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Molecular genetic analysis of five cases of 3p- syndrome (del(3)(qter-->p25:)) was performed to investigate the relationship between the molecular pathology and clinical phenotype. Fluorescence in situ hybridization studies and analysis of polymorphic DNA markers from chromosome 3p25-p26 demonstrated that all four informative cases had distal deletions. However, the extent of the deletion was variable: in two patients with the most extensive deletions the deletion breakpoint mapped between RAF1 and D3S1250, in one patient the deletion breakpoint was between D3S1250 and D3S601, and in two patients the deletion commenced telomeric to D3S601 (and telomeric to D3S1317 in one of these). All five patients displayed the classical features of 3p- syndrome (mental retardation, growth retardation, microcephaly, ptosis and micrognathia) demonstrating that loss of sequences centromeric to D3S1317 is not required for expression of the characteristic 3p- syndrome phenotype. The three patients with the most extensive deletions had cardiac septal defects suggesting that a gene involved in normal cardiac development is contained in the interval D3S1250 and D3S18. The PMCA2 gene is contained within this region and deletion of this gene may cause congenital heart defects. At least three patients were deleted for the von Hippel-Lindau (VHL) disease gene although none had yet developed evidence of VHL disease. We conclude that molecular analysis of 3p- syndrome patients enhances the management of affected patients by identifying those at risk for VHL disease, and can be used to elucidate the critical regions for the 3p- syndrome phenotype.
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PMID:Molecular genetic analysis of the 3p- syndrome. 795 Dec 34

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant condition consisting of congenital dysplasia of the eyelids with a reduced horizontal diameter of the palpebral fissures, droopy eyelids and epicanthus inversus. Two clinical entities have been described: type I and type II. The former is distinguished by female infertility, whereas the latter presents without other symptoms. Both type I and type II were recently mapped on the long arm of chromosome 3 (3q22-q23), suggesting a common gene may be affected. The centromeric and the telomeric limits of this region are well defined between loci D3S1316 and D3S1615, which reside approximately 5 cM apart. Here, we present the construction of a YAC contig spanning the entire BPES locus using 17 polymorphic markers, 2 STS and 28 ESTs. This region of approximately 5 Mb was covered by 31 YACs, and was supported by detailed FISH analysis. In addition, we have precisely mapped the propionyl-CoA carboxylase beta polypeptide (PCCB), the gene mutated in propionic acidemia, within this contig. Apart from providing a framework for the identification of the BPES gene, this contig will also be useful for the future identification of defects and genes mapped to this region, and for developing template resources for genomic sequencing.
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PMID:A YAC contig spanning the blepharophimosis-ptosis-epicanthus inversus syndrome and propionic acidemia loci. 927 42

BPES is a genetic disorder presenting with blepharophimosis, ptosis of the eyelids, epicanthus inversus, and telecanthus. BPES type I is associated with female infertility, whereas type II presents without additional symptoms. Hitherto, it remains unknown whether BPES type I results from a defect in a single gene or from a contiguous gene syndrome. Previous cytogenetic and linkage analyses have assigned a BPES locus to 3q23, in a 5-cM interval between D3S1615 and D3S1316. In this report, we describe the molecular and physical characterization of the 3q23 breakpoint in a BPES patient with a t(3;4)(q23;p15.2) translocation. Eight YACs located around and within the D3S1615-D3S1316 interval were mapped relative to the 3q23 breakpoint; 5 YACs spanning the 3q23 breakpoint were identified. Thirteen STSs and ESTs were localized on the YAC map. Subsequent hybridization of 2 YACs spanning the breakpoint to the Human RPCI1 PAC Library and the Human Chromosome 3 LLNL Cosmid Library resulted in the identification of 12 PACs and 50 cosmids respectively, allowing the construction of a detailed PAC and cosmid physical map. A refined position-telomeric to the breakpoint-of 3 candidate genes, cellular retinol-binding proteins 1 and 2 (RBP1, RBP2) and the coatomer beta' subunit (beta'-COP), was obtained on this physical map. Furthermore, a PAC and cosmid contig encompassing the breakpoint was constructed. PAC 169-C 10 and cosmid 11-L 10 crossing the breakpoint have sizes of 110 and 45 kb, respectively. The isolation of coding sequences in these clones and in the rest of the contig will greatly facilitate further efforts toward positional cloning of the gene(s) involved in BPES.
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PMID:Closing in on the BPES gene on 3q23: mapping of a de Novo reciprocal translocation t(3;4)(q23;p15.2) breakpoint within a 45-kb cosmid and mapping of three candidate genes, RBP1, RBP2, and beta'-COP, distal to the breakpoint. 1019 Oct 85

Cryptic unbalanced chromosome rearrangements in the telomeric bands of the chromosomes may constitute a significant cause of unexplained mental retardation with or without congenital anomalies. We report on a boy with a terminal deletion of the long arm of chromosome 13, combined with a partial duplication of the short arm of chromosome 20, owing to a cryptic balanced translocation in his father. The karyotype of the father was 46XY,t(13;20)(q34;p13). The propositus presented with severe mental and growth retardation, microcephaly, facial anomalies including ptosis of the right upper eyelid, a high nasal bridge, small palpebral fissures, and bilateral epicanthus, hypospadias, and scoliosis. A younger brother died at birth and had a low birth weight, hypospadias, and a horseshoe kidney. Repeated chromosome analyses with high resolution banding in the propositus and his parents were apparently normal. Chromosome painting eventually disclosed the cryptic translocation in the father with unbalanced karyotype in the propositus. The importance of additional FISH analysis in patients with unexplained mental retardation, physical anomalies, and apparently normal chromosomes is emphasized.
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PMID:Detection of a cryptic translocation t(13;20)(q34;p13) in an unexplained case of MCA/MR: value of FISH over high resolution banding. 1049 96

Blepharophimosis, ptosis, epicanthus inversus syndrome type I (BPES; OMIM 110100) is an autosomal dominant disorder affecting craniofacial development and ovarian function. We have identified a patient with BPES who carried a de novo reciprocal translocation [46, XX,t(3;21)(q23;q22.1)]. Fluorescence in situ hybridization analysis at band 3q23 using probes derived from BAC 175G20 (Research Genetics), PACs 108L15 and 169C10 (RPCI1), and cosmids AC174D4, AC68D3, AC44F5, and AC125C5 (Lawrence Livermore National Laboratory) was performed. The patient's breakpoint was found to lie within the overlapping region of the BAC and PACs but centromeric to all the cosmids. However, a 10.5-kb BamHI-digested fragment, common to the BAC and PAC clones, was shown to cross the breakpoint. The results have placed our patient's breakpoint proximal to that of the previously reported patient [46,XY,t(3;4)(q23;p15.2)] and within a 10.5-kb interval. This is the second patient in which a breakpoint was refined by molecular cytogenetics. Our findings emphasize the significance of this region for BPES.
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PMID:Molecular cytogenetic evaluation in a patient with a translocation (3;21) associated with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES). 1077 67

We report on the prenatal diagnosis of two sib female fetuses with a satellited short arm of chromosome 4 and a male fetus with a satellited long arm of chromosome X. The first two fetuses had a cryptic balanced translocation (4;15)(p16;p11.1) inherited from a mother carrying a satellited 4p and having an affected child with the Wolf-Hirschhorn syndrome. The third fetus had a satellited Xq, with a deletion of subtelomeric region of Xq. The mother was subsequently found to have the same satellited Xq but without the presence of a reciprocal translocation. She decided to continue the pregnancy. The proband with a satellited Xq manifested developmental delay, mental retardation, hypertelorism, ptosis of one eye, low-set ears, and hearing disturbance at age 6 months. Fluorescence in situ hybridization (FISH) with a specific telomeric or subtelomeric probe, and genetic marker analyses were used to confirm the diagnosis. Pregnant women with satellited non-acrocentric chromosomes are at risk for carrying fetuses with chromosome abnormalities. If the X chromosome is involved, the fetuses can be affected with X-linked recessive disorders including mental retardation. Detailed genetic counselling, cytogenetic studies, FISH and genetic marker analyses are useful in prenatal detection of abnormal chromosome rearrangements.
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PMID:Prenatal diagnosis of inherited satellited non-acrocentric chromosomes. 1082 Apr 5

Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct clinical syndrome characterised by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia. Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD), occurs in about a third of patients. In total, approximately 25 cases of 3p- syndrome have been reported world wide. We previously analysed five cases and showed that (1) the 3p25-pter deletions were variable and (2) the presence of CHD correlated with the proximal extent of the deletion, mapping a CHD gene centromeric to D3S18. To define the molecular pathology of the 3p- syndrome further, we have now proceeded to analyse the deletion region in a total of 10 patients (five with CHD), using a combination of FISH analysis and polymorphic markers, for up to 21 loci from 3p25-p26. These additional investigations further supported the location of an AVSD locus within 3p25 and refined its localisation. Thus, the critical region was reduced to an interval between D3S1263 and D3S3594. Candidate 3p25 CHD genes, such as PMCA2 (ATP2B2), fibulin 2, TIMP4, and Sec13R, were shown to map outside the target interval. Additionally, the critical region for the phenotypic features of the 3p- phenotype was mapped to D3S1317 to D3S17 (19-21 cM). These findings will accelerate the identification of the 3p25 CHD susceptibility locus and facilitate investigations of the role of this locus in non-syndromic AVSDs, which are a common form of familial and isolated CHD.
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PMID:Detailed mapping of a congenital heart disease gene in chromosome 3p25. 1092 84

Mammalian sex determination is governed by the presence of the sex determining region Y gene (SRY) on the Y chromosome. Familial cases of SRY-negative XX sex reversal are rare in humans, often hampering the discovery of new sex-determining genes. The mouse model is also insufficient to correctly apprehend the sex-determination cascade, as the human pathway is much more sensitive to gene dosage. Other species might therefore be considered in this respect. In goats, the polled intersex syndrome (PIS) mutation associates polledness and intersexuality. The sex reversal affects exclusively the XX individuals in a recessive manner, whereas the absence of horns is dominant in both sexes. The syndrome is caused by an autosomal gene located at chromosome band 1q43 (ref. 9), shown to be homologous to human chromosome band 3q23 (ref. 10). Through a positional cloning approach, we demonstrate that the mutation underlying PIS is the deletion of a critical 11.7-kb DNA element containing mainly repetitive sequences. This deletion affects the transcription of at least two genes: PISRT1, encoding a 1.5-kb mRNA devoid of open reading frame (ORF), and FOXL2, recently shown to be responsible for blepharophimosis ptosis epicanthus inversus syndrome (BPES) in humans. These two genes are located 20 and 200 kb telomeric from the deletion, respectively.
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PMID:A 11.7-kb deletion triggers intersexuality and polledness in goats. 1172 32

Monozygotic twin brothers are described who share clinical features which include: moderate mental retardation, short stature, macrocephaly, frontal bossing, ptosis, low-set ears, brachydactyly, 5th fingers clinodactyly, single palmar creases, cryptorchidism, and prelingual sensorineural deafness. One of the twins presented with mild cardiac dilatation and died at age 3(1/2) from cardiac arrest during an episode of acute respiratory infection. While chromosome analyses performed for both twins on peripheral blood showed apparently normal karyotypes, screening for all telomeric regions on the surviving propositus revealed a combination of partial 6p trisomy and partial 11q monosomy. A balanced reciprocal translocation was found in the father. The phenotype of the twins is most likely related to this cryptic chromosomal rearrangement. The fact that the phenotype in this family partially overlaps with some previously reported phenotypes is discussed.
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PMID:Craniofacial anomalies, deafness, brachydactyly, short stature, and moderate mental retardation due to a cryptic 6p;11q translocation. 1185 53

Aniridia is a rare condition occurring in 1 in 64,000 to 1 in 96,000 live births. Approximately one third of cases are sporadic and carry a 30% risk of Wilms' tumor developing before the age of 5. The remaining 66% are inherited in an autosomal dominant fashion. The aniridia candidate gene (PAX6) has a key role as a master regulator in the development of eye and central nervous tissues. The Wilms' tumor predisposing gene (WT1) plays an important role in the development of genitourinary tract diseases such as hypospadias, cryptorchism, horse-shoe kidney, and Wilms' tumor. The WT1 and PAX6 genes are about 700 kb apart, with the WT1 gene located centromeric to PAX6 in chromosome 11p13. We report a patient with incomplete aniridia, ptosis, hypospadias, and cryptorchism. Cytogenetic analysis revealed the presence of a de novo reciprocal translocation 46, XY, t (2; 11) (p25.1; p13) without microscopic deletion. We suggest that haploinsufficiency in PAX6 and WT1 genes resulted in aniridia and associated genitourinary abnormalities.
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PMID:De novo chromosome translocation t (2; 11) (p25.1; p13) in a patient with aniridia and genitourinary abnormalities. 1284 52


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