Monosomy 9p24→pter and trisomy 5q31→qter: Case report and review of two cases

Partial deletion of the short arm of chromosome 9 (p24→pter) and partial duplication of the long arm of chromosome 5 (q32→qter) were observed in an abnormal boy who died at age 8 weeks of a complex cyanotic cardiac defect. He also had minor anomalies, sagittal craniosynostosis, triphalangeal thumbs, hypospadias, and a bifid scrotum. Two other infants with similar cytogenetic abnormalities were described previously. These patients had severe congenital heart defect, genitourinary anomalies, broad nasal bridge, low hairline, apparently low-set ears, short neck, and triphalangeal thumbs, in common with our patient. We suggest that combined monosomy 9p23,24→pter and trisomy 5q31,32→qter may constitute a clinically recognizable syndrome. © 1995 Wiley-Liss, Inc.     

Clinical and molecular-cytogenetic evaluation of a family with partial Jacobsen syndrome without thrombocytopenia caused by an approximately 5 Mb deletion del(11)(q24.3)

Clinical manifestations of Jacobsen syndrome (JBS) depend on the size of the 11qter deletion, which usually varies between approximately 7 and 20 Mb. Typical JBS features include developmental delay/mental retardation, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. We report on a family in which a 4-year-old girl as well as her mother and maternal uncle present with subtle features of JBS. Notably, neither thrombocytopenia nor congenital anomalies were detected in this family. Cytogenetic analyses revealed normal karyotypes. Using fluorescence in situ hybridization (FISH) and whole-genome oligonucleotide array CGH analyses, we identified an approximately 5 Mb deletion of the terminal part of chromosome 11q in all the three affected family members. The deletion breakpoint was mapped between 129,511,419 and 129,519,794 bp. This is the smallest deletion reported in a JBS patient. Interestingly, the FLI1 (friend leukemia virus integration 1) hematopoiesis factor gene located approximately 6.5 Mb from 11qter and usually deleted in patients with JBS, is intact. Our data support previous hypotheses that FLI1 haploinsufficiency is responsible for thrombocytopenia in patients with JBS.     

Familial 4.8 MB deletion on 18q23 associated with growth hormone insufficiency and phenotypic variability

The deletion of the long arm of chromosome 18 causes a contiguous gene deletion syndrome with a highly variable phenotype, usually related to the extent of the deleted region. The most commonly reported clinical features include: decreased growth, microcephaly, facial abnormalities, hypotonia, developmental delay, intellectual disability, congenital aural atresia with hearing impairment and limb anomalies. Here we report on a familial terminal deletion of 18q23 region transmitted from a mother to two daughters, resulting in a remarkable phenotypic variability. The deletion was first detected by conventional cytogenetic analysis in one daughter and subsequently characterized using fluorescence in situ hybridization (FISH) and array-CGH. FISH analysis using subtelomeric 18p and 18q probes confirmed the 18qter deletion in the three patients, and FISH with a whole chromosome painting probe specific for chromosome 18 excluded rearrangements with other chromosomes. Array-CGH analysis allowed us to precisely define the extent of the deletion, which spans 4.8?Mb from 71,236,891 to 76,093,303 genomic positions and includes GALR1 and MBP genes, among others. High-resolution analysis of the deletion, besides a detailed clinical assessment, has provided important data for phenotype-genotype correlation and genetic counseling in this family. Furthermore, this study adds valuable information for phenotype-genotype correlation in 18q- syndrome and might facilitate future search for candidate genes involved in each phenotypic trait.     

Terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27→qter)]

We report on a terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27→qter)] in a female newborn infant who died 45 hours after delivery and had multiple congenital abnormalities including bilateral anophthalmia, congenital heart disease, and abnormal genitalia. The findings are compared to those of four previously reported cases with terminal del (3q). © 1996 Wiley-Liss, Inc.     

A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome

A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 de novo microdeletion was referred because of genotype-phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter --> p16.1::8p23 --> pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter --> q32::4p15.3 --> qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n = 13) or microdeletions (n = 7) and with apparently straightforward genotype-phenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter --> 4p16.3::8p23 --> 8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.     

Recurrent inverted duplication of 2p with terminal deletion in a patient with the classical phenotype of trisomy 2p23-pter

Inverted duplications with terminal deletions have been reported in an increasing number of chromosomes and are probably more frequent than suspected until recently. We describe the cytogenetic and molecular characterization of an inverted duplication of chromosome 2p in an 8-year-old girl. Firstly interpreted as partial duplication 2p, the rearrangement was in fact an inverted duplication associated with a terminal deletion of the short arm of the rearranged chromosome 2, the latter not being detectable by cytogenetic analysis. The complete karyotype was: 46,XX,add(2)(p23)dn.ish inv dup del(2)(:p23.2-->p25.3::p25.3-->qter) (wcp2+,N-MYC++,2pter-)dn. We precisely define the extension of both the duplication and the deletion using bacterial artificial chromosomes clones spanning the regions. The size of the inverted duplicated segment was estimated to be 28 Mb, spanning from 2p23.2 to 2p25.3, and an approximately 1.6 Mb segment at 2pter-p25.3 was deleted in the abnormal chromosome. The physical findings noted in our patient include prominent forehead, hypertelorism, flat nasal bridge, and low-set and large ears. In addition, she had congenital heart defect and scoliosis. Her psychomotor development was severely delayed from the beginning. All these clinical features are the same as observed for the typical trisomy 2p23-pter syndrome. The phenotypic effects of the terminal deletion of 2p in addition to the trisomy are discussed. This is the third patient presenting with a severe clinical phenotype and a de novo inv dup del (2p).     

Clinical and molecular‐cytogenetic studies in seven patients with ring chromosome 18

We report the results of detailed clinical and molecular‐cytogenetic studies in seven patients with ring chromosome 18. Classical cytogenetics and fluorescence in situ hybridization (FISH) analysis with the chromosome 18 painting probe identified five non‐mosaic and two complex mosaic 46,XX,dup(18)(p11.2)/47,XX,dup(18)(p11.2),+r(18) and 46,XX,dup(18)(p11.32)/47,XX,dup(18)(p11.32),+r(18) cases. FISH analysis was performed for precise characterization of the chromosome 18 breakpoints using chromosome 18–specific short‐arm paint, centromeric, subtelomeric, and a panel of fifteen Alu‐ and DOP‐PCR YAC probes. The breakpoints were assessed with an average resolution of ∼2.2 Mb. In all r(18) chromosomes, the 18q terminal deletions ranging from 18q21.2 to 18q22.3 (∼35 and 9 Mb, respectively) were found, whereas only in four cases could the loss of 18p material be demonstrated. In two cases the dup(18) chromosomes were identified as inv dup(18)(qter→p11.32::q21.3→qter) and inv dup(18)(qter→p11.32::p11.32→p11.1: :q21.3→qter)pat, with no evidence of an 18p deletion. A novel inter‐intrachromatid mechanism of formation of duplications and ring chromosomes is proposed. Although the effect of “ring instability syndrome” cannot be excluded, the phenotypes of our patients with characteristic features of 18q‐ and 18p‐ syndromes are compared and correlated with the analyzed genotypes. It has been observed that a short neck with absence of cardiac anomalies may be related to the deletion of the 18p material from the r(18) chromosome. © 2001 Wiley‐Liss, Inc.     

Partial deletion of the long arm of chromosome 11 [del(11)(q23.3→qter)] with abnormal white matter

A patient with partial deletion of the long arm of chromosome 11[del(11)(q23.3→qter)] had macrocephalic trigonocephaly, growth and mental retardation, congenital heart defect, and characteristic facial appearance familiar to that of 33 other reported patients with this deletion. Computed tomography (CT) and magnetic resonance imaging of this infant's brain demonstrated abnormality of the supratentorial white matter. This may represent either deficiency or delay in myelination or possibly a demyelination process. No abnormalities in white matter were described in seven of 33 previously reported patients whose brains were examined by ultrasound, CT, or autopsy.     

Trisomy 20q13 --> 20qter in a girl with multiple congenital malformations and a recombinant chromosome 20 inherited from a paternal inversion (20)(p13q13.1): clinical report and review of the trisomy 20q phenotype

We report on a patient with a rec(20)dup(20q) chromosome abnormality derived from a paternal chromosome 20 inversion [inv(20)(p13q13.1)]. The rearrangement results in a duplication of 20q13.1 to 20qter and a deletion of 20p13 to 20pter. The patient is a girl with craniofacial features and multiple congenital malformations that overlap with the abnormalities previously described in trisomy 20q syndrome. To our knowledge this is the first report of a patient with rec(20)dup 20q.     

Patient with terminal duplication 3q and terminal deletion 5q: comparison with the 3q duplication syndrome and distal 5q deletion syndrome

Partial duplication of chromosome 3q is a well-described condition of multiple congenital anomalies and developmental delay that resembles the Brachmann-de Lange syndrome. Similarly, an emerging phenotype of a distal 5q deletion syndrome has recently been described. The combination of both chromosome abnormalities has not been previously described. We report on a child with both a de novo duplication of distal 3q (q27 --> qter) and terminal deletion of 5q (q35.2 --> qter). The patient had facial anomalies, hypoplastic toenails, lymphedema of the dorsum of the feet, type I Chiari malformation, a seizure disorder, and moderate developmental delays. The phenotype is compared and contrasted to the few reports of patients with similar terminal 3q duplications and 5q deletions. Our patient did not have the characteristic phenotype of the 3q duplication syndrome, suggesting that the chromosome region responsible for this phenotype is more proximal than the terminal 3q27 region. In addition, comparison with three other reported cases of terminal 5q35 deletions suggests a possible association of terminal 5q deletions with central nervous system (CNS) structural abnormalities.     

First reported case of interstitial 15 q15.3-q21.3 deletion diagnosed prenatally and characterized with array CGH in a fetus with an isolated short femur

We report on a fetus with an isolated short femur detected by ultrasound and a de novo interstitial deletion of chromosome 15. The deletion was diagnosed prenatally by karyotype and further mapped by fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (array-CGH) to bands 15q15.3 to 15q21.3 with a size of 11.11?Mb. Fetal autopsy showed characteristic minor anomalies, urinary abnormalities, and delayed bone maturation, but neither craniosynostosis, nor congenital heart defects as observed in previously reported cases. Despite the existence of ultrasound abnormalities, all five cases reported so far were diagnosed after birth. This is the first case of an interstitial deletion involving chromosomal band 15q15.3-q21.3 diagnosed prenatally and characterized at the molecular level. Our observation suggests the absence of imprinted genes in the area of 15q15-q22 and strengthens the hypothesis that a critical region for craniosynostosis may be mapped outside the deleted region in the present patient.     

Patient with trisomy 9p and a hypoplastic left heart with a tricentric chromosome 9

We present a patient with a hypoplastic left heart (HLH), dislocations of the hips and knees, and minor dysmorphic features, who had an abnormal karyotype that resulted in trisomy for 9p and a portion of 9q: 46,((, dic(or tri?)(9)(9pter --> 9q34::9q21 --> 9pter).ish(WCP9++).ish(D9Z5X4 +/+++). The derivative chromosome consisted of an additional copy of the proximal q arm and p arm attached to 9qter in an inverted fashion. Fluorescence in situ hybridization (FISH) using a chromosome 9 beta-satellite probe revealed three signals on the abnormal chromosome 9, suggesting the presence of 3 pericentromeric regions on the der(9). The 9q subtelomere was present on both the normal and derivative chromosome 9, suggesting that very little material, if any, is deleted.     

Molecular characterization of a patient with central nervous system dysmyelination and cryptic unbalanced translocation between chromosomes 4q and 18q

We report on a 12-year-old boy who presented with delayed development and CNS dysmyelination. Genetic studies showed a normal 46,XY karyotype by routine cytogenetic analysis, and 46,XY.ish del(18)(q23)(D18Z1+, MBP-) by FISH using a locus-specific probe for the MBP gene (18q23). Though the patient appeared to have normal chromosome 18s by repeated high resolution banding analysis, his clinical features were suggestive of a deletion of 18q. These included hearing loss secondary to stenosis of the external auditory canals, abnormal facial features, and foot deformities. FISH studies with genomic probes from 18q22.3 to 18qter confirmed a cryptic deletion which encompassed the MBP gene. In an attempt to further characterize the deletion, whole genome screening was conducted using array based comparative genomic hybridization (array CGH) analysis. The array CGH data not only confirmed a cryptic deletion in the 18q22.3 to 18qter region of approximately 7 Mb, it also showed a previously undetected 3.7 Mb gain of 4q material. FISH studies demonstrated that the gained 4q material was translocated distal to the 18qter deletion breakpoint. The 18q deletion contains, in addition to MBP, other known genes including CYB5, ZNF236, GALR1, and NFATC1, while the gained 4q material includes the genes FACL1 and 2, KLKB1, F11 and MTNR1A. The use of these combined methodologies has resulted in the first reported case in which array CGH has been used to characterize a congenital chromosomal abnormality, highlighting the need for innovative molecular cytogenetic techniques in the diagnosis of patients with idiopathic neurological abnormalities.     

Is Dandy-Walker malformation associated with "distal 13q deletion syndrome"? Findings in a fetus supporting previous observations

We report on a fetus with a large deletion of the distal part of the long arm of chromosome 13, (del(13)(q14 --> qter)) congenital anomalies of the urinary system, lungs and extremities, and Dandy-Walker malformation (DWM). Although DWM has been associated with many chromosomal abnormalities and genetic syndromes, its relation to the distal 13q has been demonstrated recently. In 2002, McCormack et al., described two patients with deletions of the long arm of chromosome 13 who had multiple congenital abnormalities along with holoprosencephaly (HPE) and DWM. The phenotypic features and autopsy findings of a fetus with "distal 13q deletion syndrome" at 22 weeks gestation are discussed and comparison with the previous two cases is made. The findings support the previous hypothesis suggesting that haploinsufficiency at a locus within 13q22-33 due to microdeletions may be responsible for isolated DWM in some of the patients. Detailed examination of 13q (13q22-33) by means of conventional and molecular cytogenetic methods is necessary in cases with DWM.     

Chromosome 2p15p16.1 microdeletion syndrome: 2.5 Mb deletion in a patient with renal anomalies, intractable seizures and a choledochal cyst

Chromosome 2p15p16.1 microdeletion is an emerging syndrome recently described in patients with dysmorphic facial features, congenital microcephaly, mild to moderate developmental delay and neurodevelopmental abnormalities. Using clinical ultra-high resolution Affymetrix SNP 6.0 array we identified a de novo interstitial deletion on the short arm of chromosome 2, spanning approximately 2.5 Mb in the cytogenetic band position 2p15p16.1, in a female infant with characteristic features of 2p15p16.1 deletion syndrome including severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect. We further redefined the previously reported critical region, supporting the presence of a newly recognized microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 1.1 Mb segment of the 2p15p16.1 region.     

5.78 Mb terminal deletion of chromosome 15q in a girl, evaluation of NR2F2 as candidate gene for congenital heart defects

All patients with terminal deletion of chromosome 15q have been reported to show intrauterine growth retardation, postnatal growth retardation, abnormal facial appearance and developmental delay. Haploinsufficiency of IGF1R was considered to be responsible for these symptoms. However, it is difficult to explain other symptoms seen in some of the patients, such as congenital heart defects by the absence of IGF1R alone. Here, we reported a patient with congenital heart defects and a 5.78 Mb terminal deletion of chromosome 15q detected by array-CGH. Among the patients reported to share congenital heart defects and terminal deletion of chromosome 15q, our patient had the smallest deletion. Evaluating the deletion map, NR2F2 was considered a candidate gene contributing to congenital heart defects in patients with terminal deletion of chromosome 15q.     

Array-based comparative genomic hybridization facilitates identification of breakpoints of a novel der(1)t(1;18)(p36.3;q23)dn in a child presenting with mental retardation

Monosomy of distal 1p36 represents the most common terminal deletion in humans and results in one of the most frequently diagnosed mental retardation syndromes. This deletion is considered a contiguous gene deletion syndrome, and has been shown to vary in deletion sizes that contribute to the spectrum of phenotypic anomalies seen in patients with monosomy 1p36. We report on an 8-year-old female with characteristics of the monosomy 1p36 syndrome who demonstrated a novel der(1)t(1;18)(p36.3;q23). Initial G-banded karyotype analysis revealed a deleted chromosome 1, with a breakpoint within 1p36.3. Subsequent FISH and array-based comparative genomic hybridization not only confirmed and partially characterized the deletion of chromosome 1p36.3, but also uncovered distal trisomy for 18q23. In this patient, the duplicated 18q23 is translocated onto the deleted 1p36.3 region, suggesting telomere capture. Molecular characterization of this novel der(1)t(1;18)(p36.3;q23), guided by our clinical array-comparative genomic hybridization, demonstrated a 3.2 Mb terminal deletion of chromosome 1p36.3 and a 200 kb duplication of 18q23 onto the deleted 1p36.3, presumably stabilizing the deleted chromosome 1. DNA sequence analysis around the breakpoints demonstrated no homology, and therefore this telomere capture of distal 18q is apparently the result of a non-homologous recombination. Partial trisomy for 18q23 has not been previously reported. The importance of mapping the breakpoints of all balanced and unbalanced translocations found in the clinical laboratory, when phenotypic abnormalities are found, is discussed.     

Partial DiGeorge syndrome in two patients with a 10p rearrangement

We describe 2 patients with a partial DiGeorge syndrome (facial dysmorphism, hypoparathyroidism, renal agenesis, mental retardation) and a rearrangement of chromosome 10p. The first patient carries a complex chromosomal rearrangement, with a reciprocal insertional translocation between the short arm of chromosome 10 and the long arm of chromosome 8, with karyotype 46, XY ins(8;10) (8pter 8q13::10p15-->10p14::8q24.1-->8qter) ins(10:8) (10pter--> 10p15::8q24.1-->8q13::10p14-->10qter). The karyotype of the second patient shows a terminal deletion of the short arm of chromosome 10. In both patients, the breakpoints on chromosome 10p reside outside the previously determined DiGeorge critical region II (DGCRII). This is in agreement with previous reports of patients with a terminal deletion of 10p with breakpoints distal to the DGCRII and renal malformations/hypoparathyroidism, and thus adds to evidence that these features may be caused by haploinsufficiency of one or more genes distal to the DGCRII.     

Clinical phenotype and molecular analysis of a three-generation family with an interstitial deletion of the short arm of chromosome 5.

We report on a 3-generation family with an interstitial deletion of the short arm of chromosome 5. Varied manifestations were found among the affected individuals including microcephaly, hypertonia, and micrognathia; mental retardation was common to all affected individuals. High resolution chromosome analysis was interpreted as del(5) (pter- > p14.3::p13.3- > qter). Molecular comparison of the deletion in this family with individuals with other 5p deletions suggests that the clinical findings are due specifically to the chromosomal material deleted from 5p13.     

Craniosynostosis and syndactyly: expanding the 11q-- chromosomal deletion phenotype.

A patient with a partial deletion (q23 leads to qter) of the long arm of chromosome 11 presented with craniosynostosis and syndactyly. These characteristics, which have not been previously reported with 11q--, expand the phenotype of this syndrome and emphasise the need for chromosome analysis with banding techniques in multiple congenital anomaly syndromes, even if the patient could be classified as having a non-chromosomal syndrome.