Identical twins with deletion 16q syndrome: Evidence that 16q12.2-q13 is the critical band region

Summary An interstitial deletion of the long arm of chromosome 16 has been identified in identical twins. These patients are strikingly similar phenotypically to previously reported cases of deletion 16q syndrome but differ chromosomally in that their deletion involves the 16q12.2-q13 rather than the 16q21. We propose that the 16q12.2-q13 is the critical region in the production of this rare but distinctive phenotype.     

Interstitial deletion of chromosome 13 involving the region 13q14

Summary A patient with an interstitial deletion 13q14 is described who has decreased erythrocyte esterase D activity and who has not developed a retinoblastoma.     

13q deletion syndrome in an adult mentally retarded patient.

Clinical features of the 13q deletion syndrome are difficult to define and include retinoblastoma, mental and growth retardation, craniofacial abnormalities, brain, gastrointestinal, renal and heart malformations, anal atresia and limb and digit malformations. The critical region for development of major organ systems has been defined in 13q32 between the proximal marker 13S132 and distal marker D13S147. We report a severely mentally retarded male patient with a deletion of the distal part of chromosome 13 (13q32.3-->qter) without major organ malformations.     

A 1.1 Mb deletion in distal 13q deletion syndrome region with congenital heart defect and postaxial polydactyly: Additional support for a CHD locus at distal 13q34 region

13q deletion syndrome is a rare genetic disorder, especially for group 3 deletion (13q33–q34 deletion). Previously we described a patient with congenital heart defect and mental retardation and proposed that a distal 6 Mb region might contain the causative gene of congenital heart defect. Here we present a new patient with congenital heart defects (CHD), hand and foot anomalies and mild mental retardation. We identified a 1.1 Mb deletion at chromosome 13q34 with high resolution SNP-array BeadChips (HumanOmni1-Quad, Illumina, USA). This chromosome region contains ten annotated genes, including GRK1, TFDP1, RASA3 and GAS6. To our knowledge, this represents the smallest 13q34 deletion identified to date. Our study provides additional support that distal 13q34 deletion region might contain key gene(s) responsible for cardiac development.     

A YAC contig encompassing the Treacher Collins syndrome critical region at 5q31.3-32.

Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development the features of which include conductive hearing loss and cleft palate. Previous studies have localized the TCOF1 locus between D5S519 (proximal) and SPARC (distal), a region of 22 centirays as estimated by radiation hybrid mapping. In the current investigation we have created a contig across the TCOF1 critical region, using YAC clones. Isolation of a novel short tandem repeat polymorphism corresponding to the end of one of the YACs has allowed us to reduce the size of the critical region to approximately 840 kb, which has been covered with three nonchimeric YACs. Restriction mapping has revealed that the region contains a high density of clustered rare-cutter restriction sites, suggesting that it may contain a number of different genes. The results of the present investigation have further allowed us to confirm that the RPS14 locus lies proximal to the critical region and can thereby be excluded from a role in the pathogenesis of TCOF1, while ANX6 lies within the TCOF1 critical region and remains a potential candidate for the mutated gene.     

Molecular definition of the smallest region of deletion overlap in the Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS), associated with a deletion of chromosome 4p, is characterized by mental and growth retardation and typical facial dysmorphism. A girl with clinical features of WHS was found to carry a subtle deletion of chromosome 4p. Initially suggested by high-resolution chromosome analysis, her deletion was confirmed by fluorescence in situ hybridization (FISH) with cosmid probes, E13 and Y2, of D4S113. To delineate this 4p deletion, we performed a series of FISH and pulsed-field gel electrophoresis analyses by using probes from 4p16.3. A deletion of approximately 2.5 Mb with the breakpoint at approximately 80 kb distal to D4S43 was defined in this patient and appears to be the smallest WHS deletion so far identified. To further refine the WHS critical region, we have studied three unrelated patients with presumptive 4p deletions, two resulting from unbalanced segregations of parental chromosomal translocations and one resulting from an apparently de novo unbalanced translocation. Larger deletions were identified in two patients with WHS. One patient who did not clinically present with WHS had a smaller deletion that thus eliminates the distal 100-300 kb from the telomere as being part of the WHS region. This study has localized the WHS region to approximately 2 Mb between D4S43 and D4S142.     

An insertion/deletion polymorphism at the D15S63 locus in the critical Prader-Willi syndrome region in 15q11-13

The probe YR9AB detects a two-allele insertion/ deletion polymorphism at the D15S63 locus.     

Molecular definition of the shortest region of deletion overlap in the Langer-Giedion syndrome

The Langer-Giedion syndrome (LGS), which is characterized by craniofacial dysmorphism and skeletal abnormalities, is caused by a genetic defect in 8q24.1. We have used 13 anonymous DNA markers from an 8q24.1-specific microdissection library, as well as c-myc and thyroglobulin gene probes, to map the deletion breakpoints in 16 patients with LGS. Twelve patients had a cytogenetically visible deletion, two patients had an apparently balanced translocation, and two patients had an apparently normal karyotype. In all cases except one translocation patient, loss of genetic material was detected. The DNA markers fall into 10 deletion intervals. Clone L48 (D8S51) defines the shortest region of deletion overlap (SRO), which is estimated to be less than 2 Mbp. Three clones--p17-2.3 EE (D8S43), L24 (D8S45), and L40 (D8S49) - which flank the SRO recognize evolutionarily conserved sequences.     

Phenotypical characterization of 13q deletion syndrome: Report of two cases

Patients with 13q deletion syndrome are characterized with different phenotypical features depending on the size and location of the deleted region on chromosome 13. These patients fall into three groups: In Group 1, deleted region is in the proximal and does not extend into q32; in Group 2, deleted region involves proximal to the q32 and in Group 3 q33-q34 is deleted. We present two cases with 13q syndrome with two different deleted region and different severity on clinical features: One case with interstitial deletion belongs to the Group 1 with mild mental retardation and minor malformations and the other case with terminal deletion belongs to Group 3 with moderate to severe mental retardation and major malformations.     

New deletion syndrome: 1q43.

A male infant showed dysmorphology of the head and face, neck, extremities, and genitalia, as well as growth and mental retardation. His G-banded karyotype was 46,XY,--1+der(1),t(1;16)(q43;q24)mat. Combined with five previously reported cases involving similar terminal deletions beginning at 1q42 or 43, we show that the homology of phenotypic characteristics permits identification of a new deletion syndrome, the first involving chromosome 1.     

Repositioning the hereditary paraganglioma critical region on chromosome band 11q23

Hereditary paragangliomas (PGL, glomus tumors, MIM no.168000) are mostly benign, slow-growing tumors of the head and neck region. The gene (or genes) affecting risk to PGL are subject to genomic imprinting: children of affected fathers exhibit an autosomal dominant pattern of disease inheritance, whereas children of affected mothers rarely if ever develop the disease through maternal transmission. We previously confined the disease gene to an approximately 6 Mb critical region on chromosome band 11q23 (PGL1). Based on haplotype analysis of an extended Dutch pedigree, a 2 Mb sub-region between D11S938 and D11S1885 was proposed as the PGL1 critical interval. In this study, we excluded this interval by analysis of two new single tandem repeat polymorphisms (STRP) contained therein. Instead, we predicted a non-overlapping, more proximal 2 Mb critical interval between D11S1647 and D11S897, and evaluated this new region using nine STRP (D11S1986, five new, closely-linked STRP, D11S1347, D11S3178, and D11S1987). Consistent with our prediction, we observed substantial haplotype-sharing within the Dutch pedigree. We also analyzed four new American PGL families. A recombination event detected in one family further defined D11S1347 as the new telomeric border. We observed significant haplotype-sharing within this new interval among three unrelated American PGL families, strongly suggesting that they originated from a common ancestor. Thus, we confined PGL1 to an approximately 1.5 Mb region between D11S1986 and D11S1347, and showed identity-by-descent sharing for a group of American PGL families. Received: 2 November 1998 / Accepted: 21 December 1998     

Lethal polymalformative syndrome with 13q deletion secondary to a maternal X; 13 translocation

The authors report the case of a newborn full term delivered by cesarean section for evolutive hydrocephalus, in the last month of pregnancy. This hydrocephalus was confirmed by echography after birth. This also having ambiguous genitalia and atresia ani, he died a few hours later. No evidence of infectious or toxic embryofetopathy was found out as an etiologic factor, but the karyotype of the baby showed a 13 q deletion and that of the mother a non reciprocal Xqter; 13q31.3 translocation. The study of inactivation of X indicated that the inactivated X chromosome in each cell was normal. On this occasion, the authors try to bring together the main points of "13q-syndrome" and discuss on the practical approach of antenatal diagnosis which they could propose to the couple.     

Isolation of genes from the rhabdoid tumor deletion region in chromosome band 22q11.2

We employed exon trapping and large-scale genomic sequence analysis of two bacterial artificial chromosome clones to isolate genes from the region between the IGLC and BCR in chromosome 22q11.2. At the time these studies were initiated, one previously identified gene, GNAZ, was known to map to this region. Two genes, RTDR1 and RAB36, were cloned from this portion of 22q11, which is heterozygously or homozygously deleted in pediatric rhabdoid tumors of the brain, kidney and soft tissues. RTDR1 is a novel gene with a slight homology to a yeast vacuolar protein. RAB36 is a member of the Rab family of proteins. A series of primary rhabdoid tumors with chromosome 22q11 deletions were screened for mutations in the coding sequences of RTDR1, GNAZ and RAB36, but did not demonstrate any disease-specific alterations. Recently, INI1, which maps to the distal portion of the deletion region in 22q11, was identified as the candidate rhabdoid tumor suppressor gene. Further studies of RTDR1 and RAB36 are required to determine whether their absence contributes to the progression of rhabdoid tumors. Alternatively, these genes may be candidates for other diseases that map to human chromosome 22.     

Physical mapping of the human ATX1 homologue (HAH1) to the critical region of the 5q- syndrome within 5q32, and immediately adjacent to the SPARC gene

The 5q- syndrome is a myelodysplastic syndrome with the 5q deletion as the sole karyotypic abnormality. The human ATX1 homologue (HAH1), encodes a copper-binding protein with a role in antioxidant defence. We have mapped this gene to the 3 Mb critical region of gene loss of the 5q- syndrome within 5q32, flanked by the genes for ADRB2 and IL12B, using gene dosage analysis. Fine physical mapping of the HAH1 gene within this genomic interval was then performed by screening YAC and BAC contigs spanning the critical region of the 5q- syndrome using PCR amplification. The HAH1 gene maps immediately adjacent to the SPARC gene at 5q32, and is flanked by the genetic markers D5S1838 and D5S1419. The HAH1 gene is expressed in haematological tissues and plays a role in antioxidant defence. Antioxidant levels are low in most cancers and the importance of antioxidant enzymes in cancer genesis is well recognised. Genomic localisation, function and expression would suggest that the HAH1 gene represents a candidate gene for the 5q-syndrome.     

The 18q- syndrome: analysis of chromosomes by bivariate flow karyotyping and the PCR reveals a successive set of deletion breakpoints within 18q21.2-q22.2.

The 18q- syndrome is one of several terminal deletion disorders that occur in humans. Previous G-banding studies suggest that the loss of a critical band, 18q21.3, results in mental retardation, craniofacial anomalies, and metabolic defects. However, it is difficult to reconcile the consistent loss of a single region with the large variability in clinical phenotype. The purpose of this study was to reassess the extent of chromosomal loss in a cohort of 17 18q- syndrome patients by using fluorescent-activated chromosome sorting, PCR, and FISH. Bivariate flow karyotypes revealed heterogeneity among the deletions; they ranged in size from 9 to 26 Mb. To confirm this heterogeneity at a molecular level, deleted and normal chromosomes 18 of six patients were collected by flow sorting, preamplified by random priming, and assayed for marker content by the PCR. This analysis defined five unique breakpoints among the six patients. We conclude that the terminal deletions in the 18q- syndrome occur over a broad region spanning the interval from 18q21.2 to 18q22.2. Our results suggest that the variability in clinical phenotype may be more representative of a contiguous-gene syndrome with a baseline deficit of 18q22.2-qter than of the loss of a single critical region within 18q21.3.     

FISH-mapping of a 100-kb terminal 22q13 deletion

Both cytogenetically visible and cryptic deletions of the terminal region of chromosome 22q are associated with a clinical phenotype including mental retardation, delay in expressive speech development, hypotonia, normal to accelerated growth and minor facial dysmorphic features. The genes responsible for the development of the phenotype have not yet been identified, but a distal localization is probable, since the cytogenetically visible and the cryptic deletions show a similar pattern of symptoms. We report a 33-year-old woman with a submicroscopic 22q13 deletion, mild mental retardation, speech delay, autistic symptoms and mild facial dysmorphic features. The deletion was mapped by FISH using cosmid probes from terminal 22q13, and the size of the deletion was estimated to be 100 kb. Three genes are affected by the deletion in this patient. ACR and RABL2B are deleted and proSAP2 is disrupted. This observation, together with recently published data, supports the notion that proSAP2 is the most important contributor to the 22q13 deletion phenotype.     

Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome.

Using sequence-tagged sites we have performed deletion mapping of the Y chromosome in sex-reversed female patients with a Y chromosome and gonadoblastoma. The GBY gene (gonadoblastoma locus on the Y chromosome) was sublocalized to a small region near the centromere of the Y chromosome. We estimate the size of the GBY critical region to be approximately 1-2 Mb. Our analysis also indicates that copies of two dispersed Y-linked gene families, TSPY (testis-specific protein, Y-encoded) and YRRM (Y-chromosome RNA recognition motif) are present in all patients and that copies of TSPY but not YRRM fall within the GBY critical region as formally defined by deletion mapping. Two tumor samples showed expression of both genes and in one patient this expression was limited to a unilateral gonadoblastoma but absent in the contralateral streak gonad. Although our results do not directly implicate TSPY or YRRM in the etiology of the tumor, they raise the issue of whether there is one GBY gene in the critical region or possibly multiple GBY loci dispersed on the Y chromosome.