Medical Genetic Services Research Articles

The genetic background of Southern Iranian couples before marriage

Genetic service for couples plays an increasingly important role in diagnosis and risk management. This study investigated the status of consanguinity and the medical genetic history (effectiveness and coverage of medical genetic services) in couples residing in a city in southern Iran. We questioned couples who were referred to Behbahan Marital Counseling Center, Behbahan, Iran, during the period from January to November 2014, to obtain information on consanguinity, disease history, and previous referral to a medical genetics center. For the collected data was obtained descriptive statistics with STATA 11.0 software. A total of 500 couples were questioned. Mean age was 24.8 ± 5.2 years. Almost one quarter (23.4%) of the couples were consanguineous. Consanguinity was almost twice as common in rural areas as in urban areas (33.9 vs. 19.2%, p = 0.001). Only a few couples (~3.0%) had ever been referred for genetic counseling. The main reason for previous genetic counseling was consanguinity (85.7%). The majority of the participants (96.3%) had never been tested for any genetic conditions. Our findings suggest that only a small proportion of couples in Khuzestan Province, Iran (Behbahan City) were receiving adequate genetics care. This may reflect the limited accessibility of such services, and inadequate awareness and education among the care providers.

Review of the 2015 Guidelines for Maternity Care with relevance to congenital disorders.

The 4th edition of the Guidelines for Maternal Care in South Africa published by the National Department of Health in 2015 was evaluatedwith relevance to the care and prevention of congenital disorders (CDs). Disparate terminology is used for CDs throughout the guidelines,and overall less detail is included on CDs compared with the previous edition. This demonstrates a lack of awareness around the growinghealth need and contribution of CDs to the disease burden in South Africa (SA). Referrals to medical genetic services in the guidelines formothers of advanced maternal age and other high-risk categories do not take into account the insufficient capacity available for screeningand diagnosis of CDs. This highlights the lack of consultation with the medical genetics sector during the development of the guidelines. Torespond to the Sustainable Development Goals by 2030, CDs must be integrated comprehensively at all levels of healthcare in SA.

Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit.

Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations. Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome. This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.

Constitutional, legal and regulatory imperatives for the renewed care and prevention of congenital disorders in South Africa

Medical genetic services for the care and prevention of congenital disorders have declined significantly in recent years due to competing health priorities, with previously developed services becoming compromised. With an infant mortality rate of 28/1 000 live births, South Africa (SA) has passed the threshold of 40/1 000 when such services should be implemented. This article outlines the international background and SA legislative framework for medical genetic services and their implementation. International, regional and national conventions, legislation, and policy were studied for relevance to genetic services and their implementation was evaluated, including a comparison of sector capacity between 2001 and 2015. A comprehensive legislative and regulatory framework exists in SA for the provision of medical genetic services, but implementation has been fragmented and unsustained. Congenital disorders and genetic services are not prominent in national strategies and excluded from interventions aimed at combating child mortality and non-communicable diseases. Capacity today is at a lower level than in 2001. The failure to recognise the burden of disease represented by congenital disorders is the underlying reason for the implementation and service shortfall. Child mortality rates have stagnated since 2011 and can be significantly further reduced by prioritising healthcare issues other than HIV/AIDS, including congenital disorders. It is now an imperative that SA responds to World Health Assembly Resolution 63.17 and prioritises congenital disorders as a healthcare issue, providing services to uphold the dignity and human rights of the most vulnerable members of society.

Challenges identified in the management of patients with inherited metabolic disorders – A five year experience from Pakistan

BackgroundPakistan is the sixth most populous country in the World. High rates of consanguinity and inter caste marriages have resulted in a substantial burden of inherited metabolic disorders (IMDs). Despite this load, there is a dearth of both medical genetic and clinical metabolic services in Pakistan. There are inadequate numbers of appropriately trained clinicians, ill-equipped laboratories, lack of scientists and technologists equipped with skills to deal with the challenging laboratory investigations involved in IMD and a health care infra-structure unable to support a service. AimWe present the first five year experience of the first established metabolic unit at a tertiary care hospital in Pakistan and present the case for screening of parents, parents’ siblings and antenatal diagnostic testing in subsequent pregnancies in order that families can make informed choices in preventing recurrence. Subjects and methodsThis retrospective observational study comprising of patients’ chart review was conducted in the Department of Paediatrics, AKUH Karachi in Pakistan for patients who presented to the Clinical Genetics unit from January 2008 to December 2012 seeking diagnosis and treatment for the underlying IMD. ResultsWe evaluated 426 children, of which, 333 (78%) had consanguineous parents. Most patients, 151 (35%). evaluated for IMD were between 1year and 5years of age. Developmental delay, seizures, hypotonia, microcephaly, neuroregression, dystonia, ataxia and encephalopathy were the most common reasons for referrals. Only 155 (36%) patients underwent metabolic biochemical testing. Among the investigated group of patients, diagnoses were established for 85 (55%) patients equivalent to only 19.8% of the total. ConclusionNeonatal screening for IMDs and their treatment in the current situation is an unaffordable practical option in Pakistan. Screening parents, siblings and subsequent pregnancies, however, is likely to provide a cost effective and acceptable alternative in reducing the burden and enabling early, effective detection of affected progeny before the stage when neurometabolic changes become irreversible in developing countries like Pakistan with very limited resources.

A Family with γ-Thalassemia and High Hb A2 Levels

We describe a family carrying a γ-globin gene deletion associated with an increase of Hb A2 level beyond the normal range. The family included the proband, his sister and their father, all with increased Hb A2 and normal Hb F levels. The proband and his sister showed borderline values of mean corpuscular volume (MCV) and reduced values of mean corpuscular hemoglobin (Hb) (MCH). The proband was referred to our Medical Genetics Service for preconception counseling together with his partner, a typical β-thalassemia (β-thal) carrier. The results were negative for the most frequent α-thalassemia (α-thal) mutations, and had no significant sequence variations of the coding sequences and promoter of the β- and δ-globin genes. Quantitative analysis by multiplex ligation-dependent probe amplification (MPLA) of the β-globin gene cluster detected a heterozygous deletion, ranging between 2.1 and 4.7 kb, in the proband, his sister and the father. The deletion involved the Gγ gene and Gγ-Aγ intergenic region, whereas the 3' region of the Aγ gene was preserved. A subsequent gap-polymerase chain reaction (gap-PCR) showed that a hybrid GAγ fusion gene was present. The deletion segregated with the elevation of Hb A2. The MLPA analysis of the β-globin gene cluster in 150 control alleles excluded a common polymorphism. Despite stronger evidence being needed, the described family suggests a possible role of this γ-globin gene deletion in contributing to Hb A2 elevation, possibly by altering the transcription regulation of the cluster. We propose γ-globin gene dosage analysis to be performed in patients with unexplained elevated Hb A2 levels.

Survey of medical genetic services in Italy: year 2011.

BackgroundThe aim of this study was to collect information about 2011 genetic activities in Italy, with the purpose of providing guidance to the national health systems in order to improve genetic services.MethodsA web-based survey was carried out to achieve the information.ResultsData were collected from 268 macrostructures hosting 517 services and employing 3246 persons. About 295,000 cytogenetic, 35,000 immunogenetic and 263,000 molecular genetic analyses of 902 genes were recorded. Seventy-four percent of the services were accredited with institutional bodies and 57 % were also certified according to ISO 9001 standard. Twenty percent of cytogenetic laboratories had participated in an European External Quality Assessment (EQA) while 44 % participated in a national EQA. Only 28 % of the molecular laboratories had participated in a national Cystic Fibrosis EQA. The percentage of diagnoses confirmed by genetic tests varied among disorders, ranging from 52 % for coeliac disease to 4 % for fragile X syndrome.ConclusionsThis study highlights the need for reorganizing the Italian genetic services network, improving EQA participation and developing national plans for implementing next generation technologies. Concerted effort has to be addressed in the education of the professionals prescribing tests to improve appropriateness and to inform patients, who now have exposure to direct-to-consumer multifactorial genetic testing where clinical utility is unproven.

Scope of practice: a statement of the American College of Medical Genetics and Genomics (ACMG).

These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these recommendations.Genet Med 17 9.

The time-consuming demands of the practice of medical genetics in the era of advanced genomic testing.

Clinical genetics services are time- and labor-intensive. With increasing pressure for cost-effective medical care, the means of providing medical genetics services need to be evaluated in the current era of new genomic technologies. An anonymous online survey regarding activities linked to medical genetics practice was administered to an international cohort of professionals. Among 151 responses, the reported average time required for pediatric, oncogenetic, pregnancy with a malformed fetus, and preamniocentesis counseling sessions was 48, 37, 40, and 18 min, respectively. The time required to prepare a summary letter followed a similar pattern. Professionals with less experience needed more time for specific activities. The time required for the total workup of a pediatric patient ranged from 1 h and 48 min to 4 h, most of which was associated with indirect activities. Professionals performing one type of consultation (74% pediatric geneticists) perform fewer consultations per week. Respondents' narrative comments reflected the complexity of the work and challenges faced. Clinical genetics is a time-consuming profession with increased demands related to advanced genetic and genomic testing. Further consideration is required to determine how to adapt these changes to the demands of cost-effectiveness without compromising the quality of patient care.Genet Med 18 4, 372-377.

Maple syrup urine disease in Brazil: a panorama of the last two decades

ObjectiveTo characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. MethodsIn this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. ResultsEighty‐three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57‐7). Median age at onset of symptoms was 10 days (IQR 5‐30), whereas median age at diagnosis was 60 days (IQR 29‐240, p=0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n=12) and without (n=71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. ConclusionIn Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country.

Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics.

These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these recommendations.

A prospective cohort study assessing clinical referral management & workforce allocation within a UK regional medical genetics service.

Ensuring patient access to genomic information in the face of increasing demand requires clinicians to develop innovative ways of working. This paper presents the first empirical prospective observational cohort study of UK multi-disciplinary genetic service delivery. It describes and explores collaborative working practices including the utilisation and role of clinical geneticists and non-medical genetic counsellors. Six hundred and fifty new patients referred to a regional genetics service were tracked through 850 clinical contacts until discharge. Referral decisions regarding allocation of lead health professional assigned to the case were monitored, including the use of initial clinical contact guidelines. Significant differences were found in the cases led by genetic counsellors and those led by clinical geneticists. Around a sixth, 16.8% (109/650) of referrals were dealt with by a letter back to the referrer or re-directed to another service provider and 14.8% (80/541) of the remaining patients chose not to schedule an appointment. Of the remaining 461 patients, genetic counsellors were allocated as lead health professional for 46.2% (213/461). A further 61 patients did not attend. Of those who did, 86.3% (345/400) were discharged after one or two appointments. Genetic counsellors contributed to 95% (784/825) of total patient contacts. They provided 93.7% (395/432) of initial contacts and 26.8% (106/395) of patients were discharged at that point. The information from this study informed a planned service re-design. More research is needed to assess the effectiveness and efficiency of different models of collaborative multi-disciplinary working within genetics services.

Maple syrup urine disease in Brazil: a panorama of the last two decades

ObjectiveTo characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. MethodsIn this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. ResultsEighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57–7). Median age at onset of symptoms was 10 days (IQR 5–30), whereas median age at diagnosis was 60 days (IQR 29–240, p=0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n=12) and without (n=71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. ConclusionIn Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country.

The impact of routine next generation sequencing testing for familial hypercholesterolaemia – 5 months service experience

The impact of routine next generation sequencing testing for familial hypercholesterolaemia – 5 months service experience

EPA-0662 – Clinical-pathobiological bases development of mental disorders in children and adolescents in siberia

The task of mental health of children and adolescents is preventing the occurrence of mental retardation, neurotic pathocharacterological formations and other mental disorders that arise as a result of brain lesions in different age periods. Mental development of an individual's mental or ontogeny is closely related to biological characteristics of the body at different age levels. Multidisciplinary study of families of children with mental disorders and subsequent development of principles of comprehensive rehabilitation and prevention of genetic family allowed for the first time with the use of the methodology on the basis of clinical and genetic approach complex methods of family and genetic studies in the region of Siberia to study social and reproductive characteristics and genetic and demographic characteristics of households with mentally ill children in the period of demographic reproduction, to identify reproductive behavior in families, to explore socio-psychological characteristics of parents of children with disabling mental disorders, to develop and apply technology to provide specialized medical genetic services, family and genetic prevention. Modern technologies of rehabilitation and prevention of mental disorders in children and adolescents include the principle of interdepartmental cooperation, active involvement of social state agencies, teachers, and parents. Creating a child zone of psychological comfort, psychotherapeutic and psycho-correction support, psychopharmacological effects of a new class of drugs that increases the adaptability of the organism, at all stages of complex rehabilitation promotes optimal development of the individual.

Fast and robust protocol for prenatal diagnosis of mucopolysaccharidosis Type II

Introduction: Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal disorder caused by deficiency of iduronate-2-sulfatase ( IDS ). In this study, we proposed a new protocol for prenatal diagnosis, using DNA obtained from amniotic fluid cells that did not attach to the bottom of the culture flask after the first medium change. Methods: Four pregnant MPS II carriers were referred to the Medical Genetics Service of Hospital de Clinicas dePorto Alegre for a prenatal diagnosis and identification of the disease, which were performed by polymerase chain reaction (PCR) amplification, restriction fragment length polymorphism, and sequencing according to the mutation previously found in the family. Results: The analysis indicated the absence of mutation in three fetal materials and the presence of mutation in one case. Concomitantly, cytogenetic and biochemical analyses were performed after 12 days of cell culture, and only one case showed absence of enzyme activity, confirming the molecular analysis. Conclusions: This diagnostic protocol designed to provide more robust results and safer genetic counseling suggests that DNA obtained from floating amniotic fluid cells can be used as a source of fetal material to allow a faster alternative for prenatal care through molecular analysis. Determination of IDS gene mutation in fetal amniotic fluid cells together with IDS enzyme activity testing is a rapid, sensitive and accurate method for prenatal diagnosis of MPS II for high-risk pregnant women.

Familial hypercholesterolaemia (FH) in Wales is genetically heterogeneous

Familial hypercholesterolaemia (FH) in Wales is genetically heterogeneous

Encomium: Giovanni Neri—Polyhedral and down‐to‐earth mentor

Encomium: Giovanni Neri—Polyhedral and down‐to‐earth mentor

The Greater Sekhukhune-CAPABILITY outreach project

The Greater Sekhukhune-CAPABILITY Outreach Project was undertaken in a rural district in Limpopo, South Africa, as part of the European Union-funded CAPABILITY programme to investigate approaches for capacity building for the translation of genetic knowledge into care and prevention of congenital disorders. Based on previous experience of a clinical genetic outreach programme in Limpopo, it aimed to initiate a district clinical genetic service in Greater Sekhukhune to gain knowledge and experience to assist in the implementation and development of medical genetic services in South Africa. Implementing the service in Greater Sekhukhune was impeded by a developing staff shortage in the province and pressure on the health service from the existing HIV/AIDS and TB epidemics. This situation underscores the need for health needs assessment for developing services for the care and prevention of congenital disorders in middle- and low-income countries. However, these impediments stimulated the pioneering of innovate ways to offer medical genetic services in these circumstances, including tele-teaching of nurses and doctors, using cellular phones to enhance clinical care and adapting and assessing the clinical utility of a laboratory test, QF-PCR, for use in the local circumstances.

CHACO outreach project: the development of a primary health care-based medical genetic service in an Argentinean province

Dissemination of knowledge in genetics to be applied in medicine has created a growing need for capacity building in health care workers. The CAPABILITY ARGENTINA outreach project protocol was designed as a model to introduce genetics in areas without genetic services. Our aim was for genetic health care to become part of primary care in an Argentine province lacking genetic services. The program was innovative as professionals from the referral center (Garrahan Hospital S.A.M.I.C.) traveled to remote areas to train professionals through problem-based education. A logical framework was designed for a local needs assessment. Teaching materials (Powerpoint presentations, printed syllabus, and CD) and a web page were developed. A demonstration project was carried out in the Province of Chaco, Argentina. A total of 485 health workers were trained. The number of consultations increased significantly in participating areas comparing before and after the training period. To support this increase, a complementary project was set up from a public hospital sponsored from within Argentina to build a cytogenetic laboratory in the capital of the Province of Chaco. The model was improved for reproduction in other areas in Argentina. CAPABILITY ARGENTINA is a capacity building model for training of primary care professionals in genetics that may be applied to other medical specialties. The outcomes of the programme have a direct impact on clinical practice.