The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

Factors associated with acute kidney injury (AKI) and mortality in COVID-19 patients in a Sub-Saharan African intensive care unit: a single-center prospective study.

INTRODUCTION: Acute kidney injury (AKI) is a complication of severe coronavirus disease 2019 (COVID-19). Kidney damage associated with COVID-19 could take specific features due to environmental and socio-cultural factors. This study evaluates the incidence of AKI, the associated factors, and mortality in COVID-19 patients in a Sub-Saharan African intensive care unit. METHODS: In a prospective cohort study conducted in the intensive care unit (ICU) of the Centre Médical de Kinshasa (CMK), consecutive patients admitted for COVID-19 were screened for the presence of AKI between 27 March, 2020 and 27 January 2022. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines. The primary outcome was occurrence of AKI. The secondary outcome was 48 days' mortality and recovery of the renal function at intensive care unit (ICU) discharge. Survival (time-to death) curves were built using the Kaplan Meier methods. Multivariate analyses were performed by logistic regression to identify factors associated with AKI and Cox regression to explore the association between AKI and in-hospital mortality. The significance level of the p-value was set at 0.05. RESULTS: The median(IQR) sequential organ failure assessment score (SOFA) score and mean age of patients (215) including in our cohort were respectively 3(2-4) and 58.9 ± 14.9 years. The incidence of AKI was 28.4% with stages 1, 2, or 3 AKI accounted for 39.3%, 11.5%, and 49.2%, respectively. Hemodialysis was required in 16 out 215 (7.4%) patients. Dyspnea (adjusted odds ratio (aOR):2.27 [1.1--4.57] p = 0.021), SOFA ≥5 (aOR:3.11[1.29-7.53] p = 0.012), AST/ALT ratio (aOR: 1.53 [1.09-1.79] p = 0.015), N/L ratio (aOR:2.09 [1.09-3.20] p = 0.016), mechanical ventilation (aOR: 3.20 [1.66-10.51] p = 0.005) and Amikacin (aOR: 2.91 [1.37-6.18] p = 0.006) were the main factors associated with AKI. Patients with AKI had a mortality rate of 52.5% and 67.2% of the survivors did not recover kidney function at the end of hospitalization. Adjusted Cox regression analysis revealed that COVID-19-associated AKI was independently associated with in-hospital death (HR:2.96 [1.93-4.65] p = 0.013) compared to non-AKI patients. CONCLUSIONS: AKI was present in three out of ten COVID-19 patients. The most significant factors associated with AKI were dyspnea, SOFA ≥ 5, AST/ALT and N/L ratio, mechanical ventilation and Amikacin. AKI has been associated with an almost threefold increase in overall mortality and seven out of ten survivors did not recover kidney function after AKI.

Rapid Whole Genome Sequencing Diagnoses and Guides Treatment in Critically Ill Children in Belgium in Less than 40 Hours.

Rapid Whole Genome Sequencing (rWGS) represents a valuable exploration in critically ill pediatric patients. Early diagnosis allows care to be adjusted. We evaluated the feasibility, turnaround time (TAT), yield, and utility of rWGS in Belgium. Twenty-one unrelated critically ill patients were recruited from the neonatal intensive care units, the pediatric intensive care unit, and the neuropediatric unit, and offered rWGS as a first tier test. Libraries were prepared in the laboratory of human genetics of the University of Liège using Illumina DNA PCR-free protocol. Sequencing was performed on a NovaSeq 6000 in trio for 19 and in duo for two probands. The TAT was calculated from the sample reception to the validation of results. Clinical utility data were provided by treating physicians. A definite diagnosis was reached in twelve (57.5%) patients in 39.80 h on average (range: 37.05-43.7). An unsuspected diagnosis was identified in seven patients. rWGS guided care adjustments in diagnosed patients, including a gene therapy, an off-label drug trial and two condition-specific treatments. We successfully implemented the fastest rWGS platform in Europe and obtained one of the highest rWGS yields. This study establishes the path for a nationwide semi-centered rWGS network in Belgium.

Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Objective evaluation of facial features in Congolese newborns by facial measurements. The need for population-specific measurements.

The evaluation of dysmorphism is often subjective because many continuous traits are not easily measured or lack normal values. Because many common morphologic profiles vary between populations, population-specific reference ranges of relevant traits are needed. We aim to evaluate the objective assessment of facial dysmorphism in 553 Congolese newborns based on facial measurements. Measurements taken with a ruler were on average larger compared to those with a caliper, but the bias did not depend on the size of the measurement. We therefore introduced a correction factor that allows to use both techniques for facial measurements interchangeably in future studies. The outer canthal distance, palpebral fissure length, and mouth width were significantly larger in Congolese newborns (respectively mean 6.59 [SD 0.48]; mean 2.20 [SD 0.24]; mean 2.78 [SD 0.26]) when compared to references based on European newborns (respectively mean 3.59 [SD 1.76]; mean 4.20 [SD 2.26]; mean 0.47 [SD 1.21]), while the rest of measurements were significantly smaller. The interpupillary distance (IPD) calculated from inner canthal distance and outer canthal distance was not significantly different. We observed a poor agreement between clinical evaluation and measured features (kappa of 0.432). Clinicians were more likely to recognize a face as having wide-spaced eyes when it had been recognized as such during the clinical examination, more than if the child had a high interpupillary distance. This suggests that the measured IPD is not precisely reflecting what is clinically evaluated as wide-spaced eyes.

PERCHING syndrome: Clinical presentation in the first African patient confirmed by clinical whole genome sequencing.

PERCHING syndrome is a rare multisystem developmental disorder caused by autosomal recessive (AR) variants (truncating and missense) in the Kelch-like family member 7 gene (KLHL7). We report the first phenotypic and molecular description of PERCHING syndrome in a patient from Central Africa. The patient presented multiple dysmorphic features in addition to neurological, respiratory, gastroenteric, and dysautonomic disorders. Clinical Whole Genome Sequencing in the proband and his mother identified two novel heterozygous variants in the KLHL7 gene, including a maternally inherited intronic variant (NM_001031710.2:c.793 + 5G > C) classified as Variant of Uncertain Significance and a frameshift stop gain variant (NM_001031710.2:c.944delG; p.Ser315ThrfsTer23) of unknown inheritance classified as likely pathogenic. Although the diagnosis was only evoked after genomic testing, the review of published patients suggests that this disease could be clinically recognizable and maybe considered as an encephalopathy. Our report will allow expanding the phenotypic and molecular spectrum of Perching syndrome.

DNA testing for sickle cell anemia in Africa: Implementation choices for the Democratic Republic of Congo.

BACKGROUND: Hemoglobin-based tests form the reference diagnostic test for SCA. In limited resource countries, these tests face limitations including cost, low sensitivity due to recurrent transfusions in endemic malaria region, and interference from fetal hemoglobin in neonatal diagnostic. This study aimed at adapting DNA-based SCA tests to limited resource countries and evaluating the economic benefit. METHODS: 338 participants were recruited in the Democratic Republic of Congo, sorted in 3 cohorts based on venous blood, umbilical cord blood (UCB) and buccal swab sampling. RFLP was performed to identify mutated allele. The feasibility and technical validity of this RFLP was evaluated for specimens collected on DBS cards and on EDTA tubes. RFLP on DBS stored at room temperature was regularly repeated to assess sample conservation. Finally, the cost analysis was performed. RESULTS: DBS cards yielded identical results to extracted DNA. Repeated testing returned the same result after four years. The DBS-based test performed on UCB or on buccal swab had a sensitivity and a precision of 100%. Cost comparison indicated that our approach costs half price of the widely used isoelectrofocussing of hemoglobin. CONCLUSION: The implemented DNA-based test approach overcomes the limitations faced by hemoglobin-based tests, while being more affordable. We propose to implement the RFLP test as a first line diagnostic test after transfusion and as second tiers for newborn screening. However, users should be aware that this test is unable to differentiate HbC from HbS or identify other point mutation of gene deletion of HBB gene.

Value of DNA testing in the diagnosis of sickle-cell anemia in childhood in an environment with a high prevalence of other causes of anemia.

BACKGROUND: Sickle-cell anemia (SCA) is the most common genetic disease worldwide caused by a single mutation in the gene HBB. DNA testing can help to clarify the diagnosis when Hb electrophoresis is inconclusive. We evaluated the usefulness and feasibility of DNA-based diagnosis of SCA in rural Central Africa. METHODS: This is a cross-sectional study conducted from November 2016 to end October 2017 in the Hôpital Saint Luc de Kisantu, located 120 km from Kinshasa. This hospital offers the management of SCA patients, mainly identified using the Sickling test (Emmel test) combined with clinical features. We included patients aged 6 months to 18 years locally diagnosed as SCA, and we collected clinical and hematological data. All patients were offered Hb electrophoresis and DNA testing at the Center for Human Genetics of the University of Kinshasa. RESULTS: This study included 160 patients. Hemoglobin capillary electrophoresis suggested that 136 (85%) were homozygote SS, 13 (8.1%) were heterozygote (AS), and 11 (6.9%) were homozygote normal (AA). DNA testing confirmed these electrophoresis findings, with the exception of four patients, two AS in electrophoresis were found SS due to recent transfusion, and two SS in electrophoresis were found AS because they have compound heterozygous form S/ß°-thalassemia. The diagnosis of SCA was therefore wrongly ascertained with Emmel test in 15% of patients. CONCLUSION: This study reveals a high proportion of false-positive SCA diagnoses in a rural environment in Central Africa. This underlines the importance of DNA testing in conjunction with Hb electrophoresis.

Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic Encephalopathy.

Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH. In three siblings with severe developmental delays, microcephaly, autism spectrum disorder and epileptic encephalopathy, we identified a new homozygous in-frame deletion (c.999_1001delCAC; p.Thr334del) of BCKDK. Plasma and cerebrospinal fluid concentrations of BCAA were markedly reduced. Hyperactivity of BCKDH and over-consumption of BCAA were demonstrated by functional tests in cells transfected with the mutant BCKDK. Treatment with pharmacological doses of BCAA allowed the restoring of BCAA concentrations and greatly improved seizure control. Behavioral and developmental skills of the patients improved to a lesser extent. Importantly, a retrospective review of the newborn screening results allowed the identification of a strong decrease in BCAA concentrations on dried blood spots, suggesting that BCKDK is a new treatable metabolic disorder probably amenable to newborn screening programs.

Clinical presentation and evolution of Xia-Gibbs syndrome due to p.Gly375ArgfsTer3 variant in a patient from DR Congo (Central Africa).

Xia-Gibbs syndrome (XGS) is a very rare genetic condition. The clinical spectrum is very broad and variable. The phenotype and evolution in a Congolese boy with XGS have been reported. At 6 years he had speech delay, drooling, marked hyperactivity, attention deficit, aggressive behavior, and intellectual disability. Dysmorphological evaluation revealed strabismus, mild unilateral ptosis, uplifted ear lobes, flat philtrum, thin upper lip vermillion, high arched palate, and flat feet. Patient-only whole exome sequencing identified a known pathogenic frameshift variant in the AHDC1 gene [NM_001029882.3(AHDC1):c.1122dupC;(p.Gly375ArgfsTer3)]. The clinical follow-up revealed the deterioration of his fine motor skills and significant cerebellar phenotype including tremor, pes cavus, and gait instability at the age of 12 years. This patient was compared with three previously reported patients with the same variant but did not identify a consistent pattern in the evolution of symptoms with age.

Dysmorphism and major anomalies are a main predictor of survival in newborns admitted to the neonatal intensive care unit in the Democratic Republic of Congo.

In Central-Africa, neonatal infections, asphyxia and prematurity are main reasons for admission to the neonatal intensive care unit and major determinants of newborn survival. Also, the outcome of newborns with congenital anomalies is expected to be poor, due to a lack of state-of-the art care. We conducted a study of 102 newborns recruited in the Neonatal Intensive Care Unit (NICU) at the University Hospitals of Kinshasa, DR Congo, to assess the impact of congenital anomalies. The presence of a major anomaly was associated with a hazard ratio of death of 13.2 (95%CI: 3.7-46.7, p < .001). In addition, the presence of three or more minor anomalies was associated with a 4.5-fold increased risk of death (95%CI: 1.1-18.6, p = .04). We conclude that like major anomalies, the presence of three or more minor anomalies should also be given particular attention and that the evaluation of dysmorphism should be promoted in NICU.

GREB1L variants in familial and sporadic hereditary urogenital adysplasia and Mayer-Rokitansky-Kuster-Hauser syndrome.

Congenital uterine anomalies (CUA) may have major impacts on the health and social well-being of affected individuals. Their expressivity is variable, with the most severe end of the spectrum being the absence of any fully or unilaterally developed uterus (aplastic uterus), which is a major feature in Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). So far, etiologies of CUA remain largely unknown. As reports of familial occurrences argue for strong genetic contributors in some cases, we performed whole exome sequencing in nine multiplex families with recurrence of uterine and kidney malformations, a condition called hereditary urogenital adysplasia. Heterozygous likely causative variants in the gene GREB1L were identified in four of these families, confirming GREB1L as an important gene for proper uterine and kidney development. The apparent mode of inheritance was autosomal dominant with incomplete penetrance. The four families included fetuses with uterovaginal aplasia and bilateral renal agenesis, highlighting the importance to investigate GREB1L in such phenotypes. Subsequent sequencing of the gene in a cohort of 68 individuals with MRKH syndrome or uterine malformation (mostly sporadic cases) identified six additional variants of unknown significance. We therefore conclude that heterozygous GREB1L variants contribute to MRKH syndrome and this probably requires additional genetic or environmental factors for full penetrance.

Phenotype and growth in Sotos syndrome patient from DR Congo (Central Africa).

Sotos syndrome is a widely studied overgrowth syndrome. Clinical presentation includes excessive growth during childhood, macrocephaly, learning difficulties of various degrees, variable minor features, and distinctive facial gestalt. We provide in this report the first phenotypic and growth description of Sotos syndrome in a patient from Central Africa. At 6 month the patient exhibited axial hypotonia, delayed speech development and dysmorphism including long face, sparse eyebrows, hypertelorism, malar hypoplasia and dark flushing, short philtrum, depressed nasal root, anteverted nares, thick upper and lower lip vermilions, macroglossia, prominent forehead, large and peculiar ears, wide intermammillary distance, deep palmar creases, dysplastic finger nails, partial syndactyly of toes, broad, and overlapping hallux. At 19 months, malar flushing became reddish and a retraction of the middle of the lower lip was observed, resembling a bifid lip. He retained the same clinical features at 31 months. Head circumference, weight, and height where within normal ranges at birth but became all above 97th centiles at 4 months. The height velocity evolved in three phases starting with a very fast growth from birth to 6 months (54 cm/year), then a fast phase from 6 to 16 months (18 cm/year) and a slow phase from 16 to 31 months (4.8 cm/year). Conversely, the patient exhibited an acceleration of weight after the first year of life. Our patient exhibited very prominent lips and deep philtrum, which are common facial traits in African individuals. The current report shows an admixture of ethnic-specific features with syndrome-specific features in an African patient.

Morphological characterization of newborns in Kinshasa, DR Congo: Common variants, minor, and major anomalies.

The evaluation of minor physical variation is crucial in a dysmorphological examination. Currently, data on the spectrum and incidence of minor physical variants in Central African newborns is lacking. We therefore conducted a cross-sectional descriptive study of 722 newborns recruited within the first 24 hr of life, in two large maternities in Kinshasa, DR Congo. Minor anomalies were defined according to the series of articles in AJMG Part A and coded as human phenotype ontology terms. A total of 97 different morphological variants were recorded of which 13 were common. About 34.8% of the newborn carried one minor anomaly, 11.6% had two, and 4.3% had three minor anomalies. No gender differences were observed, but the incidence of specific anomalies appeared to vary with the geographical origin of parents within the DR Congo. The results of this study will aid clinicians to interpret morphological variation in Central African newborns.

Exploring association between MBL2 gene polymorphisms and the occurrence of clinical blackwater fever through a case-control study in Congolese children.

BACKGROUND: Blackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure. Thus far, the genetics of the underlying susceptibility to develop BWF is not fully elucidated. Deficiency in the MBL protein, an important component of the innate immune system, has previously been suggested to be a susceptibility factor for the development of severe malaria. This study aimed to evaluate the association between MBL2 gene polymorphisms, known to affect the MBL protein level/activity, and the occurrence of BWF among Congolese children. METHODS: This is a case-control study. Cases were patients with BWF, whereas controls, matched for gender and age, had uncomplicated malaria (UM). Dried blood spot was collected for genotyping. RESULTS: A total of 129 children were screened, including 43 BWF and 86 UM. The common allele in BWF and UM was A, with a frequency of 76.7 and 61.0%, respectively (OR: 2.67 (0.87-829) and p = 0.079). The frequency of the C allele was 18.6 and 29.1% in BWF and UM groups, respectively, with p = 0.858. Not a single D allele was encountered. Genotype AA was at higher risk for BWF whereas genotypes A0 (AB and AC) were over-represented in UM group (OR: 0.21 (0.06-0.78)) with p = 0.019. Nine haplotypes were observed in this study: 3 high MBL expression haplotypes and 6 low MBL expression haplotype. One new haplotype HYPC was observed in this study. None of these haplotypes was significantly associated with BWF. CONCLUSION: This pilot study is a preliminary research on MBL2 gene and infectious diseases in DRC. The study results show a higher risk for BWF in AA. This suggests that future studies on BWF should further investigate the contribution of a strong immune response to the occurrence of BWF.

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

A comprehensive clinical and genetic study in 127 patients with ID in Kinshasa, DR Congo.

Pathogenic variants account for 4 to 41% of patients with intellectual disability (ID) or developmental delay (DD). In Sub-Saharan Africa, the prevalence of ID is thought to be higher, but data in Central Africa are limited to some case reports. In addition, clinical descriptions of some syndromes are not available for this population. This study aimed at providing an estimate for the fraction of ID/DD for which an underlying etiological genetic cause may be elucidated and provide insights into their clinical presentation in special institutions in a Central African country. A total of 127 patients (33 females and 94 males, mean age 10.03 ± 4.68 years), were recruited from six institutions across Kinshasa. A clinical diagnosis was achieved in 44 but molecular confirmation was achieved in 21 of the 22 patients with expected genetic defect (95% clinical sensitivity). Identified diseases included Down syndrome (15%), submicroscopic copy number variants (9%), aminoacylase deficiency (0.8%), Partington syndrome in one patient (0.8%) and his similarly affected brother, X-linked syndromic Mental Retardation type 33 (0.8%), and two conditions without clear underlying molecular genetic etiologies (Oculo-Auriculo-Vertebral and Amniotic Bands Sequence). We have shown that genetic etiologies, similar to those reported in Caucasian subjects, are a common etiologic cause of ID in African patients from Africa. We have confirmed the diagnostic utility of clinical characterization prior to genetic testing. Finally, our clinical descriptions provide insights into the presentation of these genetic diseases in African patients.

Protective BCL11A and HBS1L-MYB polymorphisms in a cohort of 102 Congolese patients suffering from sickle cell anemia.

BACKGROUND: We aimed to investigate the distribution of selected BCL11A and HMIP polymorphisms (SNP's), and to assess the correlation with HPFH in a cohort of sickle cell patients. METHODS: A preliminary cross-sectional study was conducted in 102 patients. Group 1 was composed of patients with HPFH and Group 2 consisted of patients without HbF. We assessed 8 SNPs previously associated with HPFH in cohorts genetically close to the Congolese population. Observed frequencies were compared to expected frequencies. RESULTS: In the group 1, at rs7606173, the observed frequency for the genotype GG was significantly higher and the genotype GC was significantly lower than their respective expected frequencies. At rs9399137, the observed frequency of the genotype TT was significantly lower than expected. Conversely, the observed frequency of the genotype TC was significantly higher than expected. The observed frequency of the genotype TT at rs11886868 was significantly lower than the expected whereas the frequency of the genotype TC was significantly higher than observed. The lowest HbF level was recorded in patients with genotype CC at rs11886868. CONCLUSION: In this preliminary study, the results demonstrate that alleles of some of the 8 studied SNPs are not randomly distributed among patients with or without HPFH in this cohort.

Association between sickle cell anemia and alpha thalassemia reveals a high prevalence of the α3.7 triplication in congolese patients than in worldwide series.

BACKGROUND: Information about the association with alpha thalassemia in sickle cell patients is unknown in the Democratic Republic of Congo. There is very little data on the alpha thalassemia in patients suffering from sickle cell anemia in Central Africa, and their consequences on the clinical expression of the disease. METHODS: A cross-sectional study was conducted in 106 sickle cell patients living in the country's capital Kinshasa. The diagnosis of sickle cell anemia was confirmed with a molecular test using PCR-RFLP (restriction fragment length polymorphism) technique. The diagnosis of thalassemia was performed by the technique of multiplex ligation dependent probe amplification. RESULTS: The mean age of our patients was 22.4±13.6 years. The α3.7 heterozygous deletion, the α3.7 homozygous deletion and the α3.7 triplication were respectively encountered in 23.6%, 25.5% , and 11.3% of patients. Patients with normal αα/αα genotype represented 39.6% of the study population. The average of severe vaso-occlusive crises, the rates of blood transfusions per year, the rate of osteonecrosis, cholelithiasis and leg ulcers were significantly lower in the group of patients with α3.7 homozygous deletion and α3.7 triplication. CONCLUSION: The prevalence of α3.7 triplication was higher in sickle cell patients in the Democratic Republic of Congo than in worldwide series. The α3.7 triplication and α3.7 homozygous deletion were associated with less severe forms of the Sickle cell anemia in Congolese patients. These results showed the need to investigate systematically the alpha-globin gene mutations in sickle cell population in Central Africa.

Fragile X syndrome in Democratic Republic of Congo: dysmorphic, cognitive and behavioral findings in 14 subjects from three families.

This study reports on 14 individuals with Fragile X syndrome from 3 Congolese Families. The majority (8/14) were males, with an average age of 18.4 (±11.1 [14-38]) years old. Typical dysmorphic characteristics of Fragile-X syndrome including elongated face, large and prominent ears were found in both males and females with the full mutation. Macroorchidism was found in all post-pubertal boys. The cognitive ability in our cohort varies widely ranging from mild (IQ 50-70) to moderate (IQ 35-49) intellectual disability (Average IQ of 60). All our female patients have ID.