Karen Fieggen

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription‐coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late‐onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype–phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web‐based locus‐specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/). Hum Mutat 31:113–126, 2010.

BBS genotype–phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition†

Bardet‐Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal abnormalities, and cognitive impairment for which 15 causative genes have been identified. Here we present the results of a mutational analysis of our multiethnic cohort of 83 families (105 cases); 75.9% of them have their mutations identified including 26 novel changes. Comprehensive phenotyping of these patients demonstrate that the spectrum of clinical features is greater than expected and overlapped with the features of other ciliopathies; specifically Alström and McKusick‐Kauffman syndromes. Hum Mutat 32:1–10, 2011.

Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet–Biedl syndrome patient population

Background Bardet–Biedl syndrome is a pleiotropic disorder with 14 BBS genes identified. BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9 form a complex called the BBSome, which is believed to recruit Rab8GTP to the primary cilium and promote ciliogenesis. The second group, the chaperonin-like proteins BBS6, BBS10, and BBS12, have been defined as a vertebrate-specific branch of the type II chaperonin superfamily. These may play a role in the regulation of BBSome assembly. Methods and results Using sequence analysis, the role of BBS6, 10 and 12 was assessed in the patient population comprising 93 cases from 74 families. Systemic and ocular phenotypes were defined. In the study, chaperonin-like BBS gene mutations accounted for the disease in approximately 36.5% of BBS families. A total of 38 different non-polymorphic exonic sequence variants were identified in 40.5% of BBS families (41.9% cases), of which 26 were novel (68%). Six cases had mutations present in more than one chaperonin-like BBS gene. One case with four mutations in BBS10 had a phenotype of overall greater severity. The phenotypes observed were beyond the classic BBS phenotype as they overlapped with characteristics of MKKS (congenital heart defect, vaginal atresia, hydrometrocolpos, cryptorchidism), as well as Alström syndrome (diabetes, hearing loss, liver abnormalities, endocrine anomalies, cardiomyopathy). Conclusions While overlap between the MKKS and BBS phenotypes has previously been reported for cases with BBS6 mutations, we also observed MKKS phenotypes involving BBS10 and BBS12 and Alström-like phenotypes associated with mutations in BBS1, BBS2, BBS6, BBS7, BBS9, BBS10 and BBS12 for the first time.

Aetiology of childhood hearing loss in Cameroon (sub-Saharan Africa)

BACKGROUND Severe hearing loss is a global problem affecting particularly developing countries. There is scarcity of recent published data on the epidemiology of childhood deafness in sub-Saharan Africa. OBJECTIVE To determine the etiological profile of severe childhood deafness in Cameroon. METHODS Prospective cross-sectional study of patients with a severe hearing loss that started before the age of 15 years. Detailed family and medical history was obtained; careful clinical, otological and audiological examinations were performed. RESULTS A total of 582 patients with a severe hearing loss were examined. Prelingual deafness accounted for 75.1% (n = 437), with a mean age at medical diagnosis of 3.3 ± 1.2 years. This late presentation may be explained by limited parental awareness of signs raising suspicion of hearing loss, poor access to health care and the absence of neonatal screening for hearing loss in Cameroon. Identified genetic causes accounted for 14.8% (n = 86), putative environmental causes for 52.6% (n = 306) and unknown causes for 32.6% (n = 190). Amongst Genetic causes, the syndromic hearing loss accounted for 13.1% (n = 12) of cases, the rest being non syndromic (n = 74). Consanguineous families accounted for 5.7% (n = 33) of the whole sample, and 15.1% (n = 13) of genetic cases. No union between deaf parents was observed. CONCLUSION These data highlight the possible predominance of putative environmental causes of childhood deafness in Cameroon, and emphasize the need for improved policies for prevention of infectious diseases and for neonatal hearing screening. However, further molecular analyses and targeted CT scan investigations are required to more accurately gauge the contribution of genetics etiologies.

Beyond the Caster Semenya Controversy: The Case of the Use of Genetics for Gender Testing in Sport

Caster Semenya won the eight-hundred-meter title in the Berlin World Athletics Championships in 2009. Few hours after, Caster was at the center of a harsh contestation on gender. The International Association of Athletics Federations started an investigation, which was not respectful of her privacy. Caster’s case highlights the need for an improvement in the awareness of genetic counseling principles amongst professionals, the public and various stakeholders. We critically examine the historical steps of gender verification in the Olympics, the violation of genetic counseling principles in Caster’s case and outline some reflections on the complexity of the genetics of Disorders of sex development (DSD). Variability in both genotypes and phenotypes in DSD may not allow any etiological or functional classification at this point in time that could permit uncontroversial gender verification for fairer sport participation. We strongly suggest revisiting the pertinence of gender verification, and the process whereby this is done.

The burden of sickle cell disease in Cape Town.

BACKGROUND South Africa has a low incidence of sickle cell disease (SCD). However, its demographics are changing because of immigration from sub-Saharan African countries where SCD is prevalent. OBJECTIVES We aimed to determine the frequency of SCD presenting to the Haematology/Oncology Service at Red Cross War Memorial Childrens Hospital in Cape Town and to measure the associated disease burden. METHODS This was a retrospective cross-sectional study of patients first attending the Haematology Service between January 2001 and June 2010. RESULTS A total of 58 SCD patients were identified, with an annual frequency that increased over the study period by 300 - 400%. Up to 93.1% (n=54) were originally from other African countries, mainly the Democratic Republic of Congo (62.1%, n=36). One patient had sickle D-Punjab genotype, and all the other patients had the homozygous sickle cell anaemia genotype (Hb SS). Their haematological parameters demonstrated a normocytic anaemia with high white cell counts. The mean number of clinic visits per patient per year was 22.2 (range 0 - 64), and the mean number of hospital admissions per patient per year was 1.2 (range 0 - 5). All the patients were on antibiotic prophylaxis. The majority had at least one blood transfusion (65.5%, n=38), and a significant proportion required intravenous analgesia on admission (29.3%, n=17) and hydroxyurea treatment (36.2%, n=21). CONCLUSIONS Over the past 10 years the frequency of SCD has increased considerably, imposing a significant burden and new challenges to the health services in Cape Town.

UCT's contribution to medical genetics in Africa - from the past into the future.

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.

Orthodontic management of achondroplasia in South Africa

It is probable that there are between 500 and 1 000 persons with achondroplasia in South Africa, and it is inevitable that they will seek consultation and care in general and specialised dental practices. In this context, it is relevant that dental and orthodontic management is constrained by practical problems associated with upper airway obstruction and other primary and secondary syndromic components.

No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome.

BackgroundMicrocephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome (MCLMR) is a rare autosomal dominant disorder with variable expressivity. It is characterized by mild-to-severe microcephaly, often associated with intellectual disability, ocular defects and lymphedema. It can be sporadic or inherited. Eighty-seven patients have been described to carry a mutation in KIF11, which encodes a homotetrameric motor kinesin, EG5.MethodsWe tested 23 unreported MCLMR index patients for KIF11. We also reviewed the clinical phenotypes of all our patients as well as of those described in previously published studies.ResultsWe identified 14 mutations, 12 of which are novel. We detected mutations in 12 affected individuals, from 6 out of 6 familial cases, and in 8 out of 17 sporadic patients. Phenotypic evaluation of patients (our 26 + 61 earlier published = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases.ConclusionsAll inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations. It is possible that mosaic KIF11 mutations cause the remainder of sporadic cases, which the methods employed here were not designed to detect. On the other hand, some of them might have another mimicking disorder and genetic defect, as microcephaly is highly heterogeneous. In aggregate, KIF11 mutations likely cause the majority, if not all, of MCLMR.