Controles de calidad externos en el diagnóstico molecular de enfermedades genéticas. Impacto sobre la calidad de los estudios genéticos / External quality controls in the molecular diagnosis of genetic diseases. Impact on the quality of the genetic studies / Controles de qualidade externos no diagnóstico molecular de doenças genéticas. Impacto na qualidade dos estudos genéticos

Resumen La participación en programas de evaluación externa de la calidad (PEEC) dirigidos al diagnóstico de enfermedades genéticas permite obtener una medida objetiva del desempeño técnico y analítico de los laboratorios y es un requisito para la acreditación de los laboratorios clínicos bajo la norma ISO 15189. El objetivo de este estudio fue evaluar retrospectivamente el desempeño en los esquemas EMQN (European Molecular Genetics Quality Network) y CF Network (Cystic Fibrosis European Network) en el período 2014-2022. Se participó en un total de 88 esquemas. Se recolectó la información de nuestros puntajes y las medias de los laboratorios participantes en las categorías genotipificación, interpretación y exactitud de la información del paciente/informe. Se informó en forma completa el 90,9% (n=80) de los esquemas. El desempeño en genotipificación mostró puntajes superiores a la media en el 89,3% de los esquemas; 0,8% de los informes correspondieron a falsos negativos. En interpretación, el 66,7% de los esquemas evidenció un desempeño superior a la media y el 33,3% debajo de la media. La exactitud de la información del paciente/informe presentó puntajes superiores a la media en el 97,6% de los esquemas. Se observó una diferencia estadísticamente significativa en el porcentaje de esquemas con puntaje por encima de la media en el año 2022 (10/12 esquemas) respecto al año 2014 (1/6 esquemas) en la categoría interpretación (p=0,0128). En conclusión, la participación regular en PEEC tuvo impacto positivo en la calidad de los estudios y permite realizar mejoras continuas a partir de las recomendaciones sugeridas por estos programas.

Abstract Participation in external quality assessment programmes focused on rare genetic diseases makes it possible to assess the laboratory technical and analytical performance and it is a prerequisite for accreditation according to ISO 15189. The objective of this study was to perform a retrospective evaluation of our performance in the EMQN (European Molecular Genetics Quality Network) and the CF Network (Cystic Fibrosis European Network) programmes in the 2014-2022 period. The laboratory performance on genotyping, interpretation and clerical accuracy and patient identifiers in a total of 88 schemes were assessed. The information of our scores and the mean scores of all participating laboratories in the three categories were collected. A total of 90.9% of the schemes were fully completed. The performance in genotyping showed scores above the mean scores in 89.3% of the schemes; 0.8% of the reports correspond to false negative results. Regarding interpretation category, 66.7% of the schemes presented scores above the mean scores and 33.3% below the mean scores. The clerical accuracy and patient identifiers were above the mean scores in 97.6% of the schemes. A statistically significant difference in the percentage of schemes with a score above the mean for the interpretation category in the year 2022 (10/12 schemes) was observed compared to the year 2014 (1/6 schemes) (p=0.0128). In conclusion, regular participation in external quality assessment programmes had a positive impact on the quality of the studies and allows for continuous improvements based on the recommendations suggested by these programmes.

Resumo A participação em programas de avaliação externa da qualidade (PEECs) voltados para o diagnóstico de doenças genéticas permite obter uma mensuração objetiva do desempenho técnico e analítico dos laboratórios e é requisito para a acreditação dos laboratórios clínicos sob a norma ISO 15189. O objetivo desse estudo foi avaliar retrospectivamente o desempenho nos esquemas EMQN (European Molecular Genetics Quality Network) e CF Network (Cystic Fibrosis European Network) no período 2014-2022. Participou-se em um total de 88 esquemas. Foram coletadas informações de nossos escores e das médias dos laboratórios participantes nas categorias genotipagem, interpretação e precisão da informação do paciente/laudo. 90,9% (n=80) dos esquemas foram informados em sua totalidade. O desempenho na genotipagem apresentou escores acima da média em 89,3% dos esquemas; 0,8% dos laudos corresponderam a falsos negativos. Na interpretação, 66,7% dos esquemas apresentaram desempenho acima da média e 33,3% abaixo da média. A precisão das informações do paciente/laudo apresentou escores acima da média em 97,6% dos esquemas. Observou-se diferença estatisticamente significativa no percentual de esquemas com pontuação acima da média no ano de 2022 (10/12 esquemas) em relação ao ano de 2014 (1/6 esquemas) na categoria interpretação (p=0,0128). Em conclusão, a participação regular em PEECs teve um impacto positivo na qualidade dos estudos e permite fazer melhorias contínuas com base nas recomendações sugeridas por esses programas.

Osteopetrosis y fractura de cadera. Presentación de un caso y revisión de la literatura

La osteopetrosis constituye un conjunto de trastornos genéticos que determinan esclerosis del esqueleto. Se conoce también como enfermedad de Albers-Schonberg. Se trasmite tanto de forma autosómica dominante como recesiva. Su diagnóstico temprano permite tratar la patología de base y de manera precoz la fractura, para lograr la consolidación ósea e incorporar a los pacientes a su vida cotidiana con evolución favorable. Se presenta el caso de una paciente de 10 años de edad, de color de piel blanca, de sexo femenino, que desde los 4 años se seguía en consulta en el Complejo Científico Ortopédico Internacional Frank País García, donde fue diagnosticada de osteopetrosis. Seis años después se cayó de sus pies y presentó trauma en la cadera derecha. Comenzó con dolor intenso, inflamación y dificultad para la marcha. La paciente acudió al Hospital Pediátrico Universitario Paquito González Cueto de Cienfuegos donde fue valorada por los especialistas de pediatría, ortopedia y traumatología. Se le realizó radiografía de cadera donde se confirmó el diagnóstico de fractura de cadera derecha por lo que se ingresó para realizar tratamiento quirúrgico. Se presenta el caso con el objetivo de exponer el abordaje de este tipo de padecimiento y el método de tratamiento, motivados por su baja frecuencia de presentación.

Osteopetrosis constitutes a group of genetic disorders that determine skeletal sclerosis. It is also known as Albers-Schonberg disease. It is transmitted in both an autosomal dominant and recessive manner. Its early diagnosis makes it possible to treat the underlying pathology and the fracture early, in order to achieve bone consolidation and incorporate patients into their daily lives with a favorable evolution. We present the case of a 10-year-old female patient, white-skinned, who had been in consultation at the Frank País García International Orthopedic Scientific Complex since she was 4 years old, where she was diagnosed with osteopetrosis. Six years later, he fell off his feet and sustained trauma to his right hip. It started with severe pain, swelling and difficulty walking. The patient attended the Paquito González Cueto Pediatric University Hospital in Cienfuegos where she was evaluated by pediatric, orthopedic and traumatology specialists. A hip x-ray was performed where the diagnosis of right hip fracture was confirmed, for which he was admitted for surgical treatment. The case is presented with the objective of exposing the approach to this type of disease and the treatment method, motivated by its low frequency of presentation.

Clinical and cytogenetic characteristics of patients diagnosed with Turner syndrome in a clinical genetics service: cross-sectional retrospective study

ABSTRACT BACKGROUND: Turner syndrome (TS) is a rare genetic disease. Understanding its clinical findings contributes to better management of clinical conditions. OBJECTIVE: To investigate the clinical and karyotypic characteristics of patients diagnosed with TS at two reference services for clinical genetics in southern Brazil. DESIGN AND SETTING: Retrospective cross-sectional study conducted in two clinical genetics services in Porto Alegre (RS), Brazil. METHODS: The sample consisted of 59 patients with TS diagnosed from 1993 to 2019. A review of their medical records was performed and a standard protocol was filled out. RESULTS: The average age of the patients at diagnosis was 15.9 years, and 40.7% were over 13 years old. The largest proportion of them (42.4%) had been referred from an endocrinology department and their constitution was 45,X (40.7%). The most common clinical findings were short stature (85.7%), hypoplastic/ hyperconvex nails (61.2%), low posterior hairline (52.1%) and cubitus valgus (45.8%). There was no difference regarding the presence of short stature (P = 0.5943), number of dysmorphia (P = 0.143), anatomical regions affected and malformations identified through imaging examinations (P = 1.0000), regarding the presence or absence of 45,X constitution. Only 6% of the patients had used growth hormone and 43%, estrogen. CONCLUSION: We found that, in general, patients with TS were being diagnosed late. This has important implications for their treatment. In addition, only a small proportion of the patients were undergoing further examination or evaluation, which appeared to be leading to underdiagnosis of many abnormalities.

Síndrome de tetraamelia: informe de un caso / Tetra-amelia syndrome: a case report

A still born male baby with tetra-amelia syndrome is reported, with craniofacial abnormalities and pulmonary agenesis. It presented complete absence of all four limbs in association with cleft lip and palate on the right side. The mother medical history revealed no remarkable details. The fetus died shortly after its birth. The embryonic correlation of the case is discussed. Proper health education, antenatal screening and genetic counseling can reduce the risk of such congenital anomalies.

Se informa el caso clínico de un mortinato del sexo masculine con el síndrome de tetraamelia, que mostró ausencia de las cuatro extremidades, unido a anomalías craneofaciales y agenesis pulmonar. Presentó ausencia total de las 4 extremidades unido a labio leporino, paladar hendido del lado derecho. Los antecedentes maternos no revelaron detalles considerable. El feto falleció poco después de su nacimiento. Se discute la correlación embriónica del caso. La educación para la salud adecuada, la pesquisa prenatal y el consejo genético pueden reducir el riesgo de estas anomalías congénitas.

Overview of genomics and post-genomics research on type 2 diabetes mellitus: Future perspectives and a framework for further studies

In this review, we briefly outlined salient features of pathophysiology and results of the genetic association studies hithertoconducted on type 2 diabetes. Primarily focusing on the current status of genomic research, we briefly discussed the limitedprogress made during the post-genomic era and tried to identify the limitations of the post-genomic research strategies. Wesuggested reanalysis of the existing genomic data through advanced statistical and computational methods and recommended integrated genomics-metabolomics approaches for future studies to facilitate understanding of the gene-environment interactions in the manifestation of the disease. We also propose a framework for research that may be apt fordetermining the effects of urbanization and changing lifestyles in the manifestation of complex genetic disorders like type 2diabetes in the Indian populations and offset the confounding effects of both genetic and environmental factors in thenatural way

Epidemiology & social costs of haemophilia in India.

India lacks a national policy on the prevention and control of genetic disorders. Although the haemoglobinopathies have received some attention, there are scarce data on the epidemiology of other genetic disorders in India. Haemophilia, an inherited single gene disorder with an incidence of 1 per 10,000 births, manifests as spontaneous or trauma-induced haemorrhagic episodes in patients, progressing to chronic disability and premature mortality in untreated patients or patients with sub-optimal treatment. Although the genetic basis of this disorder has been well studied in India, data on the number of patients, trends of the disorder in India, social costs of the condition and opportunities and competencies for offering genetic counselling through a public health programme have not been reported. This review article summarizes the available Indian data, which show that the country harbours the second highest number of global patients with haemophilia A. The reported number of patients with haemophilia A is 11,586 while the estimated prevalence could be around 50,000 patients. This review also identifies the need to immediately initiate a national programme for haemophilia, with components of prevention, care for patients, surveillance and education and support for families.

Fibrodisplasia osificante progresiva (FOP): Informe de un caso / Fibrodysplasia ossificans progressiva (FOP): Case report

La fibrodisplasia osificante progresiva es una rara entidad genética caracterizada por la proliferación de tejido fibrótico y con tendencia a la calcificación que afecta los tejidos blandos del organismo, principalmente tras traumatismos, incluso mínimos. La anquilosis articular y la insuficiencia respiratoria restrictiva pueden observarse en los casos más extremos de la enfermedad. Dada su rareza, el diagnóstico suele ser tardío y, en muchas ocasiones, acciones iatrogénicas, como la toma de biopsias, empeoran el cuadro clínico. Existen pocos informes mundiales de niños en los cuales se diagnostique la enfermedad en el período neonatal. El presente caso hace referencia a un niño nacido de una madre con fibrodisplasia osificante progresiva con estigmas de la enfermedad al nacimiento. La presencia de hallux bilaterales inusualmente grandes y deformes, acompañados generalmente de un cuello corto y rígido, pueden orientar al diagnóstico.

Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by fibrotic tissue proliferation and calcification that affect body soft tissues, especially after minor traumas. Joint ankylosis and restrictive respiratory failure can be observed in the most extreme cases of the disease. Because of its rarity, diagnosis is often late and many medical actions, such as biopsy, can result iatrogenic and worsen the prognosis. Diagnosis in the neonatal period may be difficult. There is a little number of cases diagnosed at early ages. The following case concerns a child born from a mother with fibrodysplasia ossificans progressiva who had signs of the disease at birth. The presence of bilateral deformed and unusually large hallux, generally accompanied by a short and stiff neck, may help in the diagnostic process.

Ethical issues in genetic counselling with special reference to haemoglobinopathies.

Genetic counselling is provided in places where genetic tests are carried out. The process involves pre-test counselling as well as post-test counselling to enable the individuals to face the situation and take appropriate decisions with the right frame of mind. Major ethical principles which govern the attitudes and actions of counsellors include: respect for patient autonomy, non-maleficence, beneficence, or taking action to help benefit others and prevent harm, both physical and mental, and justice, which requires that services be distributed fairly to those in need. Other moral issues include veracity, the duty to disclose information or to be truthful, and respect for patient confidentiality. Nondirective counselling, a hallmark of this profession, is in accordance with the principle of individual autonomy. High prevalence of haemoglobinopathies with availability of good and sensitive carrier detection tests and prenatal diagnostic techniques makes these good candidates for population screening of carriers along with genetic counselling for primary prevention of the disease. Screening of the extended family members of the affected child, high risk communities and general population screening including antenatal women are the main target groups for planning a Haemoglobinopathy control programme. A critical mass of trained genetic counsellors who have understanding of the ethical issues and its appropriate handling with the required sensitivity is needed in India.

Preconception infection and genetic counseling

Congenital malformations are a common cause of illness, handicapping conditions, and death. Errors of morphogenesis leading to congenital anomalies have many recognized causes, including specific single-gene mutations, chromosome imbalances, and the action of teratogenic agents. Most congenital anomalies, however, are of multifactorial origin, occurring by complex interactions between not yet well understood genetic and environmental factors. Two to six percent of the newborn babies worldwide, i.e., 3 to 9 million infants a year, suffer from major congenital anomalies and genetic diseases. However, a great deal of this misery could be avoided. In particular, preconception care is more important than prenatal care for prevention of congenital anomalies since as many as 30 percent of pregnant women begin traditional prenatal care in the second trimester (>13 weeks of gestation), which is after the period of maximal organogenesis. Women and their partners whose ethnic background, race, or personal or family history places them at increased risk of having a fetus with a genetic disease should receive appropriate counseling. Furthermore, certain laboratory tests of the infection status of couples may be helpful in assessing the risk for and preventing some complications during pregnancy. Preconception evaluation and appropriate counseling permits parents to make informed reproductive decisions and provides reassurance.

Preliminary report on neonatal screening for congenital hypothyroidism, congenital adrenal hyperplasia and glucose-6-phosphate dehydrogenase deficiency: a chandigarh experience.

Objective To establish newborn screening in Indian scenario that could lay a framework for future such initiatives. Three disorders namely, congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH) and glucose-6- phosphate dehydrogenase deficiency (G-6-PDD) were selected for a preliminary study for newborn screening. Methods Heel-prick blood samples were collected from liveborn neonates at 24–48 h of birth as a part of a screening program after prior written consent from the parents. Blood levels of glucose-6-phosphate-dehydrogenase enzyme (G-6- PD), thyroid-stimulating hormone (TSH) and 17-α-OH progesterone (17-OHP) were measured using DELFIA time resolved fluoroimmunoassay. Results Six thousand eight hundred and thirteen (6,813) neonates (86.3%), out of a total of 7,893 live births in our institute during the period May’2007 through July’2009, were screened for CAH, CH and G6PD deficiency. Major reason for missing samples was early discharge of the neonates and admission to the neonatal intensive care unit. G-6-PD deficiency was confirmed in 61 cases, congenital hypothyroidism (CH) in 2 cases and congenital adrenal hyperplasia (CAH) in 1 neonate, accounting for an incidence of 1/112 for G-6-PDD, 1/ 3400 for CH and 1/6813 for CAH. Conclusions Preliminary data on prevalence of various genetic disorders viz. G-6-PDD, CH and CAH in the population of this region revealed that G-6-PDD is most prevalent disorder followed by CH and CAH. More efforts need to be undertaken to create awareness and emphasis on significance of preventive testing to make screening a successful program in India.

Noonan’s Syndrome of a 25 years old female.

Noonan’s syndrome is an autosomal dominant disorder with a webbed neck that mimics turner syndrome. However, the syndrome has also been found to be genetically heterogeneous. Noonan syndrome is characterized by short stature, hyperkeratosis of skin, distinct facial features, lymphoreticular abnormalities, nail dystrophy. No abnormality in chromosome number has so far been reported. Here we present a 25 year old female who came to Bangladesh Medical College Hospital in May’08, with generalized skin eruptions and left leg swelling.

Mucopolysaccharidosis and mucolipidosis / 한양의대학술지

Mucopolysaccharidosis (MPS) and mucolipidosis(ML) belong to a group of rare genetic disorders of lysosomal enzymes and share some clinical manifestations. MPS is characterized by the accumulation of glycosaminoglycans (GAG) and results from the impaired function of one of 11 enzymes required for normal GAG degradation. ML, which is clinically similar to several forms of MPS, is caused by deficiency of Nacetylglucosamine-1-phosphotransferase activity. Therapeutic strategies for MPS, including enzyme replacement therapy and bone marrow transplantation, have been developed with some success. In this review, we discuss clinical feature, diagnostic methods, management and the present status of research on MPS and ML.

Investigaçäo do retardo mental e doenças genéticas a partir de um estudo transversal em escolas do Rio de Janeiro / A cross sectional study to investigate mental retardation and genetic disorders in schools of Rio de Janeiro

De 1994 a 1997, uma equipe médica itinerante em visita a escolas de educação especial no Estado do Rio de Janeiro iniciou uma investigação genética em alunos com retardo mental (RM) com o objetivo de identificar fatores clínicos e epidemiológicos associados a deficiência mental em uma população escolar: 673 alunos foram examinados e suas famílias entrevistadas nas próprias escolas com uma adesão superior a 80%. Foram constatados: maior freqüência de indivíduos do sexo masculino (1,5M:1F; p<0,001), história familiar de RM em 25% das famílias entrevistadas, uniões consangüíneas em 5,5% (p<0,01) dos pais e aumento da idade parental ao nascimento, incluindo os alunos com síndrome de Down. Uma freqüência maior de partos domiciliares (p<0,00001), especialmente entre os alunos com mais de 20 anos, foi identificada juntamente a uma menor freqüência de partos cesarianos no total de alunos (27,6%; p<0,0001) comparado à população geral do Estado do Rio de Janeiro(46,84%). Em cerca de 20,3% dos alunos havia história de internação no berçário logo após o nascimento e convulsão não febril em 19,8% dos examinados. Os alunos com RM foram clinicamente classificados de acordo com uma hipótese etiológica, compreendendo 36,9% como possível causa genética, 21,1% de causa ambiental e 41,9% de causa idiopática. Tais resultados indicam a necessidade de uma revisão das estratégias de planejamento familiar atual, especialmente com relação às gestantes idosas onde o aconselhamento genético e métodos de diagnóstico pré-natal poderiam ser estendidos. Uma revisão das práticas obstétricas ao período pré, peri e pós-parto com o intuito de reduzir as complicações ao recém-nascido e uma real efetivação dos serviços de prevenção terciária voltados para o atendimento do deficiente tornam-se necessários através das recomendações da Coordenação de Atenção a Grupos Especiais pelo Programa de Atenção à Saúde da Pessoa Portadora de Deficiência do Ministério da Saúde (1993).

From 1994 to 1997, an itinerant medical research group initiated a genetic screening program in governmental funded schools for lhe mentally handicapped individuals in the state of Rio de Janeiro, Brazil. ln arder to identify clinical-epidemiological factors among The mentally retarded students, 673 pupils with mental retardation (MR) were examined and their families interviewed (compliance rate of 80%). A predominance of affected males (1,5M:1F - p<0,001) was observed. Familial history of MR was present in 25% of the interviewed families and 5,5% of lhe parents were consanguineous (p<0, 01). Advanced parental age at birth, including Down syndrome pupils, was observed. A significantly higher frequency of domicile labours (p<0,0001), especially for those over 20 years of age, was reported, and a low prevalence for caesarean sections (27,8%) compared to lhe general population in lhe state of Rio de Janeiro (46,84%; p<0,0001) was registered. Furthermore, 20,3% of pupils were hospitalised immediately after birth and 19,8% had a history of non-febrile convulsions. An etiological classification was attempted for each examined individual with lhe following results: 36,9% genetic, 21,1 % acquired and 41,9% idiopathic. Our results point out for lhe necessity of a review of medical practice essentially towards family planning and especially related to advalced maternal age pregnancies, where genetic counselling and prenatal diagnostic tests could be extended. Perinatal medical supervision should be intensified in arder to reduce complications related to labour and effective efforts should be put in practice to implement tertiary prevention for lhe handicapped individual as recommended by official governmental departments of lhe Brazilian Ministry of Health (1993).

Mammalian sulfoconjugate metabolism.

Sulfoconjugates occur ubiquitously as sulfopolysaccharides, sulfolipids and sulfoproteins. A variety of sulfotransferases catalyze the sulfation process with 3'- phosphoadenosine 5'-phosphosulfate as the sulfate donor. Sulfatases that catalyze the desulfation of different sulfoconjugates are known to be deficient in a number of genetic storage disorders.

Alpha-Fetoprotein Values in Maternal Serum and Amniotic Fluid for Prenatal Screening of Genetic Disorders

Prenatal alpha-fetoprotein screening may serve as an index of suspicion of many congenital anomalies of the fetus including neural tube defect and aneuploid fetus. This study was undertaken to determine the normal ranges of AFP in maternal serum and amniotic fluid at 9 to 41 weeks gestation which thus far had not been established in Korea. Normal ranges of maternal serum and amniotic fluid AFP from 9 to 34 weeks and from 16 to 41 weeks gestation were obtained respectively from 198 uncomplicated pregnant women delivered of normal singleton baby. Maternal serum AFP values showed an increasing trend from 12 weeks gestation reaching a peak level at 29 to 34 weeks gestation and after which there was a gradual decline. Amniotic fluid AFP values was the highest at 17 weeks gestation and declined as pregnancy approached term. The correlation of a median value between AF AFP and MS AFP was 100 to 1 in ratio in each week. The authors conclude that this initial experience in Korea with maternal serum AFP values could efficiently detect genetic disorders, perhaps with high sensitivity and provide a proper management scheme of pregnant women with abnormal high and low AFP values during the midtrimester of pregnancy.