Division Of Human Genetics Research Articles

Beckwith-Wiedemann Syndrome: Partnership in the Diagnostic Journey of a Rare Disorder

* Abbreviation: BWS — : Beckwith-Wiedemann syndrome Conditions like Beckwith-Wiedemann syndrome (BWS) carry a risk of an associated aggressive malignancy, and thus timely diagnosis is critical. Without a clear diagnosis and timely, appropriate medical care, complications of BWS-associated malignant tumors can be life-threatening or require organ transplant that otherwise could be avoided. Diagnosing rare pediatric syndromes remains challenging. Often the diagnosis may be aided by an astute pediatrician or a parent recognizing a subtle feature related to the syndrome. This establishes a valuable partnership between pediatrician, parent, and geneticist that can lead to a diagnosis. Without this partnership, families may embark on a diagnostic odyssey for years while their child remains at risk. We share the perspectives of 2 parents and a geneticist in an effort to raise awareness and promote early diagnosis of 1 of many rare diseases. Classically, BWS is an overgrowth and cancer predisposition disorder for which several clinical diagnostic algorithms have been developed.1 Diagnosis may be difficult when a child has only 1 feature of the syndrome (eg, macroglossia) or 1 or more less commonly known features. A pediatrician who is unfamiliar with the variability in the presentation of BWS may dismiss the diagnosis. Parents have access to a wealth of information on the Internet, and this access may enable them to identify subtle features. Pediatricians must be open to the parents’ considerations. The cases described below highlight the importance of access to information for both parents and physicians and the role that parents can take in contributing to the partnership with health care professionals. There are many pediatricians, both generalists and specialists, who create a partnership such as we … Address correspondence to Jennifer M. Kalish, MD, PhD, Division of Human Genetics, Children’s Hospital of Philadelphia, CTRB 3028, 3501 Civic Center Blvd, Philadelphia, PA 19104-4302. E-mail: kalishj{at}email.chop.edu

Clinical and genetic analysis of spinocerebellar ataxia type 7 (SCA7) in Zambian families

BackgroundTo date, 43 types of Spinocerebellar Ataxias (SCAs) have been identified. A subset of the SCAs are caused by the pathogenic expansion of a CAG repeat tract within the corresponding gene. Ethnic and geographic differences are evident in the prevalence of the autosomal dominant SCAs. Few descriptions of the clinical phenotype and molecular genetics of the SCAs are available from the African continent. Established studies mostly concern the South African populations, where there is a high frequency of SCA1, SCA2 and SCA7. The SCA7 mutation in South Africa (SA) has been found almost exclusively in families of indigenous Black African ethnic origin.ObjectiveTo present the results of the first clinical description of seven Zambian families presenting with autosomal dominant SCA, as well as the downstream molecular genetic analysis of a subset of these families.MethodsThe study was undertaken at the University Teaching Hospital in Lusaka, Zambia. Ataxia was quantified with the Brief Ataxia Rating Scale derived from the modified international ataxia rating scale. Molecular genetic testing for 5 types of SCA (SCA1, SCA2, SCA3, SCA6 and SCA7) was performed at the National Health Laboratory Service at Groote Schuur Hospital and the Division of Human Genetics, University of Cape Town, SA. The clinical and radiological features were evaluated in seven families with autosomal dominant cerebellar ataxia. Molecular genetic analysis was completed on individuals representing three of the seven families.ResultsAll affected families were ethnic Zambians from various tribes, originating from three different regions of the country (Eastern, Western and Central province). Thirty-four individuals from four families had phenotypic features of SCA7. SCA7 was confirmed by molecular testing in 10 individuals from 3 of these families. The age of onset of the disease varied from 12 to 59 years. The most prominent phenotypic features in these families were gait and limb ataxia, dysarthria, visual loss, ptosis, ophthalmoparesis/ophthalmoplegia, pyramidal tract signs, and dementia. Affected members of the SCA7 families had progressive macular degeneration and cerebellar atrophy. All families displayed marked anticipation of age at onset and rate of symptom progression. The pathogenic SCA7 CAG repeat ranges varied from 47 to 56 repeats. Three additional families were found to have clinical phenotypes associated with autosomal dominant SCA, however, DNA was not available for molecular confirmation. The age of onset of the disease in these families varied from 19 to 53 years. The most common clinical picture in these families included a combination of cerebellar symptoms with slow saccadic eye movements, peripheral neuropathy, dementia and tremor.ConclusionSCA is prevalent in ethnic Zambian families. The SCA7 families in this report had similar clinical presentations to families described in other African countries. In all families, the disease had an autosomal dominant pattern of inheritance across multiple generations. All families displayed anticipation of both age of onset and the rate of disease progression. Further clinical and molecular investigations of the inherited ataxias in a larger cohort of patients is important to understand the natural history and origin of SCAs in the Zambian population.

AB002. Human genetics at the National Research Centre in Egypt: history, achievements and challenges

Background: The National Research Centre (NRC) of Egypt is a multidisciplinary research institute that has a wide spectrum of research fields and interests. It is the largest center of all institutions affiliated to the Ministry of Scientific Research in Egypt. The NRC was established in 1956 as a national center to conduct basic and applied research. The Division of Human Genetics and Genome Research (HGGRD), as one of the most distinguished divisions at the NRC, had its origins as the Department of Human Genetics was established in 1976 by Prof. Samia Temtamy and a small number of scientists.

Mutational spectrum of COL1A1 and COL1A2 in Egyptian patients with autosomal dominant osteogenesis imperfecta with clinical severity score and genotype/phenotype correlation

Medical Molecular Genetics, Division of HumanGenetics and Genome Research, Center of ScientificExcellence of Human Genetics, National ResearchCentre, Cairo, EgyptCorrespondence to Mohamed S. Abdel-Hamid, MSc,Department of Medical Molecular Genetics, Division ofHuman Genetics and Genome Research, Center ofScientific Excellence of Human Genetics, NationalResearch Centre, El-Buhouth St, Dokki, 12311 Cairo,EgyptTel: +20 1001667730; fax: +20 233 370 931;e-mail: mohamadnrc@hotmail.comReceived 10 October 2014Accepted 23 October 2014Middle East Journal of Medical Genetics2015, 4:7–12

Association of Parental Origin with Phenotypic Profile in Turner Syndrome

Abstract Objective: The objective of the study is to report the association between the phenotype of the Turner syndrome with that of its karyotype and the parental origin of the X. 181 female referred to division of human genetics, St. John’s Medical College with different referral reasons are included in 1st phase of the study to observe the karyotype, upon obtaining the consent. Families of probands with confirmed pure or mosaic (more than 10% of mosaic status) karyotype of Turner stigmata are requested to participate in 2nd phase of study to determine the parent of origin. 20 families agreed and gave the consent for the study. Material and Method: The Karyotype analsyis was carried by GTG banding method automated karyotyping system. The parental origin was determined by X chromosome specific short tandem repeat (STR) markers. 23 Turner stigmata features were listed in the proforma. The secondary measure is to observe the associated Turner stigmata with the determined karyotype and the parental origin. Results: In 11 female probands, one had X structural abnormality (45,X/46,X,i(Xq)); 2 had X-mosaicism (45,X/ 46,XX) and 8 had 45,X. The determined parental origin of X was maternal in 8 (72.7%) and paternal in 3 (27.2%). 23 phenotypic features of Turner stigmata were tabulated. The features were further categorized as general observations, classical features of TS, features based on ultrasound findings and behavior. Percentage analysis indicated that a higher concordance of phenotype and behavior in proband with maternal X. Conclusion: In the present study, the Turner syndrome features were seemed to be associated with the maternal origin of X in Turner syndrome.

Coinheritance of sickle cell anemia and α‐thalassemia delays disease onset and could improve survival in cameroonian's patients (Sub‐Saharan Africa)

Coinheritance of sickle cell anemia and α‐thalassemia delays disease onset and could improve survival in cameroonian's patients (Sub‐Saharan Africa)

Who should control genomic data?

Who should control genomic data?

Testing for haemoglobinopathies in Johannesburg, South Africa: A 30-year review

Haemoglobinopathies are seen mostly in regions where malaria occurs or has occurred, but population migration has resulted in affected individuals being identified in many countries globally. The first molecular genetics services for diagnostic testing and prenatal diagnosis were established, both worldwide and in South Africa (SA), for haemoglobinopathies. To analyse the diagnostic service offered by the Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand, from 1983 to 2012. A retrospective file analysis (N=1 249) was performed for all individuals who had molecular genetic testing for α-thalassaemia, β-thalassaemia and sickle cell anaemia to examine indications for testing, population origins of patients and molecular genetics findings. The α-thalassaemia testing was requested predominantly to explain microcytic hypochromic haematological indices. Five α-globin deletions were identified, the most common being the -α3.7, in individuals of different ethnicities. For β-thalassaemia and sickle cell anaemia, most testing was performed for prenatal diagnosis purposes. For sickle cell anaemia, most prenatal tests were requested by African families. The β-thalassaemia families were mostly of Indian or Mediterranean origin. The most common mutation identified in all Indian groups was IVS1 nt5 (G>C) (c.92+5G>C) and in individuals from the Mediterranean, IVS1 nt110 (G>A) (c.93-21G>A). The molecular genetics service for haemoglobinopathies in SA is comprehensive and specific to the needs of local ethnic groups. Clinically significant haemoglobinopathies occur at significant frequencies in specific high-risk ethnic groups. Appropriate screening programmes should be initiated so that genetic counselling and reproductive options can be offered.

Diagnostic, carrier and prenatal genetic testing for fragile X syndrome and other FMR-1-related disorders in Johannesburg, South Africa: A 20-year review

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability (ID) worldwide, is caused by the expansion of a CGG repeat in the fragile X mental retardation gene (FMR-1) gene. OBJECTIVES; To review, retrospectively, the genetic services for FXS and other FMR-1-related disorders - including fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR-1-related primary ovarian insufficiency (POI) - at the Division of Human Genetics, Johannesburg, for diagnostic, carrier and prenatal genetic testing.Methods. The records of 2 690 patients with ID and suspected FXS (ID/?FXS) who had genetic testing for FMR-1 between 1992 and 2012 were reviewed. Of these, 2 239 had diagnostic testing, 430 carrier or cascade testing and 17 prenatal testing for FXS. Four had FXTAS or POI testing. Polymerase chain reaction (PCR) and/or Southern blotting techniques were used to test the patients' samples for FMR-1 and FMR-2 expansions. RESULTS; Of the 2 239 patients who had diagnostic testing, 128 (5.7%) had a full mutation, 12 (0.5%) had a premutation and 43 (1.9%) an intermediate allele. In 17 prenatal tests, eight fetuses tested positive for FXS. FMR-1 CGG repeat distribution analysis in 1 532 males negative for the FMR-1 expansion showed that 29 and 30 CGG repeats were the most common (61.1%), but distribution was significantly different in the black and white populations.CONCLUSION; The findings support the presence of FXS, as the most common cause of ID, in all local populations. The FMR-1 CGG repeat distribution varied from that found in other studies. The number of family members tested was relatively low suggesting that many at-risk individuals are not being referred.

A case of cohesinopathy with a novel de-novo SMC1A splice site mutation

aDivision of Human Genetics bDivision of Neuropediatrics, University Children’s Hospital, Inselspital, Bern, Switzerland cCeGaT GmbH, Tübingen, Germany Correspondence to Johannes R. Lemke, MD, Division of Human Genetics, University Children’s Hospital, Inselspital, CH-3010 Bern, Switzerland Tel: +41 31 6329446; fax: +41 31 632 9484; e-mail: [email protected] Received January 21, 2013 Accepted June 17, 2013

WS23.1 Progression of lung disease within specific genotypes of patients with cystic fibrosis (CF) – Which lung function parameter differentiates best?

WS23.1 Progression of lung disease within specific genotypes of patients with cystic fibrosis (CF) − Which lung function parameter differentiates best? S. Gallati1, M.H. Schoeni2, R. Kraemer3. 1University of Berne, Division of Human Genetics, Berne, Switzerland; 2University of Berne, Department of Paediatrics, Berne, Switzerland; 3University of Berne, Division of Paediatrics Respiratory Medicine, Berne, Switzerland

Achondroplasia Day 2012 in Johannesburg

The Division of Human Genetics (National Health Laboratory Service and University of the Witwatersrand) recently hosted the second annual Achondroplasia Day in Johannesburg. Participation in the meeting increased from 4 families in 2011 to 17 families in 2012. The main aim of the meeting was to bring individuals with achondroplasia and their families together and to facilitate improved interaction between families and the healthcare professionals involved in their care. This short report briefly describes the events of the day, and the immense benefit such activities have for families with rare genetic conditions. Additionally, we provide an overview of the basic genetics of achondroplasia and specific health needs of affected individuals. It is hoped that other centres around South Africa will be inspired to organise similar events in their respective areas to benefit their patients.

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.

The Utilization and Outcome of Diagnostic, Predictive, and Prenatal Genetic Testing for Huntington Disease in Johannesburg, South Africa

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder for which genetic counseling and testing are available in South Africa. The purpose of this study was to assess the utilization of the services available in Johannesburg for diagnostic, predictive, and prenatal genetic testing and counseling for HD and the characteristics of the patients who use them. A retrospective study was conducted using records of patients (n=287) who had genetic counseling and/or testing for HD through the Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand, Johannesburg, between January 1998 and December 2006. Age, gender, number of children, ethnicity, and test results were analyzed. Of the 287 patients included in this study, 77% had diagnostic testing, 20% predictive, and 3% prenatal testing. In the diagnostic group, 47% of subjects tested positive for HD1 and 9% for HDL2 (all Black or of mixed ancestry). Altogether, 66.7% of subjects in the predictive group had testing and 39.5% were positive. In both groups, White subjects were overrepresented. In seven prenatal tests, three fetuses (including a set of twins) tested positive for HD and termination of pregnancy was requested. The HD services for predictive and prenatal testing appear to be underutilized, especially by Black individuals, possibly because of lack of awareness among these individuals and among healthcare providers and/or a lower HD prevalence in this group. Recognition of and testing for HDL2 is important in South Africa's large Black population, and HD testing services cannot be considered complete unless testing for both HD1 and HDL2 are undertaken.

UCT and CPGR join forces with international Pharmacogenomics initiative focussing on African diseases

Cape Town, South Africa, 17 June 2011 - The Division of Human Genetics at the University of Cape Town (UCT) and the Centre for Proteomic and Genomic Research (CPGR), Cape Town, South Africa, proudly announce that they will be joining the ‘Pharmacogenomics for Every Nation Initiative’ (PGENI). Jointly, the two parties will form a South African PGENI Centre of Competence for conducting translational research relevant to the local burden of disease and the most appropriate drugs for treating diseases in African populations.

Letter to the Editor

Division of Human Genetics (Grant) John P. Dormans, MD, Department of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA (Dormans) The manuscript submitted does not contain information about medical device(s)/drug(s). No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Late manifestations of tricho‐rhino‐pharangeal syndrome in a patient: Expanded skeletal phenotype in adulthood

Late manifestations of tricho‐rhino‐pharangeal syndrome in a patient: Expanded skeletal phenotype in adulthood

Breaking New Ground in Inflammatory Bowel Disease Genetics: Genome-Wide Association Studies and Beyond

Author for correspondence: Center for Applied Genomics, Children’s Hospital of Pennsylvania, Philadelphia, PA 19104, USA Tel.: +1 267 426 0088 Fax: +1 267 426 0363 hakonarson@email.chop.edu and Division of Human Genetics, Children’s Hospital of Pennsylvania, Philadelphia, PA 19104, USA and Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA Breaking new ground in inflammatory bowel disease genetics: genome-wide association studies and beyond

Predictive testing for Huntington disease in a developing country

Predictive testing for Huntington disease (HD), by means of direct mutation analysis, has been offered at the Division of Human Genetics, University of Cape Town, from 1995. The aim of this study was to compile a comprehensive profile of the participants who had undergone predictive testing in the Western Cape from 1995 to 2005. The sociodemographic data, uptake and outcome of tests were analyzed to inform changes to improve the current genetic counseling services. A retrospective cross-sectional design using a 'multi-method' approach of both qualitative and quantitative methods was used. Data were gathered from the participants' hospital files and genetic database. Psychosocial data were obtained by face-to-face interviews with the participants in their homes or venues of choice. A total of 36 predictive tests were performed. The uptake for predictive testing was approximately 4.5% of the estimated at-risk population. The cohort of 27 individuals comprised 16 females and 11 males. Their mean age was 35.3 years; 6 were mixed ancestry and 21 were White people (European ancestry); 11 tested gene positive, 15 gene negative and 1 was in the reduced penetrance range. The most important issue identified was that the uptake of individuals classified as mixed ancestry was substantially lower than that of the White people possibly due to limited access to the predictive testing program because of the low levels of income and education in the general population of families with HD. Strategies to address these aspects have been incorporated into the program and will be reassessed after 1 year.

Osteogenesis imperfecta type IIa with pseudoanencephaly

Divisions of aAnatomical Pathology bHuman Genetics, University of Cape Town, Cape Town, South Africa Correspondence to Professor Peter Beighton, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Observatory 7925, Cape Town, South Africa Tel: +27 21 406 6530; fax: +27 21 406 6826; e-mail: [email protected] Received 5 February 2008 Accepted 4 July 2008