Characterization of an inversion duplication of the short arm of chromosome 8 by fluorescent in situ hybridization

A de novo chromosome aberration in a woman with severe mental retardation and minor anomalies has been characterized cytogenetically. The patient's karyotype was described as 46, XX, inv dup (8)(p12 → p23.1). Previous Southern blot dosage studies with the marker locus D8S7 demonstrated that the patient was monosomic for this locus, suggesting that the rearrangement generated a duplication-deficiency chromosome. We have reinvestigated this patient using fluorescent in situ hybridization with chromosome 8 cosmids and an Alu-PCR product specific for 8p. These studies have confirmed directly that the duplicated chromosome also has undergone deletion. © 1992 Wiley-Liss, Inc.     

Mapping of genes predisposing to idiopathic generalized epilepsy

Idiopathic generalized epilepsy (IGE) is characterized by recurringgeneralized seizures in the absence of detectable brain lesionsand/or metabolic abnormalities. Twin and family studies suggestthat genetic factors play a key part in IGE. A multilocus modelappears to best fit the observed inheritance patterns. Mappingof IGE-related genes has been previously attempted using parametricmethods, with conflicting results. in particular, recent evidenceargues both for and against a chromosome 6p locus (EJM1) forjuvenile myocionic epilepsy, a subtype of IGE. We have approachedthe problem of mapping IGE loci using non-parametric methods,which have recently been successful for other complex diseases.No evidence for linkage to chromosome 6p was obtained. However,we obtained evidence for involvement of a locus at chromosome8q24, close to the marker D8S256. The same 8q24 region was previouslyimplicated in families with benign neonatal familial convulsions(BNFC), a generalized epilepsy syndrome that is inherited asa simple dominant mendelian trait. There is an apparent conservedsyntenic group of genes in human 8q24 and a region of mousechromosome 15, which harbors the stargazer (stg) locus. Homozygousmutant mice at the stg locus show a form of generalized epilepsythat resembles human absence epilepsy. Our findings may haveimplications for a locus on 8q24 predisposing to IGE.     

Genetic heterogeneity of gingival fibromatosis on chromosome 2p

Gingival fibromatosis (GF) occurs in several genetic forms as a simple Mendelian trait, in malformation syndromes, and in some chromosomal disorders. Specific genes responsible for GF have not been identified. An autosomal dominant form of hereditary gingival fibromatosis (HGF, MIM 135300) was recently mapped to chromosome 2p21 in a large Brazilian family and there was an earlier report of GF in a boy with a cytogenetic duplication involving 2p13-->p21. We thus hypothesised that a common gene locus may be responsible for GF in both the Brazilian family and the boy with the chromosome 2p duplication. We performed additional genetic linkage studies on the Brazilian family and molecular cytogenetic studies on the patient with the cytogenetic duplication to correlate more precisely the genetic interval of the HGF phenotype with the duplicated 2p interval. Additional linkage analysis of new family members resulted in refinement of the candidate region for HGF to an 8 Mb region. Molecular cytogenetic analysis of the 2p13-->p21 duplication associated with GF showed that the duplicated region was proximal to the candidate interval for HGF. Thus, our results support the presence of two different gene loci on chromosome 2p that are involved in GF.     

Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest

Febrile convulsions are a common form of childhood seizure. It is estimated that between 2 and 5% of children will have a febrile convulsion before the age of 5. It has long been recognized that there is a significant genetic component for susceptibility to this type of seizure. Wallace, Berkovic and co-workers recently reported linkage of a putative autosomal dominant febrile convulsion gene to chromosome 8q13-21. We report here another autosomal dominant febrile convulsion locus on chromosome 19p. Linkage analysis in this large multi- generational family gave a maximum pairwise lod score of 4.52 with marker Mfd120 at locus D19S177. Linkage to the chromosome 8 locus was excluded in this family. Haplotype analysis using both affected and unaffected family members indicates that this febrile convulsion gene, which we call FEB2 , can be localized to an 11.7 cM, 1-2 Mb section of chromosome 19p13.3, between loci D19S591 and D19S395.      

Genetic association studies of schizophrenia using the 8p21-22 genes: prepronociceptin (PNOC), neuronal nicotinic cholinergic receptor alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1).

Schizophrenia is a common, genetically heterogeneous disorder with a lifetime prevalence of approximately 1% in the general population. Linkage studies of affected families have now strongly implicated a susceptibility locus on chromosome 8p21-22. Tests of allelic association with markers on 8p21-22 should be able to localise any quantitative trait nucleotides (QTN's) or susceptibility mutations to within a few hundred kilobases. Three brain expressed candidate susceptibility genes, prepronociceptin (PNOC), neuronal cholinergic receptor, nicotinic, alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1) have been mapped to chromosome 8p21-22. A case-control, allelic association study was performed using a novel highly polymorphic dinucleotide repeat, D8S2611 near the PNOC gene, two previously characterised dinucleotide repeats, D8S131 and D8S131P at the CHRNA2 locus and an RFLP at the 3'UTR of the arylamine N-acetyltransferase 1 (NAT1) gene. No differences were found in allele frequencies between the patient and control groups. DNA variations or mutations at or near the three genes under study are unlikely to increase susceptibility to schizophrenia in our population sample.     

Dual-probe fluorescence in situ hybridization assay for detecting deletions associated with VCFS/DiGeorge syndrome I and DiGeorge syndrome II loci

Over 90% of patients with DiGeorge syndrome (DGS) or velocardiofacial syndrome (VCFS) have a microdeletion at 22q11.2. Given that these deletions are difficult to visualize at the light microscopic level, fluorescence in situ hybridization (FISH) has been instrumental in the diagnosis of this disorder. Deletions on the short arm of chromosome 10 are also associated with a DGS-like phenotype. Since deletions at 22q11.2 and at 10p13p14 result in similar findings, we have developed a dual-probe FISH assay for screening samples referred for DGS or VCFS in the clinical laboratory. This assay includes two test probes for the loci, DGSI at 22q11.2 and DGSII at 10p13p14, and centromeric probes for chromosomes 10 and 22. Of 412 patients tested, 54 were found to be deleted for the DGSI locus on chromosome 22 (13%), and a single patient was found deleted for the DGSII locus on chromosome 10 (0. 24%). The patient with the 10p deletion had facial features consistent with VCFS, plus sensorineural hearing loss, and renal anomalies. Cytogenetic analysis showed a large deletion of 10p [46, XX,del(10)(p12.2p14)] and FISH using a 10p telomere region-specific probe confirmed the interstitial nature of the deletion. Analysis for the DGSI and the DGSII loci suggests that the deletion of the DGSII locus on chromosome 10 may be 50 times less frequent than the deletion of DGSI on chromosome 22. The incidence of deletions at 22q11.2 has been estimated to be 1 in 4000 newborns; therefore, the deletion at 10p13p14 may be estimated to occur in 1 in 200,000 live births.     

FISH studies in a patient with sporadic aniridia and t(7;11) (q31.2;p13).

A 2 year old female presenting with bilateral sporadic aniridia was found to have an apparently balanced reciprocal translocation with a chromosome 11 breakpoint within band p13. Fluorescence in situ hybridisation (FISH) studies with distal 11p13 specific cosmids showed that the chromosome 11 breakpoint lay between the aniridia (PAX6) locus and a region approximately 100 kb distal to PAX6 defined by the cosmid FO2121. Although this patient did not have a detectable deletion within PAX6, her aniridia may have resulted from a disruption of the distal chromatin domain containing either enhancers or regulators for PAX6. This case may therefore be another example of aniridia caused by a position effect as recently described in two familial aniridia patients in which the phenotype cosegregated with chromosome abnormalities with 11p13 breakpoints.     

Search for genes involved in Joubert syndrome: evidence that one or more major loci are yet to be identified and exclusion of candidate genes EN1, EN2, FGF8, and BARHL1.

Joubert syndrome (JS) is a rare autosomal recessive malformation syndrome involving agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations. JS is further characterized by hypotonia, developmental delay, intermittent hyperpnea, and abnormal eye movements. The biochemical and molecular basis of JS remains unknown, although several genes that are crucial in the development of the cerebellum have been proposed as attractive candidate genes. JS is clinically heterogeneous; this, together with previous linkage analyses, suggests that there may also be genetic heterogeneity. A locus for JS was previously identified on chromosome 9q34 by linkage analysis in a consanguineous family of Arabian origin. A putative second JS locus was recently suggested when a deletion on chromosome 17p11.2 was observed in a patient with Smith-Magenis syndrome and JS phenotype. We have investigated a cohort of apparently unrelated North American JS pedigrees for association with the loci on chromosomes 9q34 and 17p11.2 and excluded them in all cases where data were informative. Analysis of an additional 21 unrelated JS patients showed no evidence of homozygosity at the 9q34 and 17p11.2 loci that would suggest inheritance of founder JS mutation(s) or unreported consanguinity. Together, these data suggest that one or more major loci for JS remain to be identified. Consequently, we undertook mutation analysis of several functional candidate genes, EN1, EN2, and FGF8, in a total of 26 unrelated JS patients. Our data suggest that all of these genes may be excluded from a direct pathogenic role in JS. The BARHL1 gene, which localizes to chromosome 9q34 and has previously been proposed as a strong positional candidate gene for JS, was also investigated and excluded from involvement in JS that is linked to chromosome 9q34.     

Linkage disequilibrium analyses in the Costa Rican population suggests discrete gene loci for schizophrenia at 8p23.1 and 8q13.3

Linkage studies using multiplex families have repeatedly implicated chromosome 8 as involved in schizophrenia etiology. The reported areas of linkage, however, span a wide chromosomal region. The present study used the founder population of the Central Valley of Costa Rica and phenotyping strategies alternative to DSM-IV classifications in attempts to further delimitate the areas on chromosome 8 that may harbor schizophrenia susceptibility genes. A linkage disequilibrium screen of chromosome 8 was performed using family trios of individuals with a history of psychosis. Four discrete regions showing evidence of association (nominal P values less than 0.05) to the phenotype of schizophrenia were identified: 8p23.1, 8p21.3, 8q13.3 and 8q24.3. The region of 8p23.1 precisely overlaps a region showing strong evidence of linkage disequilibrium for severe bipolar disorder in Costa Rica. The same chromosomal regions were identified when the broader phenotype definition of all individuals with functional psychosis was used for analyses. Stratification of the psychotic sample by history of mania suggests that the 8q13.3 locus may be preferentially associated with non-manic psychosis. These results may be helpful in targeting specific areas to be analyzed in association-based or linkage disequilibrium-based studies, for researchers who have found evidence of linkage to schizophrenia on chromosome 8 within their previous studies.     

The involvement of 6p in melanoma

Karyotype analysis of first passage cells from a melanoma, occurring in a patient with a giant congenital nevus, revealed monosomy of chromosomes #6 and #11, and trisomy of chromosomes #8 and #22. Five marker chromosomes were present, including two ring chromosomes. The origin of three of the marker chromosomes was determined, and all were found to contain the region 6p21.1–6p23. The ring chromosomes were also thought to contain this region, to which the major histocompatibility locus has been mapped. The significance of these findings is discussed in the light of recent reports of chromosome studies of melanoma cells.     

Dual‐probe fluorescence in situ hybridization assay for detecting deletions associated with VCFS/DiGeorge syndrome I and DiGeorge syndrome II loci

Over 90% of patients with DiGeorge syndrome (DGS) or velocardiofacial syndrome (VCFS) have a microdeletion at 22q11.2. Given that these deletions are difficult to visualize at the light microscopic level, fluorescence in situ hybridization (FISH) has been instrumental in the diagnosis of this disorder. Deletions on the short arm of chromosome 10 are also associated with a DGS‐like phenotype. Since deletions at 22q11.2 and at 10p13p14 result in similar findings, we have developed a dual‐probe FISH assay for screening samples referred for DGS or VCFS in the clinical laboratory. This assay includes two test probes for the loci, DGSI at 22q11.2 and DGSII at 10p13p14, and centromeric probes for chromosomes 10 and 22. Of 412 patients tested, 54 were found to be deleted for the DGSI locus on chromosome 22 (13%), and a single patient was found deleted for the DGSII locus on chromosome 10 (0.24%). The patient with the 10p deletion had facial features consistent with VCFS, plus sensorineural hearing loss, and renal anomalies. Cytogenetic analysis showed a large deletion of 10p [46,XX,del(10)(p12.2p14)] and FISH using a 10p telomere region‐specific probe confirmed the interstitial nature of the deletion. Analysis for the DGSI and the DGSII loci suggests that the deletion of the DGSII locus on chromosome 10 may be 50 times less frequent than the deletion of DGSI on chromosome 22. The incidence of deletions at 22q11.2 has been estimated to be 1 in 4000 newborns; therefore, the deletion at 10p13p14 may be estimated to occur in 1 in 200,000 live births. Am. J. Med. Genet. 91:313–317, 2000. © 2000 Wiley‐Liss, Inc.     

Deficiency of chromosome 8p21.1----8pter: case report and review of the literature

The clinical manifestations and cytogenetic changes of a patient with 46,XY,del(8)(p21.1) are compared with those of nine other patients with a similar deficiency of chromosome 8. Patients with this chromosome anomaly have a syndrome of postnatal growth retardation, microcephaly, mental retardation, epicanthal folds, posteriorly angulated and malformed ears, short neck, relatively increased internipple distance, and congenital heart defect. A short and broad nose, a wide and flat nasal bridge, and a small jaw are observed in young patients but tend to become less apparent with increasing age. In most instances, the syndrome has been associated with a de novo chromosome abnormality. Levels of glutathione reductase in our patient were normal-a finding consistent with localization of the gene coding for this enzyme to the proximal part of band 8p21.1 if gene dosage studies are reliable.     

Deficiency of chromosome 8p21.1→8pter: Case report and review of the literature

The clinical manifestations and cytogenetic changes of a patient with 46,XY,del(8)(p21.1) are compared with those of nine other patients with a similar deficiency of chromosome 8. Patients with this chromosome anomaly have a syndrome of postnatal growth retardation, microcephaly, mental retardation, epicanthal folds, posteriorly angulated and malformed ears, short neck, relatively increased internipple distance, and congenital heart defect. A short and broad nose, a wide and flat nasal bridge, and a small jaw are observed in young patients but tend to become less apparent with increasing age. In most instances, the syndrome has been associated with a de novo chromosome abnormality. Levels of glutathione reductase in our patient were normal—a finding consistent with localization of the gene coding for this enzyme to the proximal part of band 8p21.1 if gene dosage studies are reliable.     

The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature

Background

Previous studies focusing on candidate genes and chromosomal regions identified several copy number variations (CNVs) associated with increased risk of autism or autism spectrum disorders (ASD).

Case Presentation

We describe a 17-year-old girl with autism, severe mental retardation, epilepsy, and partial 9p duplication syndrome features in whom GTG-banded chromosome analysis revealed a female karyotype with a marker chromosome in 69% of analyzed metaphases. Array CGH analysis showed that the marker chromosome originated from 9p24.3 to 9p13.1 with a gain of 38.9 Mb. This mosaic 9p duplication was detected only in the proband and not in the parents, her four unaffected siblings, or 258 ethnic controls. Apart from the marker chromosome, no other copy number variations (CNVs) were detected in the patient or her family. Detailed analysis of the duplicated region revealed: i) an area extending from 9p22.3 to 9p22.2 that was previously identified as a critical region for the 9p duplication syndrome; ii) a region extending from 9p22.1 to 9p13.1 that was previously reported to be duplicated in a normal individual; and iii) a potential ASD locus extending from 9p24.3 to 9p23. The ASD candidate locus contained 34 genes that may contribute to the autistic features in this patient.

Conclusion

We identified a potential ASD locus (9p24.3 to 9p23) that may encompass gene(s) contributing to autism or ASD.     

Inverted tandem duplication generates a duplication deficiency of chromosome 8p

An adult female with sever mental retardation and dysmorphic features is described. A de novo chromosomal aberration involving 8p was found. The karyotype was 46, XX, inv dup (8) (p12----p23.1). Dosage studies with the DNA probe D8S7, which is located at 8p23----8pter, showed that the patient was monosomic for this marker. Thus the de novo rearrangement generated a duplication-deficiency chromosome. The possible mechanisms of formation of this abnormal chromosome are discussed.     

Absence of linkage of apparently single gene mediated ADHD with the human syntenic region of the mouse mutant Coloboma

Attention deficit disorder (ADHD) is a complex biobehavioral phenotype which affects up to 8% of the general population and often impairs social, academic, and job performance. Its origins are heterogeneous, but a significant genetic component is suggested by family and twin studies. The murine strain, coloboma, displays a spontaneously hyperactive phenotype that is responsive to dextroamphetamine and has been proposed as a genetic model for ADHD. Coloboma is a semi-dominant mutation that is caused by a hemizygous deletion of the SNAP-25 and other genes on mouse chromosome 2q. To test the possibility that the human homolog of the mouse coloboma gene(s) could be responsible for ADHD, we have carried out linkage studies with polymorphic markers in the region syntenic to coloboma (20p11–p12). Five families in which the pattern of inheritance of ADHD appears to be autosomal dominant were studied. Segregation analysis of the traits studied suggested that the best fitting model was a sex-influenced, single gene, Mendelian pattern. Several genetic models were evaluated based on estimates of penetrance, phenocopy rate, and allele frequency derived from our patient population and those of other investigators. No significant linkage was detected between the disease locus and markers spanning this chromosome 20 interval. © 1995 Wiley-Liss, Inc.     

Kallmann syndrome in a patient with congenital spherocytosis and an interstitial 8p11.2 deletion

We describe the hitherto smallest interstitial 8p11.2 deletion in a patient with congenital spherocytosis, dysmorphic features, and growth delay in association with hypogonadotropic hypogonadism and anosmia. The latter features are characteristic for Kallmann syndrome. In contrast to the previously reported patients with 8p deletions, the present patient showed normal intelligence. Congenital spherocytosis is one of the most common hereditary hemolytic anemias. One of the three loci for congenital spherocytosis was assigned to chromosome 8p (located between 8p11.1 and 8p21) and mutations in or loss of the ankyrin-1 gene (ANK1) were identified. Molecular analysis confirmed the de novo loss of ANK1 in our patient. Kallmann syndrome, which is characterized by hypogonadotropic hypogonadism and anosmia, can be X-linked, autosomal dominant, or autosomal recessive. So far only the X-linked KAL1 gene has been identified. The present finding suggests an autosomal locus for Kallmann syndrome at 8p11.2. The simultaneous occurrence of congenital spherocytosis, Kallmann syndrome phenotype, dysmorphic features, and growth delay in this patient points to a new contiguous gene syndrome.     

Rubinstein-Taybi syndrome with de novo reciprocal translocation t(2;16) (p13.3; p13.3)

We describe a girl with typical Rubinstein-Taybi syndrome with apparently balanced reciprocal translocation between chromosome 2 and 16. The patient has a condition characterized by mental retardation, typical facial manifestations, broad thumbs and first toes. Cytogenetic studies of the patient showed a reciprocal translocation without visible deletion, karyotype: 46, XX, t(2;16) (p13.3; p13.3). Her parents had normal chromosomes. These results suggest that the locus of the gene for the Rubinstein-Taybi syndrome may be situated at 2p13.3 or 16p13.3.     

Rubinstein-Taybi syndrome with de novo reciprocal translocation t(2;16)(p13.3;p13.3)

We describe a girl with typical Rubinstein-Taybi syndrome with apparently balanced reciprocal translocation between chromosome 2 and 16. The patient has a condition characterized by mental retardation, typical facial manifestations, broad thumbs and first toes. Cytogenetic studies of the patient showed a reciprocal translocation without visible deletion, karyotype: 46,XX, t(2;16)(p13.3;p13.3). Her parents had normal chromosomes. These results suggest that the locus of the gene for the Rubinstein-Taybi syndrome may be situated at 2p13.3 or 16p13.3.