Telomere-telomere (end to end) fusion of chromosomes 7 and 22 with an interstitial deletion of chromosome 7p11.2-->p15.1: phenotypic consequences and possible mechanisms

We report a rare case of a de novo end to end fusion of chromosomes 7 and 22 in conjunction with an interstitial deletion of chromosome 7p11.2p15.1 in a newborn with congenital anomalies. The proband presented for chromosome analysis with bilateral cataracts, dysmorphic facies and distal limb abnormalities. Chromosome analysis showed a 45,XY,der(22)psu dic(22;7)(p13;p22.3)del(7)(p11.2p15.1) karyotype. This short arm to short arm fusion of chromosomes 7 and 22 resulted in a pseudodicentric chromosome. The interstitial deletion in the short arm of chromosome 7 was likely a result of breakage and reunion related to instability of the dicentric chromosome. Loss of genetic material in this region of chromosome 7p has been implicated in the pathophysiology of craniosynostosis and cephalopolysyndactyly syndromes.     

Phenotypic manifestation in a child with 46,X,der(X)t(X;1)(q24;q31.1)

We report on a 5-year-old girl with multiple congenital anomalies, developmental delay, and a de novo unbalanced translocation between chromosomes X and 1[46,X,der(X)-t(X;1)(q24;q31.1)] resulting in partial trisomy 1q and partial monosomy Xq. The karyotype shows inactivation of the abnormal X chromosome. The translocated portion of 1q remains active in the tissues studied. This is the third case report with partial trisomy 1q and partial monosomy Xq. However, it is the first with specific breakpoints at 1q31.1 and Xq24.     

Detection of cryptic chromosome aberrations in a patient with a balanced t(1;9)(p34.2;p24) by array-based comparative genomic hybridization

Mental retardation (MR) is one of the most common phenotypes in congenital disorders, but in many cases the pathogenesis remains unknown. Here, we report on a 5-year-old boy with mild developmental disability, cranial malformation, minor anomalies, and moderate MR. G-banded chromosome analysis revealed that he carried an apparent balanced translocation, t(1;9)(p34.2;p24). However, our array-based comparative genomic hybridization (CGH-array) analysis detected a cryptic genomic duplication and a deletion at the breakpoints. Further fluorescence in situ hybridization (FISH) showed that the duplication was approximately 7.9 Mb in size at 1p34.3-p33, and the deletion was 4 Mb at 9pter-p24. Although some features of the patient were consistent with those of monosomy 9p-syndrome, his features were not typical of cases of the syndrome, suggesting that the small deletion region involved in 9p may limit his phenotype. On the other hand, interstitial duplication at 1p34.3-p33 is very rare and his phenotype did not match with that in previous reports. CGH-array is a potentially useful technique for investigating cryptic copy-number alterations in cases of apparently balanced chromosome rearrangements in patients with unexpected clinical features.     

Molecular and clinical description of a girl with a 46,X,t(Y;4)(q11.2;p16)/45,X,der(4)t(Y;4)(q11.2;p16) karyotype and a small cryptic 4p subtelomeric deletion

We report on a 13-year-old female with short stature, minimal axillary and pubic hair, no breast development, absence of uterus and ovaries, with the following karyotype on lymphocyte cultures: 46,X,t(Y;4)(q11.2;p16)[40]/45,X,der(4)t(Y;4)(q11.2;p16)[10]. Loss of the small derivative Y chromosome in 20% of the cells was also confirmed in skin fibroblast cultures. FISH analyses using Y centromere, SRY, subtelomere XpYp/XqYq, Y and 4 painting probes, confirmed the cytogenetic findings. High-resolution STS analyses using 40 markers covering the Y chromosome did not identify any deletion on the Y. However, de novo absence of the 4p subtelomeric region was noted by FISH, although this deletion was not revealed by Array-CGH at 1 Mb resolution, the last array clone being 0.35 or 1 Mb distal to the 4p FISH probe. The female phenotype of this patient must be due to the loss of the derivative Y chromosomes in some of her cells, especially the gonads, while the 4p subtelomeric deletion does not seem to contribute to her phenotype.     

Maternal complex chromosome rearrangement ascertained through a del (13)(q12.1q14.1) detected in her mildly affected daughter

A maternal complex chromosome rearrangement (CCR) involving chromosomes 2, 13, and 20 was ascertained in a normal female through the diagnosis of a deletion of 13q in her daughter. The child has mild clinical features and developmental delay consistent with proximal deletions of 13q that do not extend into band q32 and a del(13)(q12q14.1) that does not involve the retinoblastoma locus by FISH. Maternal studies by GTG banding and FISH showed a complex karyotype with bands 13q12.3→13q12.1::20p13 translocated to 2p13 and bands 2pter→2p13::13q12.3→13q14.1 translocated into band 20p13. This would be the first report of an interstitial deletion of 13q inherited from a parental complex chromosome rearrangement. © 2001 Wiley‐Liss, Inc.     

Maternal complex chromosome rearrangement ascertained through a del (13)(q12.1q14.1) detected in her mildly affected daughter.

A maternal complex chromosome rearrangement (CCR) involving chromosomes 2, 13, and 20 was ascertained in a normal female through the diagnosis of a deletion of 13q in her daughter. The child has mild clinical features and developmental delay consistent with proximal deletions of 13q that do not extend into band q32 and a del(13)(q12q14.1) that does not involve the retinoblastoma locus by FISH. Maternal studies by GTG banding and FISH showed a complex karyotype with bands 13q12.3-->13q12.1::20p13 translocated to 2p13 and bands 2pter-->2p13::13q12.3-->13q14.1 translocated into band 20p13. This would be the first report of an interstitial deletion of 13q inherited from a parental complex chromosome rearrangement.     

A familial reciprocal translocation t(3;7) (p21.1;p13) associated with the Greig polysyndactyly-craniofacial anomalies syndrome

A translocation t(3;7) (p21.1;p13) segregating through four generations was found to be invariably associated with the Greig cephalopolysyndactyly syndrome (GS). High resolution chromosome analyses using G and R banding did not uncover any imbalance of the affected chromosomes, nor were the late replicating patterns changed. One girl with the GS died of a medulloblastoma.     

Characterization of a 16 Mb interstitial chromosome 7q21 deletion by tiling path array CGH

We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and a balanced reciprocal translocation between chromosomes 6 and 7 [karyotype 46,XX,t(6;7)(q23.3;q32.3)del(7)(q21.1q21.3)de novo]. We characterized the size and position of the deletion by tiling path array comparative genomic hybridization (CGH), and we mapped the translocation breakpoints on chromosomes 6 and 7 by FISH. The clinical features of this patient-severe mental retardation, short stature, microcephaly and deafness-are in accordance with previously reported patients with 7q21 deletions. Chromosome band 7q21.3 harbors a locus for split hand/split foot malformation (SHFM1), and part of this locus, including the SHFM1 candidate genes SHFM1, DLX5, and DLX6, is deleted. The absence of limb abnormalities in this patient suggests either a location of the SHFM1 causing factor distal to this deletion, or reduced penetrance of haploinsufficiency of a SHFM1 factor within the deleted interval.     

Molecular cytogenetic characterization of a subtle interstitial del(3)(p25.3p26.2) in a patient with deletion 3p syndrome

Deletion 3p syndrome is associated with characteristic facial features, growth failure, and mental retardation. Typically, individuals with deletion 3p syndrome have terminal deletions that result in loss of material from 3p25 to 3pter. We present a child with a clinical phenotype consistent with deletion 3p syndrome (ptosis, microcephaly, growth retardation, and developmental delay) and a subtle interstitial deletion in the distal portion of the short arm of chromosome 3, del(3)(p25.3p26.2). Fluorescence in situ hybridization (FISH) studies using 3p subtelomeric probes confirmed the terminal region of chromosome 3 was present. Sequence tagged sites (STS)-linked BAC clones mapping to chromosomal region 3p25-p26 were used to characterize the interstitial deletion by FISH. The results indicate the deletion is within a region of approximately 4.5 Mb between STS markers D3S3630 and D3S1304. This interstitial deletion lies within all previously reported terminal deletions in deletion 3p syndrome individuals, and represents the smallest reported deletion associated with deletion 3p syndrome. Characterization of the deletion may help identify genes important to growth and development that contribute to the deletion 3p syndrome phenotype when present in a hemizygous state.     

Rapid array-based genomic characterization of a subtle structural abnormality: a patient with psychosis and der(18)t(5;18)(p14.1;p11.23)

Array-based copy number analysis has recently emerged as a rapid means of mapping complex and/or subtle chromosomal abnormalities. We have compared two such techniques, using bacterial artificial chromosome (BAC) and single nucleotide polymorphism (SNP) arrays in the evaluation of a 45-year-old woman with dysmorphic features, mental retardation, psychosis, and an unbalanced derivative chromosome 18, (46,XX, der(18)t(18;?)(p12;?)). Both array-based methods demonstrated that the additional material on chromosome 18 was of 5p origin. The 5p duplication mapped telomeric to 25.320 Mb (BAC array) and 25.607 Mb (SNP array), corresponding to the band 5p14.1. Both BAC and SNP arrays also showed a deletion involving chromosome 18p extending telomeric from 8.437 Mb (BAC array) and 8.352 Mb (SNP array), corresponding to the band 18p11.23. Molecular cytogenetic mapping using fluorescence in situ hybridization (FISH) supported the array findings and further refined the breakpoint regions, confirming that the BAC and SNP chips were both useful in this regard. Both case reports and linkage analyses have implicated these chromosomal intervals in psychosis. The array-based experiments were completed over the course of several days. While these methods do not eliminate the requirement for traditional fine-mapping, they provide an efficient approach to identifying the origin and extent of deleted and duplicated material in chromosomal rearrangements.     

Distal 8p deletion (8p23.1----8pter): a common deletion?

The clinical manifestations and cytogenetic details of five patients with a de novo deletion of the short arm of chromosome 8, del(8)(p23), are described. Of the four surviving children all had mild mental retardation and subtle facial anomalies; three of the five had cardiac abnormalities. The clinical features seen in these patients are compared with those of three previous single case reports with del(8)(p23), and with patients described as having the '8p-' syndrome associated with del(8)(p21). The findings in these patients suggest that major congenital anomalies, especially congenital heart defects, are frequent even in small distal 8p deletions, but facial dysmorphism may be subtle and mental retardation less severe than in those with deletions associated with more proximal breakpoints. The five patients were detected within a four year period, suggesting that this deletion syndrome is relatively frequent. The possible mechanisms for the formation of terminal deletions are discussed.     

Inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) with manifestations of partial duplication 4p and Wolf-Hirschhorn syndrome

An 8-year-old girl with a combination of clinical manifestations of partial duplication 4p and the Wolf-Hirschhorn syndrome was studied. Chromosomal G-banding and FISH analyses showed a 33.2-Mb segment of inverted duplication at 4p14-p16.3 and a 2.8-Mb segment of deletion at 4p16.3-pter (including the Wolf-Hirschhorn syndrome critical region). The chromosomes of the parents were normal. Her karyotype was thus 46,XX, inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) de novo. The inverted duplication deletion was assumed to have arisen through chromatid breakage at 4p16.3, U-type reunion at the breakpoints to produce a dicentric intermediate, breakage of the dicentric to result in a monocentric, and telomere capture/healing of the broken end. Olfactory receptor gene clusters at 4p16.3 were ruled out as an intermediary of the duplication deletion process.     

Fortuitous detection of a submicroscopic deletion at 1q25 in a girl with Cornelia-de Lange syndrome carrying t(5;13)(p13.1;q12.1) by array-based comparative genomic hybridization

We report on a 2-year-old Japanese girl with Cornelia-de Lange syndrome (CdLS) who had mental and growth retardation, together with characteristic facial anomalies and mild extremity malformations. She had a balanced chromosomal translocation, 46,XX,t(5;13)(p13.1;q12.1) de novo. Surprisingly, this was the same translocation that had provided a clue to the identification of a major causative gene for CdLS, NIPBL [Krantz et al., 2004; Tonkin et al., 2004]. Using fluorescence in situ hybridization (FISH), the breakpoint was confirmed to lie within NIPBL at 5p13.1. Furthermore, array-based comparative genomic hybridization (array-CGH) demonstrated a cryptic 1-Mb deletion harboring six known genes at 1q25-q31.1. A FISH analysis of her parents confirmed that the deletion was de novo. Although patients with interstitial deletions at 1q are rare, some of their features were similar to those observed in our patient, indicating that her clinical manifestations are likely to be affected by not only the disruption of NIPBL but also the concomitant microdeletion at 1q25-q31.1. The present case suggests that array-CGH can uncover cryptic genomic aberrations affecting atypical phenotypes even in well-known congenital disorders.     

Molecular and cytogenetic characterization of 9p– abnormalities

We report on 2 girls with terminal deletion of the short arm of chromosome 9 with concurrent duplication unrecognizable by routine chromosome studies. The phenotype of the patients was not specifically suggestive of the 9p– syndrome in the absence of trigonocephaly and long philtrum as cardinal manifestations. In addition to psychomotor retardation, their manifestations were mild and include upward slant of palpebral fissures and dolichomesophalangy which are characteristic of del(9p). Chromosome abnormalities were de novo in both cases. The two rearranged chromosomes 9 exhibit similar G-banding patterns and suggested the possible duplication of distal 7p. Fluorescence in situ hybridization (FISH) with a chromosome-7 specific library probe indeed identified that one derivatie chromosome 9 was the result of a translocation between chromosomes 7 and 9 [der(9)t(7;9)(p15.3;p24)] but failed to detect a signal on the other derivative 9. In the second case, the concurrent abnormality was an inverted duplication of proximal 9p and deletion of distal 9p [invdup(9)(p13→p22::p22→qter)] confirmed by FISH using a chromosome 9 specific librarayprobe. FISH clearly identified the origin of these 2 abnormal choromosomes 9 and provided crucial information for clinical evaluation We emphasize the importance of utilizing updated cytogenetic and molecular techniques in the precise delineation of subtle or complex abnormalities where there are no useful phenotypic clues. © 1993 Wiley-Liss, Inc.     

Terminal deletion, del(1)(p36.3), detected through screening for terminal deletions in patients with unclassified malformation syndromes

We report on a 4 year-old girl with a 1p36.3-pter deletion. Clinical findings included minor anomalies of face and distal limbs, patent ductus arteriosus, the Ebstein heart anomaly, and brain atrophy with seizures. Conventional GTG-banded chromosome analysis revealed a normal (46,XX) result. Subsequent analysis by fluorescent in situ hybridization (FISH) using distal probes demonstrated a deletion of 1p36.6-pter. Molecular investigations with microsatellite markers showed hemizygosity at three loci at 1p36.3 with loss of the paternal allele. The deletion of 1p36.3 is difficult to identify by banding alone; indeed, our patient represents the third reported case with a del(1)(p36.3) that was detected only after more detailed analysis. In all three cases the deletion was detected through screening of patients with multiple congenital anomalies/mental retardation syndromes suggestive of autosomal chromosome aberrations for subtelomeric submicroscopic deletions by means of FISH or microsatellite marker analysis. On the basis of these observations we highly recommend that FISH with a subtelomeric 1p probe be routinely performed in patients with similar facial phenotype, severe mental retardation and seizures, and a heart malformation, particularly the Ebstein anomaly.     

Interstitial deletion of 1p22.2p31.1 and medium-chain acyl-CoA dehydrogenase deficiency in a patient with global developmental delay

We report on a 6-year-old girl who presented at 6 months of age with seizures, delayed psychomotor development and mild facial dysmorphism. A small muscular ventricular septal defect was documented on echocardiogram and brain MRI showed a frontal brain anomaly. Urine organic acid analysis revealed dicarboxylic aciduria, and plasma acylcarnitine analysis showed marked elevation of octanoyl (C8) and decanoyl (C10) carnitines with C8:C10 ratio of 9:1. These results were indicative of medium chain acyl-CoA dehydrogenase deficiency. ACADM gene sequencing showed an apparent homozygous c.166G > C (Ala31Pro) missense mutation in exon 3; however, only the mother was found to be a carrier of this novel missense mutation. This finding along with non-regressive developmental delay prompted further karyotype and genomic investigations. An interstitial deletion of chromosome 1 was detected by repeat G-banding: 46,XX,del(1)(p22.2p31.1). Parental karyotypes were normal. The deletion was characterized by array CGH analysis using a 1 Mb BAC/PAC array platform. Clones deleted extended from RP11-88B10 (1p31.1) to RP5-1007M22 (1p22.2), a 15.5 Mb deletion which includes the ACADM locus. Clinical review of 6/7 cases of interstitial deletions with breakpoints of 1p22 and 1p31/32, including the patient in this report, indicate a variable phenotype. Thus, although G-band breakpoints are similar, common breakpoints for these alterations are unlikely. This is the first report of a patient with fatty acid oxidation defect caused by a mutation in combination with an interstitial chromosomal deletion.     

Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome

Greig cephalopolysyndactyly syndrome (GCPS) is caused by haploinsufficiency of GLI3 on 7p13. Features of GCPS include polydactyly, macrocephaly, and hypertelorism, and may be associated with cognitive deficits and abnormalities of the corpus callosum. GLI3 mutations in GCPS patients include point, frameshift, translocation, and gross deletion mutations. FISH and STRP analyses were applied to 34 patients with characteristics of GCPS. Deletions were identified in 11 patients and the extent of their deletion was determined. Nine patients with deletions had mental retardation (MR) or developmental delay (DD) and were classified as severe GCPS. These severe GCPS patients have manifestations that overlap with the acrocallosal syndrome (ACLS). The deletion breakpoints were analyzed in six patients whose deletions ranged in size from 151 kb to 10.6 Mb. Junction fragments were found to be distinct with no common sequences flanking the breakpoints. We conclude that patients with GCPS caused by large deletions that include GLI3 are likely to have cognitive deficits, and we hypothesize that this severe GCPS phenotype is caused by deletion of contiguous genes.     

Physical mapping of the chromosome 7 breakpoint region in an SLOS patient with t(7;20) (q32.1;q13.2)

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder characterized by multiple congenital anomalies and mental retardation. SLOS has an associated defect in cholesterol biosynthesis, but the molecular genetic basis of this condition has not yet been elucidated. Previously our group reported a patient with a de novo balanced translocation [t(7;20)(q32.1;q13.2)] fitting the clinical and biochemical profile of SLOS. Employing fluorescence in situ hybridization (FISH), a 1.8 Mb chromosome 7-specific yeast artificial chromosome (YAC) was identified which spanned the translocation breakpoint in the reported patient. The following is an update of the on-going pursuit to physically and genetically map the region further, as well as the establishment of candidate genes in the 7q32.1 breakpoint region. Am. J. Med Genet. 68:279–281, 1997. © 1997 Wiley-Liss, Inc.     

Array-CGH characterization of a prenatally detected de novo 46,X,der(Y)t(X;Y)(p22.3;q11.2) in a male fetus

We report on an apparently normal 5-month-old boy with a X;Y complex rearrangement identified first on prenatal diagnosis and found on array-CGH to have a 7.6?Mb duplication of Xp22.3 chromosome and a deletion of Yq chromosome, distal to the AZFa locus. Karyotype analysis on amniotic fluid cell cultures revealed a de novo homogenous chromosome marker that we interpreted as an isochromosome Yp. FISH analysis using SRY probe revealed only one signal on the derivative Y chromosome. The final karyotype was interpreted as 46,X,der(Y)t(X;Y)(p22.31;q11.22). Translocation Xp22;Yq11 in male are very rare event and only 4 cases have been published, all showing mental retardation and malformations. Herein we discussed some possible explanation for this apparent phenotypic variability.