using microsatellite markers showed loss of the derivative chromosome 3 carrying a 1q segment in the three familial RCCs analysed. Additional chromosomal imbalances were identified by CGH, including amplifications of chromosomes 5 and 7 and loss of 8p and 9. No germline VHL mutation was found but two different somatic mutations, a splice (IVS1-2A>C) and a frameshift (726delG), were identified in two RCCs from the same patient confirming their distinct origin.Taken together, these results firmly support a three step model for tumorigenesis in this family. A constitutional translocation t(1q;3q) increased the susceptibility to loss of the derivative chromosome 3 which is then followed by somatic mutations of the RCC related tumour suppressor gene VHL located in the remaining copy of chromosome 3.


Keywords: familial renal cell carcinoma; translocation; von Hippel-Lindau disease; loss of heterozygosity     

No evidence for the involvement of CAG/CTG repeats from within 18q21.33-q23 in bipolar disorder

We previously identified 18q21.33-q23 as a candidate region in one BP family and constructed a yeast artificial chromosome (YAC) contig map. Here, we mapped eight known CAG/CTG repeats relative to 18q21.33-q23. We also isolated four CAG/CTG repeats from within the region using CAG/CTG YAC fragmentation, one of which is located in the 5' untranslated region of the CAP2 gene coding for a brain-expressed serine proteinase inhibitor. The triplet repeats located in the 18q21.33-q23 BP candidate region showed no expanded alleles in the linked BP family nor in a BP case-control sample. Moreover, only the CAP2 triplet repeat was polymorphic but no genetic association with BP disorder was observed.     

Monosomy 18q syndrome and atypical Rett syndrome in a girl with an interstitial deletion (18)(q21.1q22.3)

We describe a 6 1/2-year-old girl with an interstitial deletion of chromosome arm 18q (18q21.1q22.3). Her clinical manifestations are a combination of those found in monosomy 18q syndrome and those of Rett syndrome. Cytogenetic analysis demonstrated a deletion of the long arm of chromosome 18, defined by molecular analysis with polymorphic markers as a de novo interstitial deletion, paternally derived. The findings typical of the 18q- syndrome included mental retardation, midface hypoplasia, and hypoplasia of labia majora, and those typical of Rett syndrome were severe mental retardation, autistic behavior, inappropriate hand-washing movements, epilepsy, attacks of sighing and hyperventilation, and progressive scoliosis since the age of 5 years. She did not have microcephaly, and the mental delay was obvious from an early age without a period of normal development, which makes the diagnosis of Rett syndrome atypical. Previously, a girl with mosaicism for a monosomy 18q associated with Rett syndrome has been described. That girl had a terminal deletion of chromosome 18q, which seems to coincide in part with that in the present girl. It is possible that genes in the distal region of 18q are involved in the etiology of Rett syndrome.     

Beckwith-Wiedemann-like macroglossia and 18q23 haploinsufficiency

Beckwith-Wiedemann syndrome (BWS) is an overgrowth condition with tumor proclivity linked to a genetic imbalance of a complex imprinted region in 11p15.5. A female child with features fitting in with the BWS diagnostic framework and an apparent loss of imprinting (LOI) of the IGF2 gene in 11p15.5 was also reported to have a de novo chromosome 18q segmental deletion (Patient 1), thus pointing at the location of a possible trans-activating regulator element for maintenance of IGF2 imprinting and providing one of the few examples of locus heterogeneity of BWS. A second child with de novo 18q23 deletion and features of macroglossia, naevus flammeus, bilateral inguinal hernia and transient neonatal hypoglycemia, thus also fitting in with the BWS diagnostic framework, is here fully reported (Patient 2). In this child, an analysis of the BWS1 locus precluded any paternal isodisomy and showed a normal imprinting pattern (mono-allelic expression of IGF2 and normal H19 and CDKN1OT1/LIT1 methylation index). In Patients 1 and 2, deletions were shown to overlap, defining a minimal region of haplo-insufficiency of 3.8-5.6 Mb in 18q23. We conclude that this region provides a candidate location for an original macroglossia condition with strong overlap with BWS, but without obvious upstream functional relationship with the BWS1 locus in 11p15.5. Because this minimal region of haplo-insufficiency falls into a common region of deletion in 18q- syndrome, we inferred that this macroglossia condition would follow a recessive pattern of inheritance.     

14q(22) deletion in a familial case of anophthalmia with polydactyly

We report a family of anophthalmia with ocular and extraocular manifestations. The proband, his three sisters, and two sons had anophthalmia and preaxial polydactyly in the right hand. Cytogenetic analysis was done for the proband and two of his sons, one of whom was affected. Another male child was affected but was not available for cytogenetic analysis. Karyotypes of both affected individuals showed deletion on long arm of 14q22q23. Literature review shows four cases of anophthalmia with extra ocular anomalies associated with 14q (q22q23) deletion. Recently it has been suggested that the human homeobox gene, SIX6, and the BMP-4 gene are responsible for eye development. Both are located in the chromosome 14q22.3-q23 region. Deletion in this region has been known to be associated with anophthalmia and pituitary anomalies. This is the first family of anophthalmia, which showed polydactyly with a chromosomal deletion in the 14q22-q23 region and its familial transmission in two generations with a total of six affected individuals.     

Selective IgA deficiency with 18q+ and 18q-- karyotypic anomalies.

A case is described of selective immunoglobulin A deficiency in association with an 18q+ anomaly, apparently the result of a break at 18q23 and a de novo translocation. The presentation is compared with the phenotypic and immunological features in an IgA deficient 18q-- patient. The findings in these two patients suggest that gene(s) concerned with regulation of IgA synthesis are located on the distal long arm of chromosome 18 between 18q23 and qter.     

An interstitial,apparently-balanced chromosomal insertion in the etiology of Langer–Giedion syndrome in an Asian family

Langer–Giedion syndrome (LGS; MIM 150230), also called trichorhinophalangeal syndrome type II (TRPS2), is a contiguous gene syndrome caused by a one-copy deletion in the chromosome 8q23-q24 region, spanning the genes TRPS1 and EXT1. We identified an LGS family with two affected and two unaffected siblings from unaffected parents. To investigate the etiology of recurrence of LGS in this family, array CGH was performed on all family members. We identified a 7.29 Mb interstitial deletion at chromosome region 8q23-q24 in the two affected siblings, but no such deletion in the unaffected family members. However, the mother and one of the two unaffected siblings carried a 1.29 Mb deletion at chromosome region 8q24.1, sharing the distal breakpoint with the larger deleted segment found in the affected siblings. Another unaffected sibling had a 6.0 Mb duplication, sharing the proximal breakpoint of the deletion in the affected siblings. Karyotypic and FISH analyses in the unaffected mother revealed an insertional translocation of 8q23-q24 genomic material into chromosome 13: 46,XX,ins(13;8)(q33;q23q24). This insertional translocation in the mother results in the recurrence of LGS in this family, highlighting the importance of submicroscopic rearrangements in the genetic counseling for LGS.     

Translocation 46XY, t (17;18) (q25;q21) in a mentally retarded boy with progressive eye abnormalities

A 10-year-old boy with reciprocal translocation between chromosomes 17 and 18- 46XY,t (17;18) (q25; q21), appeared cytogenetically balanced. The patient was a healthy, thriving boy whose main abnormal feature was moderate mental retardation. However, abnormal ocular signs were present, including macular "fibrosis", optic disc abnormalities with a traction retinal detachment, tapeto-retinal degeneration, and tilting of the disc to the nasal side. These changes are consistent with the ocular changes previously described in the 18q- syndrome, suggesting that there has been a minimal deletion of chromosome material at the 18q21 breakpoint. The case also demonstrates that the ocular changes of the 18- syndrome may be progressive.     

Uterine tumor resembling ovarian sex cord tumor: report of a case with t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3).

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of reproductive-age and postmenopausal women. We present the first case of UTROSCT with cytogenetic analysis. The tumor occurred in a 34-year-old woman who presented with menorrhagia and a uterine mass. Histologic examination showed tumor with features of sex cord-like epithelium and abundant fibromuscular stroma without an endometrial stromal sarcoma component. The tumor cells expressed cytokeratin, CD99, vimentin, desmin, smooth muscle actin, and estrogen and progesterone receptors. The majority of the cells analyzed by cytogenetic studies showed two balanced chromosomal translocations: t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3). Several known tumor-related genes (bcl-2, MALT-1, FVT1, SCCA1, SCCA2, and DCC at 18q21; RAP1 at 4q21; and STL at 6q23) and a gonadal-development related gene (H-Y regulator gene at Xp22.3) are located at or near the translocation breakpoints. The tumor cells of sex cord-like elements were strongly and diffusely immunoreactive for bcl-2 antibody. These cytogenetic and immunohistochemical data may suggest potential molecular mechanisms of tumorigenesis of UTROSCT.     

Psychiatric disorder in a familial 15;18 translocation and sublocalization of myelin basic protein to 18q22.3

Two related patients with similar clinical features consisting of a few dysmorphic signs and psychiatric disturbance were reported to have a partial trisomy of chromosomes 15(pter-q13.3) and 18(q23-qter) deriving from a familial translocation t(15;18). One patient is affected by bipolar disorder and the other by schizoaffective disorder. Both cases have a predominantly affective course; nevertheless, a clear diagnosis is difficult in the first patient, who is 15 years of age, and only a longitudinal course will allow us to establish a definite diagnosis. The possibility that these two pathologies belong to a single category is discussed, and the presence of a susceptibility locus on chromosome 18 is hypothesized. Cytogenetic data, FISH, and DNA studies indicate that the myelin basic protein (MPB) gene is not involved in the translocation, and localize it centromeric to the breakpoint on chromosome 18(q22.3). Thus, it is unlikely to be involved in the disease. © 1996 Wiley-Liss, Inc.     

A novel t(2;6)(p12;q23) appearing during transformation of follicular lymphoma with t(18;22)(q21;q11) to diffuse large cell lymphoma

Follicular lymphoma is characterized genetically by t(14;18)(q32;q21), whereas t(18;22)(q21;q11), a rare variant form of t(14;18), has been preferentially observed in chronic lymphocytic leukemia (CLL). We describe here an unusual case of follicular lymphoma with a t(18;22)(q21;q11), that progressed to diffuse large cell lymphoma with a novel t(2;6)(p12;q23). Spectral karyotyping revealed that add(2)(p12) and add(6)(q23) were derived from a t(2;6)(p12;q23). Fluorescence in situ hybridization analysis confirmed rearrangements of the BCL2 gene at 18q21 and the BCL6 gene at 3q27. Our results indicate that a reciprocal translocation involving 6q23 could be implicated in the progression of follicular lymphoma and that t(18;22) may have a specific role in the pathogenesis of follicular lymphoma as well as CLL.