Spondyloepiphyseal dysplasia in a Cape Town family: linkage with the gene for type II collagen (COL2A1).

A moderately severe form of autosomal dominant (AD) spondyloepiphyseal dysplasia (SED) has been documented in 14 individuals in 3 generations of a family in Cape Town, South Africa. Affected persons had a short trunk; radiographic investigations indicated that skeletal involvement was worst in the hips and spine. Linkage studies with restriction fragment length polymorphisms (RFLPs) associated with the COL2A1 gene and the phenotype yielded a maximal LOD score of 4.51 at theta = 0.00. This result suggests that the structural locus for type II collagen is primarily involved in the pathogenesis of this form of SED.     

Six novel mutations of the RUNX2 gene in Italian patients with cleidocranial dysplasia

We report clinical and molecular findings in 14 patients with cleidocranial dysplasia (CCD), a well defined skeletal disorder with characteristic clinical findings and autosomal dominant inheritance. We identified ten heterozygous base changes in the RUNX2 gene, including six novel mutations [c.522insA, c.389G>A (W130X), c.662T>G (V221G), IVS2+T>A, c.1111_1129del19, and c.873_874delCA]. We did not establish a clear correlation between clinical features and genotype, the phenotypes of all patients analyzed falling within the range of variation described in CCD without an effect related to the length of the predicted protein. In two cases, however, a limb-girdle myopathy affecting the shoulder muscles was also identified. Our data add new variants to the repertoire of RUNX2 mutations in CCD.     

Inherited anaemias in the Greek community of Cape Town.

Cape Town has a Greek community of about 5000, of whom approximately 75% originate from the island of Lesbos. In a survey of inherited haematological conditions in this population, 250 unrelated volunteers were investigated. The prevalence of heterozygous beta-thalassaemia was found to be 6.4%, with a gene frequency of 0.033. G6PD deficiency was detected in 10 males and it can be estimated that the prevalence in the male members of this population is 6.7%, with a gene frequency of 0.067. Hereditary spherocytosis was found in three respondents and this represents a prevalence of 1.2%, with a gene frequency of 0.006. One subject was heterozygous for the sickle cell trait (HbS) and another volunteer had haemoglobin Lepore, which had already been diagnosed in Greece. Our findings with respect to beta-thalassaemia and G6PD deficiency are similar to those reported from regions in Greece where malaria is not highly endemic.     

Deletions of the RUNX2 gene are present in about 10% of individuals with cleidocranial dysplasia

Cleidocranial Dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies, and short stature. Hand malformations are also common. Mutations in RUNX2 cause CCD, but are not identified in all CCD patients. In this study we screened 135 unrelated patients with the clinical diagnosis of CCD for RUNX2 mutations by sequencing analysis and demonstrated 82 mutations 48 of which were novel. By quantitative PCR we screened the remaining 53 unrelated patients for copy number variations in the RUNX2 gene. Heterozygous deletions of different size were identified in 13 patients, and a duplication of the exons 1 to 4 of the RUNX2 gene in one patient. Thus, heterozygous deletions or duplications affecting the RUNX2 gene may be present in about 10% of all patients with a clinical diagnosis of CCD which corresponds to 26% of individuals with normal results on sequencing analysis. We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation. © 2010 Wiley‐Liss, Inc.     

Ectrodactyly (split-hand/split-foot) and ectodermal dysplasia with normal lip and palate in a four-generation kindred

Five members of a four-generation Mauritian family with ectrodactyly (split-hand/split-foot deformity) and ectodermal dysplasia but without clefting of the lip or palate have been investigated. The ectrodactyly ranged from virtual normality to severe tetramelic deficiencies. The ectodermal dysplasia manifested as hypotrichosis and abnormal dentition. Distinction is drawn between this autosomal dominant condition and the classical EEC syndrome; independent syndromic status is proposed.     

Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus

Neurofibromatosis type 2 (NF2) is an autosomal dominant diseasewhich predisposes to the development of schwannomas, meningiomas,ependymomas, and juvenile cataracts. The NF2 gene (NF2) hasrecently been isolated and maps to chromosome 22q12 betweenthe loci D22S212 and D22S32. Deletion studies in sporadic andNF2 associated schwannomas and meningiomas, and the presenceof Inactivating mutations in NF2 in patients suggest that itacts as a tumor suppressor gene. A candidate meningioma gene(MEN) has also been isolated from the same Interval. A new highlypolymorphic (CA)n marker, D22S268, which maps very near to NF2,has allowed us to Identify a kindred with three living affectedindividuals, where the disease Is presumably caused by a largegermline deletion. Fluorescence ^{in situ} hybridization and pulsedfield gel electrophoresis confirm the presence of a 700kb deletionwhich includes the neurofllament heavy chain subunit gene locus(NEFH), D22S268, NF2 and the putative MEN gene. The absenceof meningiomas In this pedigree raises doubts as to the existenceof a separate MEN locus In this region. These results supportthe hypothesis that NF2 results from the Inactivation of a tumorsuppressor gene on chromosome 22q.     

Location of the retinoblastoma susceptibility gene(s) and the human esterase D locus.

Retinoblastoma occurs with increased frequency in children born with a deletion of the long arm of chromosome 13. Recent reviews have noted that the region 13q14 is consistently deleted in documented cases. Prometaphase and late prophase banding allowed Yunis and Ramsay to determine that a deletion in one patient included the sub-bands q14 . 12, q14 . 13, and q14 . 2, and a portion of q14 . 11 and q14 . 3. We report the results of similar cytogenetic techniques applied in the case of a 26 month old Caucasian female with unilateral retinoblastoma, moderate developmental delay, and subtle dysmorphology. Prometaphase banding of cultured skin fibroblasts revealed the karyotype: mos46,XX/46,XX,del(13)(q13 . 1q14 . 11). Only the sub-band q14 . 11 is deleted in both our patient and that of Yunis and Ramsay. The results are consistent with the localisation of the retinoblastoma susceptibility gene(s) in the sub-band 13q14 . 11. Electrophoretic analysis and activity assays of red blood cell esterase D are consistent with hemizygous expression of that marker in our proband. Comparison with published esterase D analyses in families with retinoblastoma permits the assignment of the esterase D locus to that same sub-band, 13q14 . 11.     

Autosomal dominant retinitis pigmentosa (adRP): exclusion of a gene from three mapped loci provides evidence for the existence of a fourth locus.

Retinitis Pigmentosa (RP) is a group of inherited retinopathies which affect approximately 1 in 4,000 individuals. The disorder can be classified on the basis of inheritance; dominant, recessive and X-linked forms have been well documented. The existence of genetic heterogeneity within autosomal dominant RP (adRP) had been previously demonstrated. As a result of extensive linkage studies in 2 large Irish families and 1 American pedigree three adRP genes have been mapped. adRP genes have been localised to chromosome 3q close to the rod photoreceptor gene, rhodopsin; to chromosome 6p close to another transmembrane photoreceptor gene, peripherin/RDS and to the pericentric region of chromosome 8, although the causative gene in this region has not yet been identified. Here we report the results of a linkage study in a Spanish family, who exhibit an early-onset form of adRP. The adRP gene segregating in this family has been excluded from the three known adRP loci on chromosomes 3q, 6p and 8 using a series of both intragenic microsatellite markers from the rhodopsin and peripherin/RDS genes and markers flanking the three known loci. These results provide definitive evidence for the existence of a fourth adRP locus, further emphasising the genetic heterogeneity that exists within adRP.     

Pendred syndrome: evidence for genetic homogeneity and further refinement of linkage.

Pendred syndrome is the association between congenital sensorineural deafness and goitre. The disorder is characterised by the incomplete discharge of radioiodide from a primed thyroid following perchlorate challenge. However, the molecular basis of the association between hearing loss and a defect in organification of iodide remains unclear. Pendred syndrome is inherited as an autosomal recessive trait and has recently been mapped to 7q31 coincident with the non-syndromic deafness locus DFNB4. To define the critical linkage interval for Pendred syndrome we have studied five kindreds, each with members affected by Pendred syndrome. All families support linkage to the chromosome 7 region, defined by the microsatellite markers D7S501-D7S523. Detailed haplotype analysis refines the Pendred syndrome linkage interval to a region flanked by the marker loci D7S501 and D7S525, separated by a genetic distance estimated to be 2.5 cM. As potential candidate genes have as yet not been mapped to this interval, these data will contribute to a positional cloning approach for the identification of the Pendred syndrome gene.     

Heterogeneity in the gene locus for steroid 21-hydroxylase deficiency.

DNA was analysed from 33 patients with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. In each case Southern blots were prepared from a number of restriction enzyme digests and hybridised with probes for both the 21-hydroxylase and the adjacent fourth component of complement (C4). Evidence for deletion of the active 21-hydroxylase gene (CYP21B) was found in 13 cases and in 10 of these the deletion included the adjacent C4B gene, leading to a hybrid CYP21A/CYP21B gene. Deletion of CYP21B alone was found in one patient, the remaining two cases appearing to have the active gene replaced by the inactive pseudogene. Duplications of the CYP21A-C4B region and deletion of the pseudogene are also described. In a further 12 cases no gross abnormality could be found.     

Thirteen single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase 4 (ADH4) gene locus

The human alcohol dehydrogenase 4 (ADH4) gene encodes the class II ADH4 pi subunit, which contributes to the metabolization of a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Here we report the results of systematic screening for single-nucleotide polymorphisms (SNPs) in the ADH4 gene by means of direct sequencing combined with a polymerase chain reaction method. A total of 16 genetic variations including 13 SNPs were found; 4 in the 5′ flanking region, 4 in the 5′ untranslated region, and 8 within introns. No variation was found in coding, 3′ untranslated, or 3′ flanking regions. Eight of the 13 SNPs were not reported in the NCBI dbSNP database or any previous publications. Our SNP map presented here should provide tools to evaluate the role of ADH4 in complex genetic diseases and a variety of pharmacogenetic effects. Received: September 26, 2001 / Accepted: October 11, 2001     

Evidence for linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families.

Recent studies have suggested that the alpha 7-nicotinic receptor gene (CHRNA7) may play a role in the pathogenesis of schizophrenia. The alpha 7-nicotinic receptor gene (CHRNA7) is involved in P50 auditory sensory gating deficits, and the genomic locus for this gene lies in the chromosome 15q13-14 regions. The human gene is partially duplicated (exons 5-10) with four novel upstream exons. The marker D15S1360 has been shown to be significantly linked with the phenotype of abnormal P50 suppression in schizophrenia families. The marker L76630 is 3 kb in the 3' direction from the last exon of the CHRNA7 gene and is located in the duplicated region. The function of the two L76630 copies is unknown. We genotyped three polymorphic markers D15S1360, D15S165, and L76630 that are localized in a genomic fragment containing the CHRNA7 in 31 Azorean schizophrenia families/trios (including 41 schizophrenia individuals and 97 unaffected families members). An overall analysis utilizing the family-based association test revealed significant linkage disequilibrium between L76630 and schizophrenia (P = 0.0004). Using the extended transmission disequilibrium test and limiting the analysis to one triad per family, transmission disequilibrium of D15S1360 was near significance (P = 0.078). The 15q13 region overlaps with the location of two well-known genomically imprinted disorders: Angelman syndrome and Prader-Willi syndrome. Therefore, we investigated maternal and paternal meioses. We found significant transmission disequilibrium for D15S1360 through paternal transmission (P = 0.0006) in our schizophrenia families. The L76630 marker showed a significant disequilibrium in maternal transmissions (P = 0.028). No parent-of-origin effect was found in D15S165. Overall, our results suggest that the CHRNA7 may play a role in schizophrenia in these families. A parent of origin effect may be present and requires further study.