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Alström syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus. The gene for Alström syndrome (ALMS1) has been previously localized to human chromosome 2p13 by homozygosity mapping in two distinct isolated populations - French Acadian and North African. Pair-wise analyses resulted in maximum lod (logarithm of the odds ratio) scores of 3.84 and 2.9, respectively. To confirm these findings, a large linkage study was performed in twelve additional families segregating for Alström syndrome. A maximum two-point lod score of 7.13 (theta = 0.00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9.16 for marker D2S2110 were observed, further supporting linkage to chromosome 2p13. No evidence of genetic heterogeneity was observed in these families. Meiotic recombination events have localized the critical region containing ALMS1 to a 6.1-cM interval flanked by markers D2S327 and D2S286. A fine resolution radiation hybrid map of 31 genes and markers has been constructed.

This group has previously reported the mapping of a novel locus for autosomal dominant retinitis pigmentosa (adRP) in a South African kindred to 17q. Using a new series of microsatellite markers in this study, two-point and multipoint analysis provide evidence for the localization of the disease gene to the 17q22 region. In addition, a second South African adRP family is shown to be linked to this 17q22 locus. Disease-associated haplotypes constructed for both families and multipoint linkage analysis place the gene in the 10-cM interval between D17S1607 and D17S1874. Three candidate genes on 17q were investigated: PDEG, the gamma subunit of rod phosphodiesterase; TIMP2, tissue inhibitor of metalloproteinases-2; and PRKCA, protein kinase C alpha. Recombination events between the adRP locus and: (1) a single-stranded conformation polymorphism in PDEG; and (2) a restriction fragment length polymorphism in TIMP2 provided evidence for the exclusion of these candidate genes as being responsible for adRP in the South African kindred.

The vestibular and ototoxic effects of the aminoglycoside antibiotics (streptomycin, gentamycin, kanamycin, tobramycin, neomycin) are well known; streptomycin, in particular, has been found to cause irreversible, profound, high frequency sensorineural deafness in hypersensitive persons. Aminoglycoside ototoxicity occurs both sporadically and within families and has been associated with a mitochondrial DNA (mtDNA) 1555A to G point mutation in the 12S ribosomal RNA gene. We report on the molecular analysis of a South African family with streptomycin induced sensorineural deafness in which we have found transmission of this same predisposing mutation. It is now possible to identify people who are at risk of hearing loss if treated with aminoglycosides in the future and to counsel them accordingly. In view of the fact that aminoglycoside antibiotics remain in widespread use for the treatment of infections, in particular for tuberculosis, which is currently of epidemic proportions in South Africa, this finding has important implications for the family concerned. In addition, other South African families may potentially be at risk if they carry the same mutation.

Pigment epithelium-derived factor (PEDF), a unique 50 kD neurotrophic protein secreted by fetal Retinal Pigment Epithelial (RPE) cells, has been shown to have neurotrophic affects on human Y-79 retinoblastoma cells in vitro. The gene for PEDF is highly expressed by both human fetal and young adult RPE cells and is down-regulated in senescent but not quiescent RPE cells. The secretion of PEDF and synthesis of its mRNA transcript, which decreases dramatically and specifically in an age-related manner, makes PEDF a very good candidate for any form of late onset retinal or macular degeneration. The cDNA of the human PEDF gene has been mapped to the short arm of chromosome 17 (17p13.1-tery.)1

Item does not contain fulltext This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for approximately 2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder, features of which include a patient anterior fontanelle, a bulging calvarium, hypoplasia or aplasia of the clavicles, a wide public symphysis, dental anomalies, vertebral malformation, and short stature. The Cape Town kindred which is under our genetic management was originally described more than four decades ago and now consists of more than 1000 people. Following reports of rearrangements on chromosomes 6 and 8 in people with CCD, we have carried out linkage analyses between highly information microsatellite dinucleotide repeat markers in the rearranged regions and the disorder in a branch of this South African CCD kindred, consisting of 38 subjects, 18 of whom are affected. Maximum lod scores (at theta = 0.00) of 7.14 (for marker D6S459), 4.32 (TCTE), 4.99 (D6S452), 5.97 (D6S269), and 3.95 (D6S465) confirm linkage of the disorder to the short arm of chromosome 6. Our data indicate that the CCD gene is located within a minimal region of approximately 10 cM flanked by the marker D6S451 distally and D6S466 proximally. This information is vital towards isolating and characterising the gene for CCD, and is being used to construct a physical map of 6p21.1-6p21.3. More importantly, mapping of the locus in the South African kindred of mixed ancestry, in which the "founder" of the disorder was of Chinese origin, suggests that a single locus is responsible for classic CCD.

Retinitis pigmentosa is one of the most common causes of severe visual handicap in middle to late life. Prior to this report, seven loci had previously been mapped for the autosomal dominant form of this disorder (adRP). We now report the identification of a novel adRP locus on chromosome 17q. To map the new locus, we performed linkage analysis with microsatellite markers in a large South African kindred. After exclusion of 13 RP candidate gene loci (including rhodopsin and peripherin-RDS), we obtained significant positive lod scores at zero recombination fraction (theta = 0) for D17S808 (Z = 4.63) and D17S807 (Z = 5.69). Multipoint analysis gave a maximum lod score of 8.28 between these two markers. From haplotype analysis, the disease locus lies in the interval between markers D17S809 and D17S942. Three candidate genes for retinal dystrophies map to this chromosomal region and these genes are currently being investigated for possible involvement with adRP in this family.

The Division of Human Genetics (DHG), Faculty of Health Sciences, University of Cape Town (UCT) - established in 1972 - recently celebrated its 40th anniversary. We review its history, current status and future objectives. Dr Stuart Saunders, former Professor of Medicine and Vice-Chancellor of UCT, played a pivotal role in initiating the DHG. Dr Peter Beighton served as Professor of Human Genetics from 1972 to 1999. In this period, the initial focus was on medical genetics and the development of cytogenetic, biochemical and molecular laboratories, with the help of Prof Jacquie Greenberg. Fourteen clinical and scientific DHG members obtained doctorates; of these, 8 achieved full professorial status. Current Head of the Department, Prof Raj Ramesar, succeeded to the Chair in 1999. Expansion of the molecular laboratories followed. The DHG now has comprehensive programmes for postgraduate scientific training, research and service. Publications during the lifetime of the DHG include more than 540 articles in peer-reviewed medical, genetic and scientific journals, 20 books and contributions to over 40 chapters/editorials in scientific and medical genetic books.

Objectives To assess the clinical utility of ABCR400 microarray testing in patients with ABCA4 -associated retinopathies and to report on possible issues that could arise should genetic results be delivered without validation. Methods One hundred thirty-two probands were genotyped with the microarray. Diagnostic assays were designed to verify all mutations identified in individuals in whom at least 2 causative mutations were found. Mutations were verified in the probands, and wherever possible cosegregation analysis was performed in additional family members. Results Eighty-five of the 132 probands (64.4%) genotyped with the microarray had 2 or more disease-associated mutations identified. Verification of the genotyping, however, resulted in only 80 families being able to benefit from genetic result delivery. The remaining families could not receive results owing to the confounding effect of multiple ABCA4 mutations or the incorrect identification of mutations. Conclusions The ABCR400 microarray is useful for mutation screening; however, raw data cannot be delivered directly to patients. All mutations should be verified and, whenever possible, investigated in other family members. Clinical Relevance Validated ABCR400 results provide an unequivocal molecular diagnosis, allowing family members to be offered diagnostic, predictive, carrier, and prenatal testing. Use of the microarray can inform decision-making and identify candidates for future therapies.

Hearing impairment is a variable manifestation of several heritable conditions in which pigmentation of the skin or eyes is abnormal. Some of these disorders are well recognized although uncommon, while others are virtually private syndromes. Practical issues concerning the major conditions of this type are reviewed in this article on a basis of a survey of 4452 profoundly deaf children attending special schools in Southern Africa, together with investigations in affected families. The Waardenburg syndrome (WS), which is the most common deafness-depigmentation disorder, was present in 121 (2.7%) of the 4452 deaf scholars. Further studies in 7 multigeneration affected families confirmed phenotypic variability and indicated a need for internationally agreed diagnostic criteria. In 4 Cape Town families of mixed ancestry the WS-I gene was linked to the 2q37 locus, but in another large kindred no linkage could be demonstrated. Nonallelic heterogeneity is possible. There is uncertainty concerning possible interrelationship between WS and piebaldism. The phenotypic consistency of a South African family in which 7 persons in 3 generations had gross piebaldism in the absence of disturbance of hearing or involvement of the eyes and periorbital structures is suggestive that this disorder and WS are separate entities. Molecular investigations indicate that the gene for piebaldism in this kindred is not situated at the WS-I locus 2q37. Deafness and hyperpigmentation are present in neurofibromatosis type II (acoustic neuromata) and the multiple lentigines syndrome, while retinal pigmentation is a feature of the Usher syndrome. This latter entity is apparently much less common in Southern Africa than in other parts of the world.

Interfamilial phenotypic variations in Sorsby fundus dystrophy (SFD) have given rise to controversy as to whether SFD constitutes more than 1 nosologic entity. The recent identification of the tissue inhibitor of metalloproteinases-3 (TIMP3) as the gene causing SFD has made it possible to readdress the question of genetic and clinical heterogeneity. In this study, we have extended previous findings on a Ser181Cys founder mutation in SFD families from the British Isles and show that carriers of this mutation residing in Canada, the United States, and South Africa likewise are descendants of the British ancestor. In addition, we have reevaluated the question of variable SFD phenotypes by analyzing the available clinical data on carriers of the Ser181Cys mutation.

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders which are a common cause of genetic blindness. The relative frequencies of the different forms of RP in South Africa, as determined from the register at the DNA banking centre for RP at the Department of Human Genetics, University of Cape Town, are presented and discussed. Of the 125 families analysed, 29 (23%) showed autosomal dominant, 33 (27%) autosomal recessive and 3 (3%) X-linked inheritance. In 10 families the pedigree data were insufficient to allow accurate genetic subtyping and a further 50 patients were sporadic without a family history of RP or other syndromic features which would allow categorization.