Chromosome deletions in 13q33-34: report of four patients and review of the literature

Deletions of chromosome bands 13q33-34 are rare. Patients with such deletions have mental retardation, microcephaly, and distinct facial features. Male patients frequently also have genital malformations. We report on four patients with three overlapping deletions of 13q33-34 that have been characterized by tiling-path array-CGH. Patient 1 had mental retardation and microcephaly with an interstitial 4.7 Mb deletion and a translocation t(12;13)(q13.3;q32.3). His mother (Patient 2), who also had mental retardation and microcephaly, carried the identical chromosome aberration. Patient 3 was a girl with a de novo insertion ins(7;13)(p15.1;q22q31) and interstitial 4.5 Mb deletion in 13q33-34. She had mental retardation and microcephaly. Patient 4 was a newborn boy with severe genital malformation (penoscrotal transposition and hypospadias) and microcephaly. He had a de novo ring chromosome 13 lacking the terminal 9.3 Mb of 13q. Karyotype-phenotype comparisons of these and eight previously published del13q33-34 patients suggest EFNB2 as a candidate gene for genital malformations in males. Molecular cytogenetic definition of a common deleted region in all patients suggests ARHGEF7 as a candidate gene for mental retardation and microcephaly.     

Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions

Patients with an interstitial 13q deletion that contains the RB1 gene show retinoblastoma and variable clinical features. Relationship between phenotypic expression and loss of specific neighboring genes are unresolved, yet. We obtained clinical, cytogenetic and molecular data in 63 patients with an interstitial 13q deletion involving RB1. Whole-genome array analysis or customized high-resolution array analysis for 13q14.11q14.3 was performed in 38 patients, and cytogenetic analysis was performed in 54 patients. Deletion sizes ranged between 4.2 kb and more than 33.43 Mb; breakpoints were non-recurrent. Sequence analysis of deletion junctions in five patients revealed microhomology and insertion of 2–34 base pairs suggestive of non-homologous end joining. Milder phenotypic expression of retinoblastoma was observed in patients with deletions larger than 1 Mb, which contained the MED4 gene. Clinical features were compared between patients with small (within 13q14), medium (within 13q12.3q21.2) and large (within 13q12q31.2) deletions. Patients with a small deletion can show macrocephaly, tall stature, obesity, motor and/or speech delay. Patients with a medium deletion show characteristic facial features, mild to moderate psychomotor delay, short stature and microcephaly. Patients with a large deletion have characteristic craniofacial dysmorphism, short stature, microcephaly, mild to severe psychomotor delay, hypotonia, constipation and feeding problems. Additional features included deafness, seizures and brain and heart anomalies. We found no correlation between clinical features and parental origin of the deletion. Our data suggest that hemizygous loss of NUFIP1 and PCDH8 may contribute to psychomotor delay, deletion of MTLR1 to microcephaly and loss of EDNRB to feeding difficulties and deafness.     

Interstitial duplications of chromosome region 15q11q13: Clinical and molecular characterization

Duplications of chromosome region 15q11q13 often occur as a supernumerary chromosome 15. Less frequently they occur as interstitial duplications [dup(15)]. We describe the clinical and molecular characteristics of three patients with de novo dup(15). The patients, two males and one female (ages 3–21 years), had nonspecific findings that included autistic behavior, hypotonia, and variable degrees of mental retardation. The extent, orientation, and parental origin of the duplications were assessed by fluorescent in situ hybridization, microsatellite analyses, and methylation status at D15S63. Two patients had large direct duplications of 15q11q13 [dir dup(15)(q11q13)] that extended through the entire Angelman syndrome/Prader-Willi syndrome (AS/PWS) chromosomal region. Their proximal and distal breaks, at D15S541 or D15S9 and between D15S12 and D15S24, respectively, were comparable to those found in the common AS/PWS deletions. This suggests that duplications and deletions may be the reciprocal product of an unequal recombination event. These two duplications were maternally derived, but the origin of the chromatids involved in the unequal crossing over in meiosis differs. In one patient, the duplication originated from two different maternal chromosomes, while in the other patient it arose from the same maternal chromosome. The third patient had a much smaller duplication that involved only D15S11 and parental origin could not be determined. There was no obvious correlation between phenotype and extent of the duplication in these patients. Am. J. Med. Genet. 79:82–89, 1998. © 1998 Wiley-Liss, Inc.     

Dysmorphic phenotype and neurological impairment in 22 retinoblastoma patients with constitutional cytogenetic 13q deletion

We describe the facial dysmorphic phenotype and the neurological development of a series of 22 retinoblastoma patients sharing a cytogenetically detectable 13q deletion in a retrospective and longitudinal study. In most of the cases, high-resolution banding analysis, morphological analysis, and assessment for neurodevelopmental outcome, as well for organ malformations, were performed. Chromosomal rearrangement involving the RB1 gene included 20 13q interstitial deletions (including 16 de novo deletions) and two (de novo translocations. The most prominent dysmorphic abnormalities were anteverted ear lobes (90%), a high and broad forehead (85%), and a prominent philtrum (65%). This phenotype was associated with severe mental retardation and/or motor impairment at age 2 years in 69% of patients and correlated with the size and the location of the 13q deletion. The survival rate of our series (91%) was not different from that usually seen in retinoblastoma patients.     

Distal 13q Deletion Syndrome and the VACTERL association: case report, literature review, and possible implications

We present a case of a child with del(13) (q31.1qter), VACTERL association, and penoscrotal transposition. Deletion of the distal long arm of chromosome 13 is associated with variable phenotypes. These phenotypes are divided into three clusters; each cluster represents a specific deleted segment of 13q. Individuals with deletions of a critical region at 13q32 have multiple congenital malformations that include components of the VACTERL association. Our patient had all six manifestations of VACTERL association. In addition, he had complete penoscrotal transposition, a unique malformation reported rarely in VACTERL association and only twice previously in deletion of distal 13q. We reviewed all reported cases of distal 13q deletions to date. Of these 137 patients, 15 could be classified into the VACTERL association. Ours was the only patient with distal 13q deletion and all VACTERL association features and also the only one with tracheoesophageal fistula. Neither holoprosencephaly nor the other central nervous system malformations that have been seen in individuals with distal 13q deletions were apparent in him. The patient presented here appears to be unique among individuals with distal 13q deletion. His cluster of malformations strengthens the argument that distal 13q deletion is a cause for VACTERL association, and that this causal relationship implies a syndromic form of VACTERL. In addition, this case and those ascertained from the literature suggest that penoscrotal transposition should be considered part of both the distal 13q-deletion syndrome and some forms of VACTERL association.     

Two craniosynostotic patients with 11q deletions,and review of 48 cases

Many chromosomal abnormalities have craniofacial manifestations. One such abnormality, partial monosomy of chromosome 11q, is associated with metopic synostosis and resultant trigonocephaly. We reviewed 48 published cases of 11q deletions and translocations. Eighty percent were associated with abnormal head shape. Also commonly found were hypertelorism, ptosis of the eyelids, wide or low nasal bridge, apparently low-set malformed ears, down-turned mouth, micro/retrognathia, digital and cardiac anomalies, and psychomotor retardation. We report on two patients referred for abnormal head shape. The first case had brachycephaly, flat occiput, hypertelorism, and maxillary hypoplasia. Karyotype was 46,XY,del(11)(q24.1→qter). The second patient had trigonocephaly, hypotelorism, posteriorly angulated ears, horizontal crease below his lower lip, syndactyly, shawl scrotum, cryptorchidism, and inguinal hernias. Karyotype showed partial trisomy of chromosome 4q as well as partial monosomy of 11q [46,XY,11,+der(11)t(4;11)(q31.3;q25)], a combination not previously reported. Deletions of 11q appear to produce a wide spectrum of abnormalities. © 1995 Wiley-Liss, Inc.     

Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy‐Walker malformation

Two patients with partial deletions of the long arm of chromosome 13, del(13)(13q21‐q34) and del(13)(13q22‐q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy‐Walker malformation (DWM) are described. The occurrence of HPE and the DWM in both of these patients suggests that, in addition to ZIC2, which is important for normal development of the forebrain, there is at least one other dosage‐sensitive gene in 13q22‐q33 that plays an important role in brain development. The DWM is anatomically and developmentally distinct from HPE. The presence of a DWM in each of these two patients with partial deletions of the long arm of chromosome 13 suggests that haploinsufficiency at a locus in 13q22‐q33 may cause this anomaly. These findings suggest that microdeletions in 13q22‐q33 may be found in a proportion of patients with an apparently isolated DWM. Therefore, careful high‐resolution cytogenetic analysis (550 band level or greater) of 13q22‐q33 may be considered in these patients. Furthermore, future molecular studies of this region may reveal candidate gene loci for the DWM. © 2002 Wiley‐Liss, Inc.     

Neocentromere at 13q32 in one of two stable markers derived from a 13q21 break

A 10-month-old girl with psychomotor retardation, microcephaly, bilateral microphthalmia, and postaxial polydactyly of the feet was karyotyped using banding techniques and (single or dual color) fluorescent in situ hybridization (FISH) with four probes: D13Z1/D21Z1, pancentromeric, pantelomeric, and a mix of 13q subtelomeric and 13/21 alphoid repeats. She was found to have a 47-chromosome karyotype in which a normal 13 was replaced by two stable markers derived from a breakpoint at 13q21.1, namely a del(13)(q21.1) and an isofragment(13) (qter→q21.1::q21.1→qter). The latter had a single C-negative but Cd-positive primary constriction at 13q32 which, however, was not obvious in about 12% of the cells. FISH studies showed that the small 13q- had the 13-centromere and a 13q telomere (as shown for a specific 13q subtelomeric signal) onto the broken end whereas the isofragment lacked alphoid signals but had 13q subtelomeric sequences on both ends. Parental karyotypes were normal. The patient's rearrangement represents the eighth chromosome-13–derived marker with a nonalphoid neocentromere located at 13q. All in all, such neocentromeres have been described in 29 markers derived from chromosomes 2, 3, 8–11, 13–15, 20, and Y, and plausibly result from the epigenetic activation of a latent centromere, which may even be a telomere with neocentric activity. The 13q telomere found in the del(13q) was probably captured from the homologous chromosome. Am. J. Med. Genet. 85:385–388, 1999. © 1999 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. © 2001 Wiley‐Liss, Inc.     

Neural tube defects and the 13q deletion syndrome: evidence for a critical region in 13q33-34

Neural tube defects (NTD) are common findings in the 13q deletion syndrome, but the relationship between the 13q- syndrome and NTDs is poorly understood. We present a child with a 13q deletion and lumbosacral myelomeningocele. This was a boy with microcephaly, telecanthus, minor facial anomalies, and ambiguous genitalia. Cytogenetic and fluorescence in situ hybridization analysis showed a de novo 46,XY,del(13)(q33.2-->qter) with no visible translocation. By using microsatellite markers, the deletion breakpoint was mapped to a 350-kb region between D13S274 and D13S1311 and was paternal in origin. An analysis of 13q deletions with NTDs, including the present case, suggests that a deletion in 13q33-34 is sufficient to cause an NTD. The deletions associated with NTDs are distal to and nonoverlapping with the previously defined critical region in 13q32 for the major malformation syndrome [Brown et al., 1999: Am J Hum Genet 57: 859-866]. Our analysis also suggests that one or more genes in 13q33-34 produces NTDs by haploinsufficiency.     

Analysis of a 1‐megabase deletion in 15q22‐q23 in an autistic patient: Identification of candidate genes for autism and of homologous DNA segments in 15q22‐q23 and 15q11‐q13

We have identified a one megabase deletion in the 15q22‐15q23 region in a patient with autism, developmental delay, and mild dysmorphism. Genes that map within the deletion region and genes that are interrupted or rearranged at the deletion breakpoints are candidate genes for autism. Fluroescence in situ hybridization studies in this patient revealed that part or all of the PML gene is absent from one chromosome 15 and a BAC clone containing the D15S124 gene locus hybridizes to only one chromosome 15. BAC clones containing the PTPN9, and SLP‐1[hUNC24] genes showed markedly reduced hybridization in the 15q22‐q23 region on one chromosome 15 in the patient. These BACs also hybridize to the 15q11‐q13 region in close proximity to SNRPN and HERC2, and in this region there is equal intensity of signal on the normal and on the deleted chromosome. There are previous reports of deletions and duplications of the 15q11‐q13 region in patients with autism. Our patient represents the first report of a 15q22‐q23 deletion. Hybridization of the PTPN9 and Slp‐1 Bac clones to the 15q11‐q13 and the 15q22‐q23 regions of chromosome 15 may be due to the presence of PTPN9 or SLP‐1 gene sequences or to the presence of other gene sequences or to non‐coding homologous DNA sequences. The PTPN9 gene encodes a non‐receptor protein tyrosine phosphatase. The Slp‐1 [hUNC24] gene is expressed mainly in the brain. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:765–770, 2000. © 2000 Wiley‐Liss, Inc.     

Characterization of de novo microdeletions involving 17q11.2q12 identified through chromosomal comparative genomic hybridization

High-resolution array-comparative genome hybridization (CGH) is a powerful tool for detection of submicroscopic chromosome deletions and duplications. We describe two patients with mild mental retardation (MR) and de novo microdeletions of 17q11.2q12. Although the deletions did not involve the neurofibromatosis type 1 (NF1) gene, they overlap with long-range deletions of the NF1 region which have been encountered in a small group of NF1 patients with more severe MR. Given the overlap of the deletions in our two patients with the large-sized NF1 microdeletions but not with the more frequent and smaller NF1 deletions, we hypothesize that more than one gene in the 17q11.2q12 region may be involved in MR. We discuss candidate genes for MR within this interval that was precisely defined through array-CGH analysis.     

Reassessment of the 12q15 deletion syndrome critical region

Interstitial deletions of the long arm of chromosome 12 are rare and only few cases have been reported in literature so far, with different phenotypic features related to size and gene content of deleted regions. Five patients reported a 12q15-q21 deletion, sharing a 1.3 Mb small region of overlap (SRO) and presenting with developmental delay, nasal speech and mild dysmorphic features.We identified by microarray analysis a new case of 12q15 deletion. Our patient clinical features allow the refinement of the SRO to CNOT2, KCNMB4, and PTPRB genes, improving genotype-phenotype correlations.     

Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes

Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader–Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4–BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3–BP4 interval and an additional four individuals with deletions of the BP3–BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3–BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3–BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3–BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals.     

Epimutation at human chromosome 14q32.2 in a boy with a upd(14)mat-like clinical phenotype

Recently, three reports described deletions and epimutations affecting the imprinted region at chromosome 14q32.2 in individuals with a phenotype typical for maternal uniparental disomy of chromosome 14 [upd(14)mat]. In this study, we describe another patient with upd(14)mat-like phenotype including low birth weight, neonatal feeding problems, muscular hypotonia, motor and developmental delay, small hands and feet, and truncal obesity. Conventional cytogenetic analyses, fluorescence in situ hybridization subtelomere screening, multiplex ligation-dependent probe amplification analysis of common microdeletion and microduplication syndromes, and methylation analysis of SNRPN all gave normal results. Methylation analysis at 14q32.2 revealed a gross hypomethylation of the differentially methylated regions (intergenic DMR and MEG3 -DMR). Further molecular studies excluded full or segmental upd(14)mat as well as a microdeletion within this region. Evidently, the upd(14)mat-like clinical phenotype is caused by an epimutation at 14q32.2. The clinical and molecular features of this novel case are discussed with respect to the recently published cases.     

多发性骨髓瘤1q染色体异常与13q缺失的相关性研究

目的 探讨多发性骨髓瘤(multiple myeloma,MM)中13q14的缺失[del(13q14)]和1q染色体异常的相关性.方法 应用CD138单克隆抗体磁珠分选系统纯化48例初治MM患者的骨髓浆细胞,结合SpectrumorangeTM直接标记的位于13q14和1q12的序列特异性DNA探针和间期荧光原位杂交技术检测48例MM患者del(13q14)及1q染色体异常情况.结果 48例MM患者中,用D13S319探针检测,del(13q14)异常22例(45.8%);用CEP1探针检测.23例(47.9%)发现1q染色体异常.其中2例为1q缺失,21例为1q重复.22例伴有del(13q14)MM患者中16例出现1q染色体异常;26例未检测到del(13q14)MM患者中仅7例发现1q染色体异常.经X2检验两者间差异有统计学意义(X2=10.02,P＜0.01).结论 del(13q14)及1q染色体异常在MM中的发生率较高,两者间存在高度相关性.     

Prevalence of 22q11 region deletions in patients with velopharyngeal insufficiency

Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect are all associated with hemizygosity of 22q11. While the prevalence of the deletions in these phenotypes has been studied, the frequency of deletions in patients presenting with velopharyngeal insufficiency (VPI) is unknown. We performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 23 patients with VPI (age range 5–42 years) followed in the Craniofacial Clinic at the University of Florida. The VPI occurred either as a condition of unknown cause (n=16) or as a condition remaining following primary cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and one of seven with VPI following surgery had a deletion in the region. This study documents a high frequency of 22q11 deletions in those presenting with VPI unrelated to overt cleft palate surgery and suggests that deletion testing should be considered in patients with VPI. Am. J. Med. Genet. 77:8–11, 1998. © 1998 Wiley-Liss, Inc.     

Delineation of the minimal region of loss at 13q14 in multiple myeloma

Previous studies have focused on the incidence and prognostic implications of 13q14 deletions in multiple myeloma (MM), but none has sought to delineate the minimal common deleted region (CDR). In an effort to do so, dual-color interphase fluorescence in situ hybridization (FISH) was applied on 82 myeloma cases, initially by use of three probes for 13q14 (RB1, D13S319, and D13S25). Deletions were detected in 29/82 (35.4%) cases, and all except one were monoallelic. Subsequently, contiguous YACs, PACs, and a BAC spanning the 13q14-q21 region were employed for deletion mapping in addition to a 13q telomere probe. Large deletions extending to the 13q34 region were found in 55% of the deleted cases, whereas an additional 13.8% showed loss of both 13q34 and 13q14 regions with retention of 13q21. A CDR of approximately 350 kb was identified at 13q14 with the proximal border approximately 120 kb centromeric from D13S319, encompassing an area rich in expressed sequence tagged sites and containing DLEU1, DLEU2, and RFP2 genes. Direct sequencing of the RFP2 gene revealed no mutations in six patients and four MM cell lines harboring deletions of the CDR. However, a role for RFP2 in the pathogenesis of MM cannot yet be excluded, given that alternative mechanisms such as haploinsufficiency remain possible.     

Interstitial deletion of 14q24.3-q32.2 in a male patient with plagiocephaly, BPES features, developmental delay, and congenital heart defects

Distal interstitial deletions of chromosome 14 involving the 14q24‐q23.2 region are rare, and only been reported so far in 20 patients. Ten of these patients were analyzed both clinically and genetically. Here we present a de novo interstitial deletion of chromosome 14q24.3‐q32.2 in a male patient with developmental delay, language impairment, plagiocephaly, BPES features (blepharophimosis, ptosis, epicanthus), and congenital heart defect. The deletion breakpoints were fine mapped using fluorescence in situ hybridization (FISH) and the size of the deletion is estimated to be approximately 23 Mb. Based on genotype–phenotype comparisons of the 10 previously published patients and the present case, we suggest that the shortest regions for deletion overlap may include candidate genes for speech impairment, mental retardation, and hypotonia. © 2010 Wiley‐Liss, Inc.     

Preliminary definition of a “critical region” of chromosome 13 in q32: Report of 14 cases with 13q deletions and review of the literature

We report on 14 patients with partial deletions of chromosome 13q. These patients exhibit a wide spectrum of phenotypes. Deletions limited to proximal bands q13–q31 are associated with growth retardation but not with major malformations. We review the literature since 1975 and summarize 13q deletion cases which have a phenotype involving one or more major malformations and mental retardation. Analysis of the breakpoints of these cases, as well as those reported by us, supports the hypothesis that only deletions involving at least part of band q32 are associated with major malformations and digital abnormalities. Patients with more distal deletions have severe mental retardation but do not have major malformations or growth retardation. A group of patients in whom the breakpoint is stated to be within q32 has had an intermediate phenotype. This suggests that it may be possible to define subregions within q32 whose deletion is associated with particular developmental defects. © 1993 Wiley-Liss, Inc.