RESUMO
BACKGROUND: Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures. METHODS: We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016-2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD. RESULTS: Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (n = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD. CONCLUSIONS: A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record-keeping could improve CD ascertainment.
Assuntos
Anormalidades Congênitas , Humanos , África do Sul/epidemiologia , Feminino , Gravidez , Prevalência , Adulto , Recém-Nascido , Anormalidades Congênitas/epidemiologia , Vigilância de Evento Sentinela , Sistema de Registros , Masculino , Diagnóstico Pré-Natal/métodosRESUMO
STAC3 disorder, or Native American myopathy, is characterised by congenital myopathy, hypotonia, musculoskeletal and palatal anomalies, and susceptibility to malignant hyperthermia. A STAC3 c.851 G > C (p.Trp284Ser) pathogenic variant, common in the Lumbee Native American tribe, has been identified in other populations worldwide, including patients of African ancestry. We report on the frequency of STAC3 c.851 G > C in a cohort of 127 patients presenting with congenital hypotonia that tested negative for spinal muscular atrophy and/or Prader-Willi syndrome. We present a clinical retrospective, descriptive review on 31 Southern African patients homozygous for STAC3 c.851 G > C. The frequencies of various phenotypic characteristics were calculated. In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3 c.851 G > C. A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated from a healthy cohort. A common haplotype spanning STAC3 was identified in four patients. Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia. The novel finding that STAC3 disorder is a common African myopathy has important clinical implications for the diagnosis, treatment and genetic counselling of individuals, with neonatal and/or childhood hypotonia with or without arthrogryposis multiplex congenita, and their families. The spread of this variant worldwide and the allele frequency higher in the African/African-American ancestry than the Admixed Americans, strongly indicates that the STAC3 c.851 G > C variant has an African origin which may be due to an ancient mutation with migration and population bottlenecks.
RESUMO
OBJECTIVES: This study aimed to explore the decision-making process of patients with pregnancies affected by serious congenital abnormalities. METHODS: The study design was an exploratory qualitative study. The sample for this study was pregnant individuals who had a prenatal diagnosis of a serious congenital abnormality and were offered termination of pregnancy. Semi-structured face-to-face interviews with closed and open-ended questions, recorded and transcribed verbatim, were used to collect the data; this was then analyzed using a thematic data analysis approach. RESULTS: Five topics were developed: "Health care services", "Home", "Being a mother", "Finding meaning", and "The aftermath". The first four topics describe the decision-making process where the participants filtered through multiple factors to reach their final decision. Although the participants consulted with their families, partners, and community, they made the final decision themselves. The final topics describes activities which were necessary for closure and coping. CONCLUSION: This study has provided valuable insight into the decision-making process, which can be used to improve services offered to patients. PRACTICE IMPLICATIONS: Information should be communicated clearly with follow-up appointments to discuss further. Healthcare professional should show empathy and assure the participants that their decision is supported.
Assuntos
Anormalidades Congênitas , Tomada de Decisões , Gravidez , Feminino , Humanos , Diagnóstico Pré-Natal , Mães , Pesquisa Qualitativa , Adaptação Psicológica , Anormalidades Congênitas/diagnósticoRESUMO
Congenital heart defects and skeletal malformations syndrome (CHDSKM; OMIM #617602) is a rare syndrome characterized by distinctive facial features, congenital cardiac lesions, failure to thrive, and skeletal abnormalities. Hearing impairment, renal, and ophthalmological abnormalities have also recently been reported. We report here the clinical and molecular phenotype of an adolescent male who presented with multisystem involvement suggestive of a connective tissue disorder. The proband presented with the typical dysmorphic, skeletal, and skin findings of CHDSKM. In addition, he had several features not previously documented, including severe and rapidly progressive aortic root dilatation as well gastro-intestinal reflux secondary to esophageal dysmotility with gastric strictures. Genetic testing revealed a recurrent variant in the ABL1 gene, c.1066G>A, p.Ala356Thr. These novel features contribute to the growing body of knowledge regarding this rare and recently described condition as well as lend strength to previous calls for close surveillance of the aortic root from a young age in CHDSKM.
Assuntos
Anormalidades do Olho , Cardiopatias Congênitas , Masculino , Humanos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Coração , Aorta , África SubsaarianaRESUMO
OBJECTIVE: Many studies, largely from high-income countries (HIC), have reported outcomes in babies with trisomy 18 (T18), with a paucity of data from Africa. Knowledge of outcomes is important in counselling women prenatally diagnosed with T18. We aimed to review all prenatally diagnosed cases of T18 between January 2006 and December 2021. METHOD: Demographic data, diagnosis, gestation and outcome data were obtained from the Astraia® database and patient files. RESULTS: We included 88 pregnant women of whom 46 terminated their pregnancies (30 beyond 24 weeks' gestation). Three underwent foeticides, one had a caesarean section for maternal obstetric reasons and 26 underwent inductions of labour without foetal monitoring. Four neonates were live born but none lived >8 h. In those who continued their pregnancies, the mean gestation at delivery was 34.8 weeks, 14 (33%) were live births and only 5 survived for >24 h with none surviving to 1 year of life. CONCLUSION: In our cohort, infants with T18 had lower live birth rates and shorter survival than in the current literature from HIC. This may be due to the implementation of non-aggressive intrapartum care and comfort care for the neonates. This has implications for counselling in our setting.
Assuntos
Cesárea , Diagnóstico Pré-Natal , Lactente , Recém-Nascido , Feminino , Gravidez , Humanos , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Taxa de Sobrevida , África do Sul/epidemiologia , Nascido Vivo/epidemiologia , Hospitais PúblicosRESUMO
This web-based survey of 311 respondents from 25 countries provides additional information about the early presentation of Rubinstein-Taybi syndrome. Most (86%) infants present during the neonatal period, with 69% of these within 24 hours of life. Prolonged hospital stay is common (61%).
Assuntos
Síndrome de Rubinstein-Taybi , Humanos , Lactente , Recém-Nascido , Síndrome de Rubinstein-Taybi/complicações , Síndrome de Rubinstein-Taybi/diagnósticoRESUMO
PURPOSE: The Western Cape Pregnancy Exposure Registry (PER) was established at two public sector healthcare sentinel sites in the Western Cape province, South Africa, to provide ongoing surveillance of drug exposures in pregnancy and associations with pregnancy outcomes. PARTICIPANTS: Established in 2016, all women attending their first antenatal visit at primary care obstetric facilities were enrolled and followed to pregnancy outcome regardless of the site (ie, primary, secondary, tertiary facility). Routine operational obstetric and medical data are digitised from the clinical stationery at the healthcare facilities. Data collection has been integrated into existing services and information platforms and supports routine operations. The PER is situated within the Provincial Health Data Centre, an information exchange that harmonises and consolidates all health-related electronic data in the province. Data are contributed via linkage across a unique identifier. This relationship limits the missing data in the PER, allows validation and avoids misclassification in the population-level data set. FINDINGS TO DATE: Approximately 5000 and 3500 pregnant women enter the data set annually at the urban and rural sites, respectively. As of August 2021, >30 000 pregnancies have been recorded and outcomes have been determined for 93%. Analysis of key obstetric and neonatal health indicators derived from the PER are consistent with the aggregate data in the District Health Information System. FUTURE PLANS: This represents significant infrastructure, able to address clinical and epidemiological concerns in a low/middle-income setting.
Assuntos
Gestantes , Cuidado Pré-Natal , Atenção à Saúde , Feminino , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez/epidemiologia , Sistema de Registros , África do Sul/epidemiologiaRESUMO
OBJECTIVE: Resources for management of epilepsy in Africa are extremely limited reinforcing the need to develop innovative strategies for optimizing care. Studies have shown that the prevalence of epilepsy in low- and middle-income countries is substantially greater than in more resourced countries. The objective of this report was to demonstrate that mobile Health (mHealth) technologies have the potential to improve the management of epilepsy in Africa. METHODS: The feasibility of technology-based home monitoring was investigated in an observational study of 40 children with refractory epilepsy or epilepsy associated with intellectual disability and/or behavior difficulties in South Africa. Technology-based home monitoring was implemented for six months. Physical activity, sleep, and heart rate were continuously monitored with a wearable device. Caregivers completed regular mobile Patient Reported Outcomes (mPROs) and reported seizures and ad hoc events using a dedicated app. Feasibility was assessed and descriptively measured for recruitment, retention, and engagement of the participants. RESULTS: The mHealth technology was able to capture important information that gives an impression of the overall experience of the children and their caregivers. Thirty-seven participants (94.9%) reported at least one clinical event. Seventy-nine percent of caregivers reported seizure events in their children, which were the primary event anticipated. Median engagement with the wearable device and monthly mPROs was 30.8% and 57.1%, respectively. However, most participants (87%) had to be given smartphones for them to have Bluetooth capabilities and access to the study app. Tolerability to the device was impacted by the difficult living circumstances of caregivers that induced fear of loss or theft. SIGNIFICANCE: The study showed how the use of remote patient monitoring in the form of mHealth can benefit epilepsy patients, despite highly variable engagement with the technology. The combination of mPROs and wearable devices generated informative datasets that will allow clinicians but also the children and their caregivers to better understand and manage the disease.
Assuntos
Exercício Físico , Dispositivos Eletrônicos Vestíveis , Criança , Estudos de Viabilidade , Humanos , Smartphone , África do SulRESUMO
PURPOSE: Successful implementation of innovative Precision Medicine initiatives in the management of children with complex epilepsy is largely dependent on the caregivers' engagement with the technology as well as its accessibility and acceptability. We investigated the feasibility of implementing these initiatives in the South African setting by gathering information on the caregivers' experiences, perspectives, and expectations for Precision Management of Epilepsy (PME) initiatives. METHODS: We purposively recruited 12 participants from a cohort of 40 caregivers of children with complex epilepsy recruited for a PME study attending Red Cross War Memorial Children's Hospital (RCWMCH) in Cape Town, South Africa. Face-to-face semi-structured interviews were conducted using a pragmatic qualitative approach and themes were extracted using a thematic framework approach. RESULTS: All participants had ideas about the cause of epilepsy, but many did not think that epilepsy is a medical condition. There were several difficulties in adhering to medical treatment which was sometimes combined with traditional remedies and practices. Understanding of Precision Medicine in the context of research was limited and although participants were unclear about benefits, most were optimistic about the future. mHealth devices introduced new feelings and challenges for many participants. The four themes which emerged were: (1) Cause of epilepsy: uncertainty and conflicting views; (2) Need for healing; (3) PME mHealth devices; and (4) Feasibility of implementation of PME initiatives. CONCLUSION: For Precision Medicine to be widely accepted and beneficial, how people understand the cause of epilepsy, difficulties in adherence to treatment, and personal experiences need to be addressed.
Assuntos
Cuidadores , Epilepsia , Criança , Epilepsia/terapia , Humanos , Motivação , Medicina de Precisão , Pesquisa Qualitativa , África do SulRESUMO
Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.
Assuntos
Anormalidades Múltiplas/epidemiologia , Face/anormalidades , Síndrome de Noonan/epidemiologia , Síndrome de Turner/epidemiologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Povo Asiático/genética , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Face/patologia , Reconhecimento Facial , Feminino , Hispânico ou Latino/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Síndrome de Noonan/fisiopatologia , Fenótipo , Vigilância da População , Síndrome de Turner/diagnóstico , Síndrome de Turner/genética , Síndrome de Turner/fisiopatologia , População Branca/genética , Adulto JovemRESUMO
BACKGROUND: Cockayne Syndrome (CS) is a rare autosomal recessive multi-systemic disorder, characterized; by developmental delay, microcephaly, severe growth failure and sensorial impairment. Renal complications have been reported but remain underinvestigated. The objective of this study was to perform a review of renal disease in a cohort of CS patients. METHODS: We retrospectively collected relevant clinical, biochemical and genetic data from a cohort of 136 genetically confirmed CS patients. Blood pressure (BP), proteinuria, albuminemia, uric acid, creatinine clearance, renal ultrasounds and renal biopsy result were analysed. RESULTS: Thirty-two patients had a renal investigation. We found that 69% of investigated patients had a renal disorder and/or an elevated BP. Fifteen out of 21 patients (71% of investigated patients) had an increased BP, 10 out of 16 patients (62% of investigated patients) presented with proteinuria and 4 of them had a nephrotic syndrome. Thirteen patients out of 29 (45%) had a decreased Glomerular Filtration Rate (GFR), 18 out of 25 patients (72%) had a hyperuricemia. No correlation with the genetic background or clinical types of CS was found, except for the renal clearance. CONCLUSIONS: Renal disease, increased blood pressure and hyperuricemia were highly prevalent in our study. We believe that CS patients should benefit from a nephrological follow-up and that anti-uric acid drug and Angiotensin-converting enzyme (ACE) inhibitor should be discussed in these patients.
Assuntos
Síndrome de Cockayne/patologia , Rim/patologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal/patologia , Adulto , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Síndrome de Cockayne/complicações , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Insuficiência Renal/complicações , Insuficiência Renal Crônica/complicações , Adulto JovemRESUMO
BACKGROUND: In 2013, a pregnancy exposure registry and birth defects surveillance (PER/BDS) system was initiated in eThekwini District, KwaZulu-Natal (KZN), to assess the impact of antiretroviral treatment (ART) on birth outcomes. OBJECTIVES: At the end of the first year, we assessed the risk of major congenital malformations (CM) and other adverse birth outcomes (ABOs) detected at birth, in children born to women exposed to ART during pregnancy. METHOD: Data were collected from women who delivered at Prince Mshiyeni Memorial Hospital, Durban, from 07 October 2013 to 06 October 2014, using medicine exposure histories and birth outcomes from maternal interviews, clinical records and neonatal surface examination. Singleton births exposed to only one ART regimen were included in bivariable analysis for CM risk and multivariate risk analysis for ABO risk. RESULTS: Data were collected from 10 417 women with 10 517 birth outcomes (4013 [38.5%] HIV-infected). Congenital malformations rates in births exposed to Efavirenz during the first trimester (T1) (RR 0.87 [95% CI 0.12-6.4; p = 0.895]) were similar to births not exposed to ART during T1. However, T1 exposure to Nevirapine was associated with the increased risk of CM (RR 9.28 [95% CI 2.3-37.9; p = 0.002]) when compared to the same group. Other ABOs were more frequent in the combination of HIV/ART-exposed births compared to HIV-unexposed births (29.9% vs. 26.0%, adjusted RR 1.23 [1.14-1.31; p < 0.001]). CONCLUSION: No association between T1 use of EFV-based ART regimens and CM was observed. Associations between T1 NVP-based ART regimen and CM need further investigation. HIV- and ART-exposed infants had more ABOs compared to HIV-unexposed infants.
RESUMO
The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.
RESUMO
Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Síndrome de Cornélia de Lange/genética , Deficiência Intelectual/genética , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Proteoglicanas de Sulfatos de Condroitina/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/epidemiologia , Síndrome de Cornélia de Lange/fisiopatologia , Face/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Recém-Nascido , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Fenótipo , Grupos Raciais/genética , Adulto JovemRESUMO
This report describes the first case of a child with genetically confirmed Brown-Vialetto-van Laere syndrome in sub-Saharan Africa. This is an extremely rare clinical condition that presents with an auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise that manifests with diaphragmatic and vocal cord paralysis. It is an autosomal recessive condition for which the genetic mutation has only recently been linked to a riboflavin transporter deficiency. We describe an 11-month-old affected male infant. He has required long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he had limited recovery of motor function. His respiratory chain enzyme studies were abnormal suggestive of mitochondrial (mt) dysfunction. In the setting of limited resources, recognition of this striking clinical phenotype is important to highlight, specifically regarding the genetic implications of the condition and the potentially remedial response to vitamin supplementation.
Assuntos
Paralisia Bulbar Progressiva/terapia , Perda Auditiva Neurossensorial/terapia , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/genética , África Subsaariana , Paralisia Bulbar Progressiva/genética , Paralisia Bulbar Progressiva/patologia , Paralisia Bulbar Progressiva/fisiopatologia , Suplementos Nutricionais , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Lactente , Masculino , Fenótipo , Riboflavina/administração & dosagemRESUMO
Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.
Assuntos
Variação Biológica da População , Heterogeneidade Genética , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética , Antropometria/métodos , Fácies , Humanos , Fenótipo , Grupos Populacionais , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Síndrome de Williams/epidemiologiaRESUMO
BACKGROUND: A relatively high frequency of autosomal recessively inherited osteogenesis imperfecta (OI) type 3 (OI-3) is present in the indigenous black southern African population. Affected persons may be severely handicapped as a result of frequent fractures, progressive deformity of the tubular bones and spinal malalignment. OBJECTIVE: To delineate the molecular basis for the condition. METHODS: Molecular investigations were performed on 91 affected persons from seven diverse ethnolinguistic groups in this population. RESULTS: Following polymerase chain reaction amplification and direct cycle sequencing, FKBP10 mutations were identified in 45.1% (41/91) OI-3-affected persons. The homozygous FKBP10 c.831dupC frameshift mutation was confirmed in 35 affected individuals in the study cohort. Haplotype analysis suggests that this mutation is identical among these OI-3-affected persons by descent, thereby confirming that they had a common ancestor. Compound heterozygosity of this founder mutation was observed, in combination with three different deleterious FKBP10 mutations, in six additional persons in the cohort. Four of these individuals had the c.831delC mutation. CONCLUSION: The burden of the disorder, both in frequency and severity, warrants the establishment of a dedicated service for molecular diagnostic confirmation and genetic management of persons and families with OI in southern Africa.
RESUMO
Fanconi anaemia (FA) is a genotypically and phenotypically heterogeneous genetic condition, characterized cytogenetically by chromosomal instability and breakage secondary to impaired DNA repair mechanisms. Affected individuals typically manifest growth restriction and congenital physical abnormalities and most progress to hematological disease including bone marrow aplasia. A rare genetic subtype of FA (FA-D1) is caused by biallelic mutations in the BRCA2 gene. Affected individuals manifest severe congenital anomalies and significant pigmentary changes and are additionally at risk for early onset leukemia and certain solid organ malignancies, including Wilms tumors and brain tumors. Parents of affected individuals are obligate carriers for heterozygous BRCA2 mutations and are thus potentially at risk for adult onset cancers which fall within the hereditary breast and ovarian cancer spectrum. We present two cases of black South African patients with FA diagnosed with biallelic BRCA2 mutations and discuss the phenotypic consequences and implications for them and their families. Recognition of this severe end of the phenotypic spectrum of FA is critical in allowing for confirmation of the diagnosis as well as cascade screening and appropriate care of family members.
Assuntos
Proteína BRCA2/genética , Anemia de Fanconi/genética , Predisposição Genética para Doença/genética , Pré-Escolar , Feminino , Genes BRCA2 , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Linhagem , África do SulRESUMO
BACKGROUND: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally caused by mutations in LMNA leading to accumulation of the toxic protein progerin and consequently, to nuclear envelope alterations. In this work, we describe a novel phenotypic feature of the progeria spectrum affecting three unrelated newborns and identify its genetic cause. METHODS AND RESULTS: Patients reported herein present an extremely homogeneous phenotype that somewhat recapitulates those of patients with HGPS and mandibuloacral dysplasia. However, pathological signs appear earlier, are more aggressive and present distinctive features including episodes of severe upper airway obstruction. Exome and Sanger sequencing allowed the identification of heterozygous de novo c.163G>A, p.E55K and c.164A>G, p.E55G mutations in LMNA as the alterations responsible for this disorder. Functional analyses demonstrated that fibroblasts from these patients suffer important dysfunctions in nuclear lamina, which generate profound nuclear envelope abnormalities but without progerin accumulation. These nuclear alterations found in patients' dermal fibroblasts were also induced by ectopic expression of the corresponding site-specific LMNA mutants in control human fibroblasts. CONCLUSIONS: Our results demonstrate the causal role of p.E55K and p.E55G lamin A mutations in a disorder which manifests novel phenotypic features of the progeria spectrum characterised by neonatal presentation and aggressive clinical evolution, despite being caused by lamin A/C missense mutations with effective prelamin A processing.