The Incursion and Spread of Highly Pathogenic Avian Influenza H5N8 Clade 2.3.4.4 Within South Africa.

The report of a mass die-off of white-winged terns (Chlidonias leucopterus) along the shores of Lake Victoria in Uganda in January 2017 was a warning that highly pathogenic avian influenza (HPAI) H5N8 clade 2.3.4.4 had entered the avian populations of the African Rift Valley. In early June 2017, Zimbabwe reported an outbreak of the virus in commercial breeder chickens near Harare, and on June 19, 2017, the first case of HPAI H5N8 was confirmed in a broiler breeder operation near Villiers, Mpumalanga Province, South Africa, representing the first ever notifiable influenza in gallinaceous poultry in South Africa. Forty viruses were isolated from wild birds, backyard hobby fowl, zoo collections, commercial chickens, and commercial ostriches over the course of the outbreak and full genomes were sequenced and compared to determine the epidemiologic events in the introduction and spread of clade 2.3.4.4 H5N8 across the country. We found that multiple virus variants were involved in the primary outbreaks in the north-central regions of South Africa, but that a single variant affected the southernmost regions of the continent. By November 2017 only two of the nine provinces in South Africa remained unaffected, and the layer chicken industry in Western Cape Province was all but decimated. Two distinct variants, suggesting independent introductions, were responsible for the first two index cases and were not directly related to the virus involved in the Zimbabwe outbreak. The role of wild birds in the incursion and spread was demonstrated by shared recent common ancestors with H5N8 viruses from West Africa and earlier South African aquatic bird low pathogenicity avian influenza viruses. Improved wild bird surveillance will play a more critical role in the future as an early warning system.

Incursión y propagación del virus de la influenza aviar altamente patógena H5N8 clado 2.3.4.4 en Sudáfrica. El informe de una muerte masiva de fumareles aliblancos (Chlidonias leucopterus) a lo largo de las orillas del lago Victoria en Uganda en enero del 2017 fue una advertencia de que la influenza aviar de alta patogenicidad (HPAI) H5N8, clado 2.3.4.4 había ingresado en las poblaciones de aves del Valle del Rift Africano. A principios de junio del 2017, Zimbabwe reportó un brote del virus en pollos reproductores comerciales cerca de Harare, y el 19 de junio del 2017, el primer caso de influenza aviar de alta patogenicidad H5N8 se confirmó en una operación de pollos de engorde en la provincia de Mpumalanga cerca de Villiers, Sudáfrica, que representa el primer caso de influenza notificable en aves gallináceas en Sudáfrica. Se aislaron cuarenta virus de aves silvestres, aves de traspatio, colecciones de zoológicos, pollos comerciales y avestruces comerciales durante el transcurso del brote. Se secuenciaron los genomas completos y se compararon para determinar los eventos epidemiológicos en la introducción y propagación del subtipo H5N8 clado 2.3.4.4 a través del país. Se encontró que múltiples variantes del virus estaban involucradas en los brotes primarios en las regiones centro y norte de Sudáfrica, pero que una sola variante afectaba a las regiones más al sur del continente. En noviembre de 2017, solo dos de las nueve provincias de Sudáfrica permanecían sin afectarse y la industria de pollos en la Provincia de Cabo Occidental resultó casi diezmada. Dos variantes distintas, que sugieren introducciones independientes, fueron responsables de los dos primeros casos índices y no estuvieron directamente relacionados con el virus involucrado en el brote de Zimbabwe. El papel de las aves silvestres en la incursión y diseminación fue demostrado por los ancestros comunes compartidos con los virus H5N8 de África Occidental y los virus de la influenza aviar de baja patogenicidad de aves acuáticas de Sudáfrica detectados anteriormente. La mejora de la vigilancia de aves silvestres jugará un papel más crítico en el futuro como un sistema de alerta temprana.

Promoter region variation in NFE2L2 influences susceptibility to ototoxicity in patients exposed to high cumulative doses of cisplatin.

Ototoxicity is a disabling reaction to cisplatin chemotherapy. Much of the inter-individual variability in the development of hearing impairment among cisplatin-receiving patients has not been fully accounted for. In particular, little is known about the pharmacogenomics of cisplatin-induced ototoxicity. This study sought to investigate the role of variation in five candidate genes in a cohort of South African cancer patients. Five variants within the candidate genes were genotyped in 214 patients, of which SLC22A2 rs316019 and NFE2L2 rs6721961 associated with reduced rates of ototoxicity. In the patients who were exposed to cumulative cisplatin doses ⩾200 mg m-2 (n=113), the variant rs6721961 associated with ototoxicity according to three different grading scales of hearing loss (ASHA, P=0.005; Chang, P=0.028; CTCAE, P=0.004). The NFE2L2 promotor variant rs6721961 may therefore be protective against hearing loss in cisplatin-receiving cancer patients.

Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL), type 1 is an autosomal recessive disorder which has been identified in more than 30 affected children in the Afrikaans-speaking community of South Africa. Sequencing of B3GALT6 revealed a specific mutation, c.235A > G, in homozygous form in four families, while three others were compound heterozygotes for this mutation in combination with the c.200C > T mutation. In addition, a proband from one family carried the c.16C > T mutation combined with c.200C > T. In a series of five Iranian persons, mutations in B3GALT6 have been implicated in a syndrome characterised by skeletal abnormalities with intellectual disability, bone and connective tissue fragility. Other mutations in B3GALT6 resulted in the classical SEMD-JL phenotype in seven Japanese families and in a syndrome which has been likened to a progeroid form of Ehlers-Danlos syndrome (EDS). It is evident that there is considerable intragenic heterogeneity in B3GALT6. One of the mutations, c.200C > T, in the affected South Africans was also present in one of the Japanese persons and the respective phenotypes were identical. The multiplicity of allelic mutations and the phenotypic differences in the affected persons supports the concept that a spectrum of connective tissue disorders is programmed by mutations in B3GALT6.

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters.

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.

Arg120stop nonsense mutation in the RP2 gene: mutational hotspot and germ line mosaicism?

Mutations in the RP2 gene account for up to 20% of X-linked recessive retinitis pigmentosa (RP). Arg120stop is to date the most frequently reported mutation found in RP2. Mutation screening was performed during the course of a large screening program of retinal degenerative disorders (RDDs) in South Africa using exon 1 and 2 of RP2 in 20 unrelated families with an X-linked mode of retinal degenerative inheritance. Direct sequencing analysis revealed a C-->T transition at position 358 in the proband in a family of German origin. Subsequent analysis revealed that this Arg120stop mutation cosegregated with the disease in an additional affected family member. The nonsense mutation, Arg120stop, could not however, be detected in the somatic cells of the obligate carrier female. This, the first report of a germ line mutation for a family with RP, has many implications for genetic counseling of retinal degeneration (RD). To avoid inaccurate risk assessment for RP due to epigenetic events, such as the rare occurrence of germ line mosaicism, genetic counseling in families with XLRP should always be guided by molecular testing.