An 8‐cM interstitial deletion on 4q21‐q22 in DNA from an infant with hepatoblastoma overlaps with a commonly deleted region in adult liver cancers

We performed molecular analysis of a germline interstitial deletion of chromosome 4 [del(4)(q21.22q23)], which had been observed in a male infant manifesting early‐onset hepatoblastoma (HBL). The chromosomal anomaly in this child was associated with a unique congenital syndrome including HBL, atrial septal defect, ventricular septal defect, patent ductus arteriosus, mental retardation, and seizures. However, the patient did not exhibit a megalencephaly typical of 4q21‐22 deletions. His HBL was associated with an increasing serum α‐fetoprotein level and rapid growth. To define the chromosomal deletion at the molecular level in this child, we analyzed his lymphoblasts with fluorescence in situ hybridization, using as probes a panel of BAC/PAC genomic clones containing STS markers covering the 4q12‐27 region. The analysis revealed that the affected chromosome had an 8‐cM deletion within 4q21‐q22, flanked by markers D4S2964 and D4S2966. This microdeletion overlaps with the commonly deleted region at 4q21‐q22 that was recently defined in adult hepatocellular carcinomas. © 2001 Wiley‐Liss, Inc.     

Molecular and cytogenetic analysis of chromosome 7 in uterine leiomyomas

Uterine leiomyomas are benign tumors that arise clonally from smooth muscle cells of the myometrium. Cytogenetic studies of uterine leiomyomas have shown that about 40% have chromosome abnormalities and that deletion of 7q is a common finding. The observations suggest the possible location of a growth-suppressor gene within the 7q21-q22 region. Molecular genetic analysis of cytogenetically normal tumors has frequently shown somatic loss of specific tumor suppressor genes detected by loss of heterozygosity in the critical region. To test the hypothesis that chromosome region 7q21-q22 contains a growth-suppressor gene involved in the development of leiomyomas, we examined 92 leiomyomas for allelic loss of 7q markers spanning the cytogenetically defined critical region. Forty tumors with cytogenetically defined 7q deletion, 45 tumors without cytogenetically visible 7q deletion, and seven tumors with no cytogenetic information were examined for allelic loss of loci D7S489, D7S440, D7S492, D7S518, D7S471, D7S466, and D7S530. Loss of heterozygosity for one or more of these loci was observed in 23 of 40 (57.5%) of the tumors with deletion of 7q and in 2 of 45 cases without a cytogenetically visible deletion. The tumors with cytogenetic deletion of 7q, but no loss of 7q21-q22 markers, were mosaics, with only a minority of cells containing the cytogenetic deletion. The critical region of loss is defined by the markers D7S518 and D7S471, each showing loss in approximately 50% of informative cases. These markers define a 10 cM region of 7q21-q22 that is consistent with the cytogenetically defined smallest region of overlap and exclude loss of the MET oncogene locus and WNT1, the murine mammary tumor-virus integration site, from the critical region. Our results further define a region that is consistently lost in leiomyomas with cytogenetic deletion of chromosome arm 7q. This region may contain a tumor suppressor gene involved in the development of a subset of leiomyomas.     

Interstitial 1q25.3-q31.3 deletion in a boy with mild manifestations

We describe a 4-year-old boy with an accessory right thumb, short and broad toes, cryptorchidism, micrognathia, abnormally modeled ears, and delayed speech development. The chromosome analysis of patient's peripheral blood lymphocytes by conventional GTG banding demonstrated a small deletion in the long arm of chromosome 1. Confirmation and defined localization of the deleted segment to chromosomal bands 1q25.3-q31.3 was obtained by high resolution prometaphase analysis. Molecular studies, using a set of polymorphic chromosome 1q specific microsatellite markers, localized the deletion between the markers D1S2127 and D1S1727 on the paternally inherited chromosome 1. The maximum physical distance between these markers is approximately 21 Mb. The previously described two patients with 1q25-q31 deletions both had severe clinical manifestations, just as the other 10 patients with the proposed "intermediate 1q deletion syndrome," associated with 1q25-q32 deletions. Distinct from all these patients, the clinical picture of our patient is markedly milder, i.e., without growth retardation, microcephaly, or clear mental retardation.     

先天性心脏病患者22q11微缺失检测及相关分析

目的探讨5个短串联重复（short tandem repeat，STR）标记用于检测22q11微缺失的可行性，了解中国汉族未经挑选的先天性心脏畸形患者中22q11微缺失的发生情况。方法选择位于22q11缺失区域的5个STR标记，对163例中国汉族先天性心脏畸形（congenital heart defect，CHD）息者及双亲进行单倍型分析，对检出的阳性病例及部分阴性病例进行荧光原位杂交（fluorescence in situ hybridization，FISH）验证。结果5个标记均具有较好的信息量，22D_4_1和22D_4_2杂合率分别为0．65和0．52，22D_4_3、22D_4_4和D22S873杂合率均在0．7以上，可用于汉族人群多态性分析；163例先天性心脏畸形患者用STR标记检出12例22q11微缺失，其中9例得到FISH检测证实，2例微小缺失和1例远端缺失FISH检测为阴性；CHD患者22q11微缺失检出率为7．36％，室间隔缺损微缺失检出率为8．18％（9／110），法乐氏四联征检出率为14．3％（3／21），其它类型的CHD未检出缺失。结论5个STR标记可用于汉族人群22q11微缺失的检测，且有快速、成本低的优点；中国汉族CHD患者中存在一定比率的22q11微缺失，尤其是室间隔缺损和法乐氏四联征较为常见。     

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.     

An interstitial deletion of chromosome 7 at band q21: a case report and review

We report on a girl with moderate developmental delay and mild dysmorphic features. Cytogenetic investigations revealed a de novo interstitial deletion at the proximal dark band on the long arm of chromosome 7 (7q21.1-q21.3) in all analyzed G-banded metaphases of lymphocytes and fibroblasts. Fluorescence in situ hybridization (FISH) and molecular studies defined the breakpoints at 7q21.11 and 7q21.3 on the paternal chromosome 7, with the proximal deletion breakpoint between the elastin gene (localized at 7q11.23) and D7S2517, and the distal breakpoint between D7S652 and the COL1A2 gene (localized at 7q21.3-q22.1). Deletions of interstitial segments at the proximal long arm of chromosome 7 at q21 are relatively rare. The karyotype-phenotype correlation of these patients is reviewed and discussed. The clinical findings of patients with a deletion at 7q21 significantly overlap with those of patients with maternal uniparental disomy of chromosome 7 (matUPD(7)) and Silver-Russell syndrome (SRS, OMIM 180860). Therefore, 7q21 might be considered a candidate chromosomal region for matUPD(7) and SRS.     

Involvement of bands 9q21-q22 in five cases of acute nonlymphocytic leukemia

Five patients with acute nonlymphocytic leukemia (ANLL) with chromosomal aberrations involving bands 9q21-q22 are described. The abnormalities were an interstitial deletion in two cases of ANLL FAB type M4 and M4 with eosinophilia, a terminal deletion in two cases of M4 and M5 type ANLL, and a translocation in an M2 ANLL. A review of reported cases of ANLL with abnormalities of chromosome 9 revealed a clustering of breaks at the region 9q21-q22, suggesting a possible role for these bands in leukemogenesis.     

Counselling dilemmas associated with the molecular characterisation of two Angelman syndrome families.

We report the molecular characterisation of two families with Angelman syndrome referred for prenatal diagnosis, in which atypical molecular findings resulted in counselling dilemmas. The first is a familial case of Angelman syndrome in which the two affected children have mutations which affect the imprinting mechanism, as shown by the presence of paternal DNA methylation patterns at D15S63 and SNRPN and biparental inheritance of 15q11-q13 markers. DNA prepared from a 21 week fetal blood sample detected a fetus with normal maternal and paternal DNA methylation patterns at D15S63, but inheritance of the same maternal chromosome 15q11-q13 as the two affected sibs. This is probably a result of germline mosaicism in the mother. The second is a case of Angelman syndrome with an atypical deletion of 15q11-q13, which involves both unusual proximal and distal breakpoints. The deletion was characterised in order to assess the risk of Angelman syndrome in a second pregnancy in the mother of this child.     

Interstitial deletion of the long arm of chromosome 4 [del(4)(q21.22q23)] and a liver tumor

We report on a boy with proximal interstitial deletion of chromosome 4, del(4)(q21. 22q23). The patient was born at term with a low birth weight, flat nasal bridge, micrognathia, wide-spaced nipples, clinodactyly of fifth fingers, overlapping fingers, postaxial polydactyly of the right foot, micropenis, hypospadias, a dermal sinus, and cardiac malformations. He developed psychomotor retardation, seizures, and a liver tumor with an increased serum α-fetoprotein level and rapid growth. The patient carried a deletion of chromosome 4 involving the 4q21-q22 region that was reported to form a unique syndrome. The absence of central nervous system overgrowth and the presence of a malignant liver tumor are unique to our patient, compared to others with the 4q21-q22 deletion syndrome. The clinical manifestations and relationship between the liver tumor and chromosomal anomaly are discussed. Am. J. Med. Genet. 78:291–293, 1998. © 1998 Wiley-Liss, Inc.     

Defining the region(s) of deletion at 6q16-q22 in human prostate cancer

Deletion of the long arm of chromosome 6 (6q) frequently occurs in many neoplasms, including carcinomas of the prostate and breast and melanoma, suggesting the location of a tumor-suppressor gene or genes at 6q. At present, however, the region of deletion has not been well defined, and the target gene of deletion remains to be identified. In this study, we analyzed 44 primary prostate cancers with 16 polymorphic markers for loss of heterozygosity (LOH) by using PCR-based techniques. We also examined 23 cell lines/xenografts of prostate cancer with 38 markers for LOH by the method of homozygosity mapping of deletion. LOH at 6q16 - q22 was detected in 21 of 44 (48%) primary tumors and in 12 of 23 (52%) cell lines/xenografts. Two regions of LOH were defined. One was 7.5 cM at 6q16 - q21 between markers D6S1716 and D6S1580, and the other was 4.3 cM at 6q22 between D6S261 and D6S1702. Whereas no correlation was found between LOH at 6q16-q22 and patient age at diagnosis or Gleason score, tumors at higher stage appear to have more frequent LOH. These findings suggest that deletion of 6q16 - q22 is a frequent event in prostate cancer, and that the deletion originates from two distinct regions. These results should be useful in identifying the target gene(s) of deletion at 6q.     

Ebstein anomaly associated with rearrangements of chromosomal region 11q

Ebstein anomaly (EA) is a relatively uncommon congenital heart defect and it is very rarely associated with a chromosomal anomaly. We report two distinct rearrangements of the chromosomal region 11q arm in two unrelated patients with Ebstein anomaly, renal malformation, minor anomalies, and the Pierre Robin sequence. The first patient had an interstitial deletion of chromosome 11 [46,XY,del(11)(11q21q23), and the other had a tertiary trisomy of chromosome 11qter (47,XX,+der(22)t(11;22)(q23; q11.2) Its association with either a chromosome 11q deletion or a duplication in some individuals suggests that a rearrangement of the 11q region is likely to cause a shift of the individuals' underlying liability to develop EA above a certain threshold. Am. J. Med. Gen. 80:157–159, 1998. © 1998 Wiley-Liss, Inc.     

Pierre Robin sequence and interstitial deletion 2q32.3-q33.2

Pierre Robin sequence (PRS) consists of the nonrandom association of micrognathia, cleft palate (CP), and glossoptosis. It also includes respiratory and feeding difficulties that appear to be neurogenic rather than mechanical in causation. Genetic determinants are thought to underlie this functional and morphological entity, based on the existence of Mendelian syndromes with PRS, and the rare observations of familial nonsyndromic PRS, in which some of the affected individuals have isolated CP. We report the association of PRS with deletion 2q32.3-q33.2 due to an unbalanced reciprocal translocation 46,XX, t(2;21), del 2(q32.3q33.2), and we refine the deletion interval with regard to YAC probes and polymorphic DNA markers. The deletion was shown to be flanked by D2S369 (telomeric) and D2S315 (centromeric), thus it maps to a recently determined chromosomal region known to be nonrandomly associated with CP. This observation supports the hypothesis for the genetic bases of nonsyndromic PRS, strengthens its possible genetic association with isolated CP, and provides a candidate PRS locus, in chromosomal region 2q32.3-q33.2.     

Tetrasomy 21 pter→q22.1 and Down syndrome: Molecular definition of the region

Down syndrome is usually caused by complete trisomy 21. Rarely, it is due to partial trisomy of the segment 21q22. We report on a 33-month-old girl with tetrasomy 21 pter → q22.1 resulting from an extra chromosome idic(21)(q22.1). She has craniofacial traits typical of Down syndrome, including brachycephaly, third fontanel, upward slanting palpebral fissures, round face, and protruding tongue. Speech development is quite delayed whereas motor development is only mildly retarded. The molecular content of the extra isodicentric chromosome was defined by molecular genetic investigations using 13 single copy probes unique to chromosome 21, and SOD1 expression studies. The child was found to have 4 copies of the region defined by D21S16 (21cen) through D21S93 on 21q22.1 and two copies of the remaining region defined by SOD1 → D21S55 → D21S123. In view of the recent assignment of Down syndrome facial characters to the 21q22 region, defined in part by D21S55, it is significant that this child shows a subset of Down syndrome facial manifestations, without duplication of this region. These results suggest that genes contributing to the facial and some of the hand manifestations of Down syndrome also exist in the chromosomal region proximal to D21S55 in band 21q22.1. © 1994 Wiley-Liss, Inc.     

Split foot and developmental retardation associated with a deletion of three microsatellite markers in 7q21.2-q22.1

A deletion of 7q21.2-q22.1 has been found in a patient with split foot and developmental retardation. Molecular analysis using polymerase chain reaction (PCR) showed deletion of three microsatellite markers, D7S527, D7S479 and D7S554, in the patient's paternal chromosome. These results pinpoint the critical region for an ectrodactyly locus (SHFD1) on chromosome 7.     

Hypoplastic left heart in a female infant with partial trisomy 4q due to de novo 4;21 translocation

We present a female infant with mild dysmorphic features and congenital heart defect: hypoplastic left heart with aortic atresia and hypoplastic aortic arch, ventricular septal defect, and a nonrestrictive atrial communication. Chromosome analysis showed an unbalanced translocation that contained additional material from 4q translocated onto 21q. This resulted in partial trisomy 4 and monosomy for the 21q telomeric region. The derivative chromosome was characterized using G-banding, M-FISH, and whole chromosome painting. The karyotype was described as 46,XX,der(21)t(4;21)(q25;q22.3).ish(wcp4+;wcp21+). Additional analyses with FISH probes specific for 21q 22.3, 21q22.2, 21q21.1, and 21q11.2 did not indicate any chromosome 21 duplication within the derivative chromosome 21. Monosomy for the telomeric portion of 21q was demonstrated using a tel 21q probe (Oncor). The patient underwent stage 1 Norwood procedure to manage her heart defect. Poor feeding and failure to thrive complicated the postsurgical period. The child subsequently underwent funduplication and feeding tube placement, and at 4.5 months of age presented with microcephaly and developmental delay. Hypoplastic left heart was previously reported with increased frequency in relatively common numeric chromosomal aberrations, such as monosomy X, trisomies 21, 18, and 13, and in various structural chromosomal defects. Our report presents new evidence for the co-occurrence of hypoplastic left heart with a duplicated portion of chromosome 4 distal to 4q25. In addition, monosomy for the telomeric region of chromosome 21 may have implications in the phenotype.     

Interrupted aortic arch in a child with trisomy 5q31.1q35.1 due to a maternal (20;5) balanced insertion

Complex congenital heart defects (CHD) are associated with a variety of single gene abnormalities and chromosomal rearrangements. Of the various forms of CHD, aortic arch interruption, a conotruncal heart defect, is relatively uncommon. Here we report a male neonate with aortic arch interruption type B, secundum atrial septal defect, perimembranous ventricular septal defect, patent ductus arteriosus, aortic and subaortic stenosis, and trisomy 5q31.1q35.1 resulting from a maternal balanced insertion (20;5). Chromosomal deletions, including deletion 22q11, have been reported with interrupted aortic arch (IAA); however, to our knowledge this is the first report of a trisomy of distal chromosome 5q associated with aortic arch interruption. Here we compare this child's features to other cases of trisomy 5q31.1q35.1, and review other causes of IAA. We conclude that gene dosage in this chromosomal region likely influences aortic arch development.     

Genetic heterogeneity in inherited spastic paraplegia associated with epilepsy

We have recently mapped a new rare form of spastic paraplegia complicated by bilateral cataracts, gastroesophageal reflux with persistent vomiting, and amyotrophy to chromosome 10q23.3-q24.2. This locus, named SPG9, is located in an interval spanning about 12 cM of genomic DNA, between markers D10S536 and D10S603, where different neurological disorders have been mapped. In particular, a gene for partial epilepsy has been assigned to a 3 cM interval between markers D10S185 and D10S577, which is completely included in the SPG9 critical region. A few families affected with spastic paraplegia and epilepsy have been reported; in the present study, we tested a pedigree with concurrence of spastic paraplegia, epilepsy, and mental retardation inherited as an autosomal dominant trait, using markers located in the SPG9 interval. Haplotype reconstruction excluded the linkage to 10q23.3-q24.2. In addition, the seven different loci so far reported to be associated with autosomal dominant pure forms of spastic paraplegia have been tested and excluded by linkage analysis and haplotype reconstruction, including SPG4 on chromosome 2p22-p21, where a familial form of spastic paraplegia associated with dementia and epilepsy has been mapped. These data confirm genetic heterogeneity in familial spastic paraplegia with epilepsy and suggest a specific locus for the family here analyzed.