A de novo interstitial deletion of chromosome 15 band q25 as revealed by FISH-technique

We report a new chromosomal finding in a 20-month-old girl. The minor clinical features included: moderate mental retardation, microcephaly, mild hypotonia and hypertelorism. Initially, what appeared to be a terminal deletion of the long arm of one chromosome 15 [15q26 → qter] was determined to be an interstitial deletion involving band 15q25 as revealed by FISH-technique, showing the presence of intact telomeric hybridization signals. The cytogenetic diagnosis was thus modified to 46,XX, del (15) (pter → q24::q26 → qter). Nevertheless, the function of the enzyme telomerase should not be ignored, as healing could occur following such terminal deletions. Consequently, it will remain a difficult task to distinguish terminal deletions from those that are interstitial.     

Congenital diaphragmatic hernia in a family segregating a reciprocal translocation t(5;15)(p15.3;q24)

Congenital diaphragmatic hernia (CDH) is a relatively common malformation of unknown cause with high mortality due to hypoplasia of the lungs and pulmonary hypertension. We studied a family in which two fetuses had CDH, and two pregnancies resulted in first trimester missed abortions. Both fetuses with CDH had an apparently normal karyotype. In a subsequent pregnancy, fluorescent in situ hybridization analysis of amniocytes showed a balanced translocation 46,XY, t(5;15) (p15.3;q24) also present in the mother and in a normal child, suggesting that the diaphragmatic hernia in the first two fetuses was caused by a cryptic unbalanced translocation. This hypothesis is supported by a previous observation of CDH in a distal deletion of 15q as part of a multiple congenital anomalies syndrome. It is suggested that a gene distal to 15q21 is important for the normal development of the diaphragm.     

Origin of a paternal (13q; 15q) translocation leading to dup(13q) in two half sibs

We report on two half-sibs, a male and a female with dup(13)(q1405 → qter) that resulted from a der(15),t(13;15)(15qter → 15q25::13q1405 → 13qter), h +, pat. Their manifestations were similar to those with duplication of the distal half 13q. The father was a balanced de novo translocation carrier. Since the der(15) had a long secondary constriction, it was possible to trace the site of the mutation to the germ cell of the patients paternal grandmother who had this distinctive long secondary constriction in one of her normal 15 chromosomes.     

Origin of a paternal (13q;15q) translocation leading to dup(13q) in two half sibs

We report on two half-sibs, a male and a female with dup(13)(q1405 leads to qter) that resulted from a der(15),t(13;15)(15qter leads to 15q25::13q1405 leads to 13qter), h+, pat. Their manifestations were similar to those with duplication of the distal half 13q. The father was a balanced de novo translocation carrier. Since the der(15) had a long secondary constriction, it was possible to trace the site of the mutation to the germ cell of the patients paternal grandmother who had this distinctive long secondary constriction in one of her normal 15 chromosomes.     

Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome

The recurrent microdeletion 15q24 syndrome is rare with only 5 cases reported thus far. Here we describe an additional patient with this deletion, presenting with many features common to this syndrome, including developmental delay, loose connective tissue, digital and genital anomalies and a distinct facial gestalt. Interestingly, in addition, this patient has a large congenital diaphragmatic hernia, as was described in one other patient with a 15q24 microdeletion, indicating that this feature might be part of the syndrome. Chromosome 15q24 has a highly polymorphic architecture that is prone to genomic rearrangements underlying this novel microdeletion syndrome.     

Case of 15q26-qter deletion associated with a Prader-Willi phenotype

Prader-Willi syndrome (PWS) is one of the common neurogenetic disorders associated with intellectual disability. PWS involves a complex inheritance pattern and is caused by an absence of gene expression on the paternally inherited 15q11.2-q13 region, either due to deletion, maternal uniparental disomy or imprinting defect. The syndrome is characterized principally by severe neonatal hypotonia, a weak suck in infancy that is later followed by hyperphagia and obesity, developmental delay, intellectual disability and short stature. In the case of the chromosome 15q26-qter deletion syndrome or Drayer's syndrome, very few reports have been published. Its characteristics include intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia. The present paper describes a female patient in whom clinical findings were suggestive of PWS and deletion in the 15q26-qter region. Both karyotyping and methylation-specific polymerase chain reaction were shown to be normal. Nevertheless, fluorescence in situ hybridization showed a 15qter deletion that was later mapped by single nucleotide polymorphism (SNP)-array. The deleted genomic region involves the insulin-like growth factor-1 receptor (IGF1R) gene, which is related to short stature, developmental delay and intellectual disability. This case had various clinical characteristics in common with the cases of 15q26-qter deletionand characteristics compatible with PWS.     

Craniosynostosis associated with partial duplication of 15q and deletion of 2q

We report on an infant with multiple congenital anomalies including complex craniosynostosis associated with an unbalanced karyotype, 46,XY, ? 2, + der(2),t(2;15)(q37;q26)pat. The previous report of a child with cloverleaf skull and partial duplication of 15q25→qter and the Man-on-Mouse Homology map suggests that a critical segment for synostosis of sutures may be in this region. © 1992 Wiley-Liss, Inc.     

A recognizable phenotype in a child with partial duplication 13q in a family with t(10q;13q)

A case of partial duplication 13q14 → qter is reported in a 9-year-old male with clinical symptoms which include trigonocephaly and synophrys, producing an easily identifiable phenotype. The chromosome duplication resulted from a familial t(10;13)(qter;q14). Subsequently, a normal balanced carrier sibling was diagnosed prenatally.     

A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients

A 15q24 microduplication, reciprocal to the minimal critical region for the recently described 15q24 microdeletion syndrome, was found in a 2-year-old boy by 244k Agilent oligoarray CGH analysis. The boy had global developmental delay and dysmorphic facial features, digital and genital abnormalities. The duplication was inherited from a healthy father, but was considered clinically significant, as the patient shared clinical features with 15q24 microdeletion syndrome patients. To our knowledge this is the first report of a patient with a 15q24 microduplication.     

Proximal and distal 15q25.2 microdeletions–genotype–phenotype delineation of two neurodevelopmental susceptibility loci

Distal 15q25.2 microdeletions have recently been reported as a copy number variation (CNV) locus for neurodevelopmental and neuropsychiatric disorders with variable outcome. In addition, more proximal microdeletions of 15q25.2 have been described as a susceptibility locus for cognitive deficits, congenital diaphragmatic hernia (CDH), and Diamond–Blackfan anaemia (DBA). We describe two patients with 15q25.2 deletion, one with the more distal deletion and the other with a deletion overlapping both the distal and proximal 15q25.2 deletions and compare them to the 18 so far reported patients with 15q25.2 deletions. We provide a characterization of the 15q25.2 microdeletions and contribute to the genotype–phenotype delineation for these two novel microdeletion syndromes. © 2012 Wiley Periodicals, Inc.     

Characterization of an analphoid supernumerary marker chromosome derived from 15q25-->qter using high-resolution CGH and multiplex FISH analyses

Supernumerary marker chromosomes (SMCs) without detectable alphoid DNA are predicted to have a neocentromere and have been referred to as mitotically stable neocentromere marker chromosomes (NMCs). We report the molecular cytogenetic characterization of a new case with analphoid NMC derived from 15q25-->qter using high-resolution comparative genomic hybridization (HR-CGH) and multiplex fluorescence in situ hybridization analyses with various alpha-satellite DNA probes, all-human-centromere probe (AHC), whole chromosome painting probes, and a subtelomere probe. The propositus is a dysmorphic infant who, at age 3 months, showed accelerated growth, partial deafness, and a phenotype similar to that of the eight previously reported cases of distal 15q tetrasomy. Chromosome studies showed that he had a de novo extra SMC in 80% of cells examined. HR-CGH revealed rev ish enh(15)(q25qter). Molecular cytogenetic analysis and molecular DNA polymorphism study demonstrated that this extra SMC is an NMC containing an inverted duplication of the distal long arm of chromosome 15 (tetrasomy 15q25-->qter) which originated paternally, i.e. ish der(15)(qte-->q25::q25[neocen]-->qter)(AHC-, CEP15-, WCP15+, PCP15q++). This case further elucidates the phenotype related to tetrasomy of this specific chromosome segment and represents a new report of a neocentromere on distal chromosome 15q suggesting that this region appears to be susceptible to the formation of neocentromeres.     

Partial trisomy 14q24 leads to qter.

A newborn male with partial trisomy for the distal part of the long arm of chromosome 14 (14q24 leads to qter) is described. The anomaly arose as an adjacent 1 meiotic segregation product from a balanced translocation t(11;14) (q25;q24) in the mother (figure). To our knowledge only one previous case involving the same segment has been reported. The karyotype was confirmed as 46,XY,der(11),t(11;14)(q25;q24) mat.     

A report of three patients with an interstitial deletion of chromosome 15q24

Partial monosomy of the q2 region of chromosome 15 has been infrequently reported. Moreover, interstitial deletions involving 15q22-q24 have been described in only nine patients to date. The phenotype of these reported individuals is subject to the extent of the deletion but typically includes altered muscle tone and significant developmental delays. In addition, eye abnormalities, such as strabismus, microphthalmia, or colobomas, ear abnormalities including cleft earlobe and preauricular tags, and urogenital defects are common features. Congenital heart defects, diaphragmatic hernia, abnormalities of the central nervous system, and skeletal anomalies have been reported but appear to be less frequent clinical manifestations. In this report, we describe three new patients with interstitial deletions involving 15q24, two with cryptic deletions identified by fluorescence in situ hybridization (FISH) with a probe for the PML gene and one with a cytogenetically visible deletion of 15q22.3-q24. The clinical presentation of these individuals is similar to those previously described and includes global developmental delays, hypotonia, and genital abnormalities in the males. The identification of these three cases demonstrates that the above clinical features are associated with a new cytogenetic deletion syndrome. Furthermore, we suggest that FISH analysis with a probe for the PML gene be performed in patients with these physical findings.     

Mosaic tetrasomy 15q25→qter in a newborn infant with multiple anomalies

We describe a premature boy with metopic craniosynostosis, facial anomalies, atrialseptal defect, hydronephrosis and flexion contractures of lower limbs, and mosaic tetrasomy 15q25→qter. The extra chromosome material was present in the form of an acentric marker. A number of clinical manifestations observed in this child were also found in 3 previously reported patients who were trisomic for the same part of chromosome 15 and in 2 patients who were tetrasomic for a larger segment of 15q. © 1996 Wiley-Liss, Inc.     

Apparent Fryns syndrome in a boy with a tandem duplication of 1q24-31.2

We report on a newborn boy with manifestations of Fryns syndrome who also had a mosaic tandem duplication of chromosome 1q24-31.2. The child had a diaphragmatic hernia, cleft palate, hypoplastic and absent digits, micrognathia, long philtrum, thin upper lip, and anteverted nose. The baby died at age 5 hours. An autopsy demonstrated absent right middle lobe of the lung, bilateral renal cysts, hypoplastic renal arteries, urethral stricture, hydronephrosis, and aortic coarctation. The brain was abnormal with absent olfactory tracts and cerebral and cerebellar heterotopias. This is the first report of a chromosome anomaly in a child with Fryns phenotype. It suggests that the gene for Fryns syndrome may be located in the region 1q24-31.2.     

De novo direct duplication of 15q15→q24 in a newborn boy with mild manifestations

Duplication of distal 15q results in a recognizable clinical phenotype. We report here on a 25-day-old boy with a de novo interstitial duplication of chromosome region 15q15-q24. The manifestations in this patient are milder than those of previously described patients and include minor facial anomalies, velopharyngeal insufficiency, branchial cleft cyst, and hydronephrosis. Fluorescence in situ hybridization (FISH) using a chromosome 15 painting probe confirmed that the extra material is of chromosome 15 origin. Further analysis with the SNRPN probe demonstrated that the duplication is telomeric to the Prader-Willi/Angelman syndrome critical region. This case delineates a broader spectrum for patients with duplication 15q syndrome. Am. J. Med. Genet. 87:395–398, 1999. © 1999 Wiley-Liss, Inc.     

Cryptic duplication and deletion of 9q34.3 --> qter in a family with a t(9;22)(q34.3;p11.2)

A newborn male was referred for genetic evaluation because of multiple congenital abnormalities. Physical findings included a round face, telecanthus, hypertelorism, a short upturned nose with anteverted nares, small ears, micrognathia, short toes, and congenital heart disease. Chromosome analysis detected a possible deletion of 9qter because of satellite material on 9qter. Delineation by FISH and microarray CGH studies showed 46,XY,der(9)t(9;22)(q34.3;p11.2). The mother and maternal grandfather had a balanced t(9;22)(q34.3;p11.2) rearrangement. Also, the maternal great-aunt of the propositus was found to have a duplication of 9q34.3 --> qter. FISH was required to delineate her karyotype, which was 46,XX.ish der(22)t(9;22)(q34.3;p11.2). This maternal great-aunt and one of her daughters (cytogenetics not done) have a relatively normal phenotype, only reporting mild learning disabilities in school. Since the 22p material involved in this rearrangement is clinically irrelevant, this report describes an individual with a pure deletion of 9q34.3 --> qter and another with a pure duplication of 9q34.3 --> qter.     

A case of Prader – Willi syndrome arising as a result of familial unbalanced translocation t(11;15)(q25;q13)

We report on a case of Prader-Willi syndrome (PWS) with a true reciprocal unbalanced translocation, 45,XX,-15,der(11)t(11;15)pat. The proposita was diagnosed clinically as having severe PWS. Molecular studies revealed loss of the paternal methylation pattern at locus D15S63 and a deletion encompassing the loci from at least D15S10 to D15S97 of paternal chromosome 15. FISH studies confirmed the deletion of 15q11-q13 region and the presence of two telomeres on all chromosomes. The proposita's father, the father's sister and their mother are all carriers of the same balanced translocation t(11;15)(q25;q13). By genomic imprinting we would expect that if the father's sister were to give birth to a child with the same unbalanced translocation as the proband, it would be affected by Angelman syndrome.
To date, a similar familial unbalanced translocation due to loss of the small chromosome 15 derivative has not been described.     

Duplication 6q24 → 6qter in an infant from a balanced paternal translocation

Duplication of 6q24 → 6qter was identified by GTG banding in an infant girl whose father was a balanced translocation carrier 46,XY,t(3;6)(p26 → q2402). At birth and at 4 mo she had proportionate short stature, microcephaly, asymmetric micrognathia, bow-shaped upper vermilion, long upper lip, submucous cleft palate, antimongoloid slant of palpebral fissures, telecanthus, prominant eyes, short neck with anterior and lateral webbing, short sternum, overlapping toes, wrist contractures, and hypertonicity. Later she was noted to have psychomotor retardation. Eleven previously published cases and our patient suggest that duplication of 6q (involving at least 6q25 → 6qter) produces a highly characteristic syndrome.